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Abstract: Early-onset torsion dystonia is an autosomal dominant movement disorder associated with the DYT1 gene (TOR1A) defect which results in a deletion of a glutamic acid residue in the protein torsinA. The pathophysiology of dystonia is poorly understood. Well characterized animal models can help to give insights into the underlying mechanisms and thereby to develop new therapeutics. In the present study, we further characterized transgenic DYT1 mice, which were initially described to exhibit “dystonia-like” postures. In the present study, several behavioural tests in untreated animals did not show strong differences between transgenic and control mice, but nearly all transgenic mice showed “dystonia-like” postures. However, these movements, also observed in control mice, have to be regarded as a clasping reflex. Since dystonia is thought to be related to dopaminergic dysfunctions, pharmacological investigations have been performed to clarify if dopaminergic substances alter motor behaviour in transgenic mice. Chronic treatment with L-DOPA (combined with carbidopa) enhanced the hindlimb claspings only in transgenic mice, while acute applications of drugs, which exert more selective effects on the dopaminergic system, caused similar reactions in transgenic mice and control mice. Therefore, these data do not provide clear evidence for dysfunctions of the dopaminergic system in this mouse model. [ABSTRACT FROM AUTHOR]

Toltrazuril is effective against all coccidial parasites in most animal species. Pharmacological studies showed that toltrazuril was well absorbed in the gastrointestinal tract and rapidly metabolised to toltrazuril sulfoxide and toltrazuril sulfone (ponazuril), the latter being considered as marker residue for toltrazuril residues. The maximum residue limits (MRLs) for toltrazuril sulfone in edible tissues from poultry range from 100 μg/kg in muscle to 600 μg/kg in liver. The substance is currently not allowed for use in poultry producing eggs for human consumption. However, several veterinary medicinal products containing the active substance are authorised in the European Union for use in pullets. According to product literature, withdrawal periods for edible tissues from chickens of 12 up to 18 days as well as restrictions for use before the onset of laying must be observed. Depending on the chicken breed, the start of the laying activity can vary between the 17th and 20th week of age. In monitoring programs, certain cases of residues in eggs were detected although zero tolerance was applicable at that time. The objective of the presented study was to evaluate the residue depletion profiles of toltrazuril and its major metabolites after the treatment of 15-week-old laying hens with an authorised toltrazuril-containing veterinary medicinal product. The pullets were treated on two consecutive days with TOLTRA-K (25 mg/ml) oral solution via drinking water at a dosage of 7 mg of toltrazuril per kg of body weight per day according to the recommended posology. Individual egg samples were collected after the beginning of the laying activity and were analysed in duplicate by LC-MS/MS to determine residues of toltrazuril and its metabolites. Residues of toltrazuril sulfone in egg samples were detected for several weeks and a statistical model was established to determine the time span needed to meet the zero tolerance. [ABSTRACT FROM AUTHOR]

The advent of new testing systems and 'omics'-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European 'regulatory status quo', while elucidating new perspectives for regulatory toxicity testing. [ABSTRACT FROM AUTHOR]