Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

AbstractThere are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data

Pinning down electron correlations in RaF via spectroscopy of excited states

We report the spectroscopy of 11 electronic states in the radioactive molecule radium monofluoride (RaF). The observed excitation energies are compared with state-of-the-art relativistic Fock-space coupled cluster (FS-RCC) calculations, which achieve an agreement of >99.71% (within ~8 meV) for all states. High-order electron correlation and quantum electrodynamics corrections are found to be important at all energies. Establishing the accuracy of calculations is an important step towards high-precision studies of these molecules, which are proposed for sensitive searches of physics beyond the Standard Model.Comment: Submitted for publicatio

Primary intestinal lymphangiectasia (Waldmann's disease)

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur

Search for neutral B meson decays to two charged leptons

The decays $\mathrm{B_d^0,\,B_s^0 \rightarrow e^+e^-,\,\mu^+\mu^-,\, e^\pm\mu^\mp}$ are searched for in 3.5 million hadronic ${\mathrm{Z}}$ events, which constitute the full LEP I data sample collected by the L3 detector. No signals are observed, therefore upper limits at the 90\%(95\%) confidence levels are set on the following branching fractions: % \begin{center}% {\setlength{\tabcolsep}{2pt} \begin{tabular}{lccccclcccc}% % Br$({\mathrm{B_d^0 \rightarrow {\mathrm{e^+e^-}}}})$ & $<$ & $1.4(1.8)$ & $\times$ & $10^{-5}$; & \hspace*{5mm} & Br$({\mathrm{B_s^0 \rightarrow {\mathrm{e^+e^-}}}})$ & $<$ & $5.4(7.0)$ & $\times$ & $10^{-5}$; \\% Br$({\mathrm{B_d^0 \rightarrow \mu^+\mu^-}})$ & $<$ & $1.0(1.4)$ & $\times$ & $10^{-5}$; & \hspace*{5mm} & Br$({\mathrm{B_s^0 \rightarrow \mu^+\mu^-}})$ & $<$ & $3.8(5.1)$ & $\times$ & $10^{-5}$; \\% Br$({\mathrm{B_d^0 \rightarrow {\mathrm{e^\pm\mu^\mp}}}})$ & $<$ & $1.6(2.0)$ & $\times$ & $10^{-5}$; & \hspace*{5mm} & Br$({\mathrm{B_s^0 \rightarrow {\mathrm{e^\pm\mu^\mp}}}})$ & $<$ & $4.1(5.3)$ & $\times$ & $10^{-5}$. \\% % \end{tabular}% } \end{center}% % The results for ${\mathrm{B_s^0\rightarrow{\mathrm{e^+e^-}}}}$ and ${\mathrm{B_s^0 \rightarrow {\mathrm{e^\pm\mu^\mp}}}}$ are the first limits set on these decay modes

Search for neutral charmless B decays at LEP

A search for rare charmless decays of \Bd and \Bs mesons has been performed in the exclusive channels \Bd_{(\mathrm s)}\ra\eta\eta, \Bd_{(\mathrm s)}\ra\eta\pio and \Bd_{(\mathrm s)}\ra\pio\pio. The data sample consisted of three million hadronic \Zo decays collected by the L3 experiment at LEP from 1991 through 1994. No candidate event has been observed and the following upper limits at 90\% confidence level on the branching ratios have been set \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\eta)<4.1\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\eta)<1.5\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\pio)<2.5\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\pio)<1.0\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\pio\pio)<6.0\times 10^{-5},\,\, \mathrm{Br}(\Bs\ra\pio\pio)<2.1\times 10^{-4}. \end{displaymath} These are the first experimental limits on \Bd\ra\eta\eta and on the \Bs neutral charmless modes

Study of the Weak Charged Hadronic Current in b Decays

Charged and neutral particle multiplicities of jets associated with identified semileptonic and hadronic b decays are studied. The observed differences between these jets are used to determine the inclusive properties of the weak charged hadronic current. The average charged particle multiplicity of the weak charged hadronic current in b decays is measured for the first time to be 2.69$\pm$0.07(stat.)$\pm$0.14(syst.). This result is in good agreement with the JETSET hadronization model of the weak charged hadronic current if 40$\pm$17\% of the produced mesons are light--flavored tensor (L=1) mesons. This level of tensor meson production is consistent with the measurement of the $\pi^0$ multiplicity in the weak charged hadronic current in b decays. \end{abstract

Measurement of the lifetime of the τ\tau lepton

The lifetime of the tau lepton is measured using data collected in 1994 by the L3 detector at LEP. The precise track position information of the Silicon Microvertex Detector is exploited. The tau lepton lifetime is determined from the signed impact parameter distribution for 30 322 tau decays into one charged particle and from the decay length distribution for 3891 tau decays into three charged particles. Combining the two methods we obtain $\tau_{\tau}$ = 290.1 $\pm$ 4.0 fs