RESUMEN
This article summarizes the 7th Workshop on the Terminology in Developmental Toxicology held in Berlin, May 4-6, 2011. The series of Berlin Workshops has been mainly concerned with the harmonization of terminology and classification of fetal anomalies in developmental toxicity studies. The main topics of the 7th Workshop were knowledge on the fate of anomalies after birth, use of Version 2 terminology for maternal-fetal observations and non-routinely used species, reclassification of "grey zone" anomalies and categorization of fetal observations for human health risk assessment. The paucity of data on health consequences of the postnatal permanence of fetal anomalies is relevant and further studies are needed. The Version 2 terminology is an important step forward and the terms listed in this glossary are considered also to be appropriate for most observations in non-routinely used species. Continuation of the Berlin Workshops was recommended. Topics suggested for the next Workshop were grouping of fetal observations for reporting and statistical analysis.
Asunto(s)
Anomalías Inducidas por Medicamentos/clasificación , Feto/anomalías , Terminología como Asunto , Animales , Humanos , Medición de RiesgoRESUMEN
We report on particle deposition in the tracheobronchial and pulmonary regions of the respiratory tract of the minipig and its dependence on particle size. Four animals breathing spontaneously via the nose were exposed for 1 h to known concentrations of three different polydisperse dry aerosols composed of bovine serum albumin (BSA) and an oxide of a rare earth element: Y2O3, Sm2O3, and Er2O3. The mass size distributions of the rare earth elements of the three test aerosols have mass median aerodynamic diameters of 0.9, 2.5, and, 4.3 microm, and geometric standard deviations of sigma(g) = 2.0, 1.8, and, 1.7. The extrathoracic, tracheobronchial, and pulmonary regions of the respiratory tract were dissected, separately lyophilized, and chemically digested by microwave-assisted high pressure digestion. The tracer element in each compartment was determined by inductively coupled plasma mass spectrometry. A mass balance equation relating the tracer mass found in the lung compartments to the tracer mass inhaled was solved by linear regression to obtain the deposition fraction as function of particle sizes for the tracheobronchial and the pulmonary lung region. Estimated values for the respiratory minute volume were used in this context. For coarse particles > 6 microm, the deposition fraction is < 5% for both compartments. The deposition fraction for particles with aerodynamic diameter of approximately 3 microm is 21% in the tracheobronchial airways and 40% in the pulmonary airways.
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Pulmón/metabolismo , Metales de Tierras Raras/farmacocinética , Material Particulado/farmacocinética , Porcinos Enanos/fisiología , Aerosoles/farmacocinética , Animales , Bronquios/metabolismo , Femenino , Modelos Animales , Modelos Biológicos , Mucosa Nasal/metabolismo , Óxidos/farmacocinética , Tamaño de la Partícula , Pruebas de Función Respiratoria/veterinaria , Porcinos , Tráquea/metabolismoRESUMEN
In this paper, changes in serum levels of the cardiac biomarkers troponin I and the heart-type fatty acid-binding protein (H-FABP) following administration of a long-acting beta(2)-sympathicomimeticum (long-acting beta-agonist, LABA) to dogs were measured. We measured troponin I in dogs in a 4-week repeated-dose study with inhalative administration of formoterol (13microg/kgd) and a glucocorticoid/formoterol combination (143/16microg/kgd). The medians of troponin I increased within 3 days in both groups, far beyond the cut-off level (0.1microg/L), but returned to baseline levels on study day 9. The increase was more pronounced in the formoterol-only group (3.29microg/L) compared to the glucocorticoid/formoterol combination group (1.32microg/L). In a second study, we measured serum troponin I as well as serum H-FABP levels in several samples over 7 days in dogs, receiving a single inhalative dose of a glucocorticoid/formoterol combination (120/12mug/kgd). The median of the troponin I concentration increased above the cut-off level within 2h and that of H-FABP within 4h. The medians of both parameters were temporarily above the cut-off levels even on study day 7. Both studies were conducted according to national animal welfare guidelines. To our knowledge, this is the first report that shows a corresponding increase of troponin I and H-FABP in dogs treated with formoterol. Both parameters are more sensitive in detecting a drug-induced cardiac injury compared to total LDH, total CK as well as CK MB activity. However, it is recommended to take at least three blood samples per day to assess a temporary increase of troponin I.
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Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Etanolaminas/efectos adversos , Proteínas de Unión a Ácidos Grasos/sangre , Troponina I/sangre , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Animales , Biomarcadores/sangre , Ritmo Circadiano , Preparaciones de Acción Retardada , Perros , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Etanolaminas/administración & dosificación , Femenino , Fumarato de Formoterol , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Masculino , Isquemia Miocárdica/sangre , Isquemia Miocárdica/inducido químicamente , Factores de TiempoRESUMEN
Teratogenic effects caused by a new nitroimidazopyridazine were examined in Wistar (WU) rats after repeated oral administration of 0, 2.5, 10, and 40 mg/kg, given on days 6-17 post coitum (p.c.) (Day of mating = Day 0) in a regular study on embryo-fetal development according to ICH S5A. At day 20 p.c., fetuses were removed and carefully examined under a dissecting microscope for external, visceral and skeletal malformations. The exposure to the high dose of the test compound during the organogenesis and early histogenesis periods of prenatal development induced prominent CNS malformations (exencephaly, neural tube defects (NTD)) associated with external malformations (hyperflexion of the forelimbs). To support the data from this study additional histological evaluation of the brains was performed with the following results: disorganization of the cerebral cortex associated with ectopic subcommissural organs. Additionally, an in vitro test (whole embryo culture, WEC) showed alterations of the developing neural tube after the incubation of rat embryos with the test compound on gestation days 9.5-11.5. Our data demonstrated that nitroimidazopyridazine caused NTDs and limb malformations during organogenesis. Based on these data the further development of the test compound was stopped.
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Anomalías Inducidas por Medicamentos/etiología , Encéfalo/anomalías , Miembro Anterior/anomalías , Piridazinas/toxicidad , Teratógenos/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Técnicas de Cultivo de Embriones , Embrión de Mamíferos/efectos de los fármacos , Femenino , Exposición Materna , Técnicas de Cultivo de Órganos , Embarazo , Ratas , Ratas WistarRESUMEN
This article is a report on the Fourth Berlin Workshop on Terminology in Developmental Toxicology, which was held in April 2002. The workshop is part of an international project in the field of harmonization of terminology in developmental toxicology supported by IPCS. The goal of the Harmonization Project is to ensure better chemical risk assessment. The aim of this Fourth Workshop was to discuss the results of a previously conducted survey on classification of external and visceral anomalies, which are listed in the international glossary, developed under the auspices of IFTS (1997 glossary). The discussions among experts from research institutions, regulatory agencies, and industries were mainly focussed on terms for which there was disagreement and/or uncertainties and the possible reasons. For the illustration of "gray-zone" anomalies, pictures were provided by the participants, which constituted the basis for detailed discussions. There was high agreement that most of the external anomalies (>66%) should be classified as malformations. The few external anomalies for which there was low agreement to classify as a malformation were discussed in detail. None of the external findings, which had in the survey a high agreement, were categorized as a variation.A high agreement regarding the classification of approximately one-third of visceral anomalies was achieved with 34 and 2% being described as malformation and variation, respectively. Most of the visceral findings had low agreement indices and there appeared to be several reasons for this. Thus, the response, 'Not known/not used in the laboratory' (N) was often given. A couple of reasons for difficulties in the classification of an anomaly were that it is only rarely seen upon fetal examination or tends to be species specific. Furthermore, the classification of some anomalies as malformation or variation will remain vague as the decision must be made on a case-by-case basis. Factors affecting the decision include: the availability of appropriate historical control data, description of the grading and severity, whether the anomaly occurs in isolation or whether there is a relationship with an abnormal process, and finally, if the change represents an irreversible one, affecting human and/or animal health. It was concluded that a severity grading, supported by pictures of the anomaly, would be especially helpful to classify certain changes as malformation or as variation. Several of the soft tissue changes were considered likely to be the consequence of functional disorders and thus not strictly developmental anomalies. The possibility to describe a finding as 'Not Malformation' (Unclassified) was agreed upon. As a general conclusion it was emphasized that the observation of a permanent structural change should be considered to be a warning of possible consequences to humans, even when there is no apparent adverse effect on health and survival in adult animals of the species under investigation. Therefore, research is needed to further investigate postnatal consequences. Future collaboration in the field of reproductive and developmental toxicology should aim to further develop and implement a harmonized approach to the interpretation of study data. Therefore, this terminology work will continue in close cooperation with the IPCS Harmonization Project. A Steering Group should be established to facilitate the implementation of harmonized terminology into daily scientific work and its regulatory application.