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1.
Regul Toxicol Pharmacol ; 68(1): 119-39, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24287156

RESUMEN

Information on toxicokinetics is critical for animal-free human risk assessment. Human external exposure must be translated into human tissue doses and compared with in vitro actual cell exposure associated to effects (in vitro-in vivo comparison). Data on absorption, distribution, metabolism and excretion in humans (ADME) could be generated using in vitro and QSAR tools. Physiologically-based toxicokinetic (PBTK) computer modelling could serve to integrate disparate in vitro and in silico findings. However, there are only few freely-available PBTK platforms currently available. And although some ADME parameters can be reasonably estimated in vitro or in silico, important gaps exist. Examples include unknown or limited applicability domains and lack of (high-throughput) tools to measure penetration of barriers, partitioning between blood and tissues and metabolic clearance. This paper is based on a joint EPAA--EURL ECVAM expert meeting. It provides a state-of-the-art overview of the availability of PBTK platforms as well as the in vitro and in silico methods to parameterise basic (Tier 1) PBTK models. Five high-priority issues are presented that provide the prerequisites for wider use of non-animal based PBTK modelling for animal-free chemical risk assessment.


Asunto(s)
Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Modelos Biológicos , Alternativas a las Pruebas en Animales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Farmacocinética , Medición de Riesgo
2.
Altern Lab Anim ; 36(2): 161-87, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18522484

RESUMEN

A formal validation study was performed, in order to investigate whether the commercially-available reconstructed human epidermis (RHE) models, EPISKIN, EpiDerm and SkinEthic, are suitable for in vitro skin absorption testing. The skin types currently recommended in the OECD Test Guideline 428, namely, ex vivo human epidermis and pig skin, were used as references. Based on the promising outcome of the prevalidation study, the panel of test substances was enlarged to nine substances, covering a wider spectrum of physicochemical properties. The substances were tested under both infinite-dose and finite-dose conditions, in ten laboratories, under strictly controlled conditions. The data were subjected to independent statistical analyses. Intra-laboratory and inter-laboratory variability contributed almost equally to the total variability, which was in the same range as that in preceding studies. In general, permeation of the RHE models exceeded that of human epidermis and pig skin (the SkinEthic RHE was found to be the most permeable), yet the ranking of substance permeation through the three tested RHE models and the pig skin reflected the permeation through human epidermis. In addition, both infinite-dose and finite-dose experiments are feasible with RHE models. The RHE models did not show the expected significantly better reproducibility, as compared to excised skin, despite a tendency toward lower variability of the data. Importantly, however, the permeation data showed a sufficient correlation between all the preparations examined. Thus, the RHE models, EPISKIN, EpiDerm and SkinEthic, are appropriate alternatives to human and pig skin, for the in vitro assessment of the permeation and penetration of substances when applied as aqueous solutions.


Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Epidermis , Procedimientos de Cirugía Plástica , Absorción Cutánea/fisiología , Animales , Cafeína/farmacología , Epidermis/efectos de los fármacos , Epidermis/fisiología , Ácido Flufenámico/farmacología , Humanos , Ivermectina/farmacología , Manitol/farmacología , Técnicas de Cultivo de Órganos , Reproducibilidad de los Resultados , Absorción Cutánea/efectos de los fármacos , Pruebas de Irritación de la Piel/métodos , Porcinos
4.
Toxicol In Vitro ; 25(1): 315-23, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20932890

RESUMEN

Allergic contact dermatitis is a delayed T-cell mediated allergic response associated with relevant social and economic impacts. Animal experiments (e.g. the local lymph node assay) are still supplying most of the data used to assess the sensitization potential of new chemicals. However, the 7th amendment to the EU Cosmetic Directive will introduce a testing ban for cosmetic ingredients after 2013. In vitro alternative methods are thus being actively developed. Although promising results have been obtained with cell lines, their reduced functionality and inherent genomic instability led us to reinvestigate the use of peripheral blood monocyte-derived dendritic cells (PBMDCs) for the establishment of a reliable in vitro sensitization test. To solve the issues associated with the use of primary cells, the culture and exposure conditions (cytokine concentrations, incubation time, readout, pooled vs. single donors and cytotoxicity) were re-assessed and optimized. Here we propose a stable and reproducible protocol based on PBMDCs. This should allow a wider acceptance of PBMDCs as a reliable test system for the detection of human skin sensitizers and the inclusion of this protocol in an integrated testing strategy.


Asunto(s)
Alérgenos/toxicidad , Cosméticos/toxicidad , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Monocitos/citología , Pruebas de Toxicidad , Alternativas a las Pruebas en Animales , Antígeno B7-2/metabolismo , Diferenciación Celular , Separación Celular/métodos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/farmacología , Células Dendríticas/metabolismo , Dermatitis Alérgica por Contacto/prevención & control , Citometría de Flujo , Haptenos/inmunología , Humanos , Receptores de Lipopolisacáridos/metabolismo , Reproducibilidad de los Resultados , Pruebas de Toxicidad/métodos
5.
ALTEX ; 28(1): 50-5, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21311850

RESUMEN

Allergic contact dermatitis is a delayed-type hypersensitivity reaction induced by small reactive chemicals (haptens). Currently, the sensitising potential and potency of new chemicals is usually characterised using data generated via animal studies, such as the local lymph node assay (LLNA). There are, however, increasing public and political concerns regarding the use of animals for the testing of new chemicals. Consequently, the development of in vitro, in chemico or in silico models for predicting the sensitising potential and/or potency of new chemicals is receiving widespread interest. The Colipa Skin Tolerance task force currently collaborates with and/or funds several academic research groups to expand our understanding of the molecular and cellular events occurring during the acquisition of skin sensitisation. Knowledge gained from this research is being used to support the development and evaluation of novel alternative approaches for the identification and characterisation of skin sensitizing chemicals. At present three non-animal test methods (Direct Peptide Reactivity Assay (DPRA), Myeloid U937 Skin Sensitisation Test (MUSST) and human Cell Line Activation Test (hCLAT)) have been evaluated in Colipa interlaboratory ring trials for their potential to predict skin sensitisation potential and were recently submitted to ECVAM for formal pre-validation. Data from all three test methods will now be used to support the study and development of testing strategy approaches for skin sensitiser potency prediction. This publication represents the current viewpoint of the cosmetics industry on the feasibility of replacing the need for animal test data for informing skin sensitisation risk assessment decisions.


Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Dermatitis Alérgica por Contacto/patología , Alérgenos/toxicidad , Animales , Biomarcadores , Línea Celular , Cosméticos/normas , Células Dendríticas/efectos de los fármacos , Haptenos , Humanos , Industrias/normas , Medición de Riesgo , Piel/patología
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