8 research outputs found
Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity
New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances
Nonanimal Approaches to Assessing the Toxicity of Inhaled Substances: Current Progress and Future Promise:Roundtable Discussion
Prevalidation of Rat GM-CFU Assay for In Vitro Toxicology Application
In vitro haematotoxicity assays are thought to have the potential to significantly reduce and refine the use of animals for haematotoxicity testing. These assays are successful in all types of studies except human toxicology studies in the preclinical setting in which are not required for regulatory testing. Furthermore, these assays could play a key role in bridging the gap between preclinical toxicology studies in animal models and clinical investigations.
In previous studies, the Colony Forming Unit-Granulocyte Macrophage ¿CFU-GM¿ assay has been validated for testing drug haematotoxicity (both in mouse bone marrow and human cord blood) and for predicting in vivo human maximal tolerated dose (MTD) by adjusting in vivo data on mouse toxicity. Recently, a Colony Forming Unit-Megakaryocyte (CFU-Mk) assay in human progenitors has also been prevalidated for testing the drug toxicity on megakaryocytes.
The rat CFU-GM assay has been used by many researchers for its ability to evaluate in vitro haematotoxicity. Although it has not been developed, a standardised procedure for data comparison could be very important since the rat is the most widely used species for in vivo testing of toxicants. This report presents the results of the prevalidation study developed to analyze the intra-laboratory 15
and inter-laboratories variability of a standardized operating procedure (SOP) for this assay and its performance for the in vitro determination of inhibitory concentration (IC) values of drugs on rat myeloid progenitors (CFU-GM).
The results demonstrate that the CFU-GM assay can be applied by using cryopreserved rat bone marrow cells (r BMC) and represents a useful tool for evaluating the toxicity of a compound in terms of both relative toxicity when different molecules are compared and prediction of the degree of in vivo toxicity. Using this assay could greatly reduce the number of rats used in experimental conditions and could also contribute to the accumulation of more toxicity data on compounds to be registered according to the criteria established by the European Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) program.JRC.I.3-Molecular Biology and Genomic
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In Vitro Exposure Systems and Dosimetry Assessment Tools for Inhaled Tobacco Products: Workshop Proceedings, Conclusions and Paths Forward for In Vitro Model Use
In 2009, the passing of the Family Smoking Prevention and Tobacco Control Act facilitated the establishment of the FDA Center for Tobacco Products (CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 4-6 April 2016, the Institute for In Vitro Sciences, Inc. (IIVS) convened a workshop conference entitled, In Vitro Exposure Systems and Dosimetry Assessment Tools for Inhaled Tobacco Products, to bring together stakeholders representing regulatory agencies, academia and industry to address the research priorities articulated by the FDA CTP. Specific topics were covered to assess the status of current in vitro smoke and aerosol/vapour exposure systems, as well as the various approaches and challenges to quantifying the complex exposures in in vitro pulmonary models developed for evaluating adverse pulmonary events resulting from tobacco product exposures. The four core topics covered were: a) Tobacco Smoke and E-Cigarette Aerosols; b) Air-Liquid Interface-In Vitro Exposure Systems; c) Dosimetry Approaches for Particles and Vapours/In Vitro Dosimetry Determinations; and d) Exposure Microenvironment/Physiology of Cells. The 2.5-day workshop included presentations from 20 expert speakers, poster sessions, networking discussions, and breakout sessions which identified key findings and provided recommendations to advance these technologies. Here, we will report on the proceedings, recommendations, and outcome of the April 2016 technical workshop, including paths forward for developing and validating non-animal test methods for tobacco product smoke and next generation tobacco product aerosol/vapour exposures. With the recent FDA publication of the final deeming rule for the governance of tobacco products, there is an unprecedented necessity to evaluate a very large number of tobacco-based products and ingredients. The questionable relevance, high cost, and ethical considerations for the use of in vivo testing methods highlight the necessity of robust in vitro approaches to elucidate tobacco-based exposures and how they may lead to pulmonary diseases that contribute to lung exposure-induced mortality worldwide
Pathway-Based Predictive Approaches for Non-Animal Assessment of Acute Inhalation toxicity
New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances.JRC.F.3-Chemicals Safety and Alternative Method