RESUMO
A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross-study analysis of toxicology studies. Cross-study analysis can be used to understand a single compound's toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND datasets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A cross-study analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of 2 different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.
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Testes de Toxicidade , Animais , Testes de Toxicidade/métodos , Bases de Dados Factuais , Toxicologia/métodos , Humanos , MasculinoRESUMO
BACKGROUND: Paracetamol overdose is the most common cause of acute liver failure in the United States. Administration of acetylcysteine is the standard of care for this intoxication. Laboratory values and clinical criteria are used to guide treatment duration, but decision-making is nuanced and often complex and difficult. The purpose of this study was to evaluate the effect of the introduction of a medical toxicology service on the rate of errors in the management of paracetamol overdose. METHODS: This was a single center, retrospective, cohort evaluation. Patients with suspected paracetamol overdose were divided into two groups: those attending in the 1 year period before and those in the 1 year after the introduction of the medical toxicology service. The primary outcome was the frequency of deviations from the established management of paracetamol intoxication, using international guidelines as a reference. RESULTS: Fifty-four patients were eligible for the study (20 pre-toxicology-service, 34 post-toxicology-service). The frequency of incorrect therapeutic decisions was significantly lower in the post-toxicology service implementation versus the pre-implementation group (P = 0.005). DISCUSSION: Our study suggests that a medical toxicology service reduces the incidence of management errors, including the number of missed acetylcysteine doses in patients with paracetamol overdose. The limitations include the retrospective study design and that the study was conducted at a single center, which may limit generalizability. CONCLUSIONS: The implementation of a medical toxicology service was associated with a decrease in the number of errors in the management of paracetamol overdose.
Assuntos
Acetaminofen , Acetilcisteína , Overdose de Drogas , Centros de Atenção Terciária , Humanos , Acetaminofen/intoxicação , Estudos Retrospectivos , Overdose de Drogas/terapia , Overdose de Drogas/tratamento farmacológico , Feminino , Masculino , Adulto , Acetilcisteína/uso terapêutico , Pessoa de Meia-Idade , Analgésicos não Narcóticos/intoxicação , Antídotos/uso terapêutico , Toxicologia/métodos , Adulto JovemRESUMO
The Special Issue "Toxicology, Nanotoxicology and Occupational Diseases" of the International Journal of Molecular Sciences includes six articles presenting the results of recent experimental studies in the fields of toxicology, nanotoxicology, and occupational health [...].
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Nanoestruturas , Doenças Profissionais , Exposição Ocupacional , Toxicologia , Humanos , Nanoestruturas/química , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Toxicologia/métodosRESUMO
Predictive and computational toxicology, a highly scientific and research-based field, is rapidly progressing with wider acceptance by regulatory agencies around the world. Almost every aspect of the field has seen fundamental changes during the last decade due to the availability of more data, usage, and acceptance of a variety of predictive tools and an increase in the overall awareness. Also, the influence from the recent explosive developments in the field of artificial intelligence has been significant. However, the need for sophisticated, easy to use and well-maintained software platforms for in silico toxicological assessments remains very high. The MultiCASE suite of software is one such platform that consists of an integrated collection of software programs, tools, and databases. While providing easy-to-use and highly useful tools that are relevant at present, it has always remained at the forefront of research and development by inventing new technologies and discovering new insights in the area of QSAR, artificial intelligence, and machine learning. This chapter gives the background, an overview of the software and databases involved, and a brief description of the usage methodology with the aid of examples.
Assuntos
Relação Quantitativa Estrutura-Atividade , Toxicologia , Inteligência Artificial , Simulação por Computador , Bases de Dados Factuais , Software , Toxicologia/métodosRESUMO
The pharmacology and toxicology of a broad variety of therapies and chemicals have significantly improved with the aid of the increasing in vitro models of complex human tissues. Offering versatile and precise control over the cell population, extracellular matrix (ECM) deposition, dynamic microenvironment, and sophisticated microarchitecture, which is desired for the in vitro modeling of complex tissues, 3D bio-printing is a rapidly growing technology to be employed in the field. In this review, we will discuss the recent advancement of printing techniques and bio-ink sources, which have been spurred on by the increasing demand for modeling tactics and have facilitated the development of the refined tissue models as well as the modeling strategies, followed by a state-of-the-art update on the specialized work on cancer, heart, muscle and liver. In the end, the toxicological modeling strategies, substantial challenges, and future perspectives for 3D printed tissue models were explored.
Assuntos
Bioimpressão/métodos , Modelos Biológicos , Impressão Tridimensional , Animais , Matriz Extracelular/metabolismo , Humanos , Farmacologia/métodos , Engenharia Tecidual/métodos , Toxicologia/métodosRESUMO
Drug-induced liver injury (DILI) is the major reason for failures in drug development and withdrawal of approved drugs from the market. Two-dimensional cultures of hepatocytes often fail to reliably predict DILI: hepatoma cell lines such as HepG2 do not reflect important primary-like hepatic properties and primary human hepatocytes (pHHs) dedifferentiate quickly in vitro and are, therefore, not suitable for long-term toxicity studies. More predictive liver in vitro models are urgently required in drug development and compound safety evaluation. This review discusses available human hepatic cell types for in vitro toxicology analysis and their usage in established and emerging three-dimensional (3D) culture systems. Generally, 3D cultures maintain or improve primary hepatic functions (including expression of drug-metabolizing enzymes) of different liver cells for several weeks of culture, thus allowing long-term and repeated-dose toxicity studies. Spheroid cultures of pHHs have been comprehensively tested, but also other cell types such as HepaRG benefit from 3D culture systems. Emerging 3D culture techniques include usage of induced pluripotent stem-cell-derived hepatocytes and primary-like upcyte cells, as well as advanced culture techniques such as microfluidic liver-on-a-chip models. In-depth characterization of existing and emerging 3D hepatocyte technologies is indispensable for successful implementation of such systems in toxicological analysis.
Assuntos
Técnicas de Cultura de Células/métodos , Hepatócitos/citologia , Esferoides Celulares/citologia , Testes de Toxicidade/métodos , Toxicologia/métodos , Reatores Biológicos , Humanos , Cultura Primária de CélulasRESUMO
Cellular adaptive mechanisms emerging after exposure to low levels of toxic agents or stressful stimuli comprise an important biological feature that has gained considerable scientific interest. Investigations of low-dose exposures to diverse chemical compounds signify the non-linear mode of action in the exposed cell or organism at such dose levels in contrast to the classic detrimental effects induced at higher ones, a phenomenon usually referred to as hormesis. The resulting phenotype is a beneficial effect that tests our physiology within the limits of our homeostatic adaptations. Therefore, doses below the region of adverse responses are of particular interest and are specified as the hormetic gain zone. The manifestation of redox adaptations aiming to prevent from disturbances of redox homeostasis represent an area of particular interest in hormetic responses, observed after exposure not only to stressors but also to compounds of natural origin, such as phytochemicals. Findings from previous studies on several agents demonstrate the heterogeneity of the specific zone in terms of the molecular events occurring. Major factors deeply involved in these biphasic phenomena are the bioactive compound per se, the dose level, the duration of exposure, the cell, tissue or even organ exposed to and, of course, the biomarker examined. In the end, the molecular fate is a complex toxicological event, based on beneficial and detrimental effects, which, however, are poorly understood to date.
Assuntos
Hormese/fisiologia , Toxicologia/métodos , Adaptação Fisiológica/fisiologia , Animais , Biomarcadores/metabolismo , Humanos , OxirreduçãoRESUMO
The 25R-NBOH family is a group of thermally labile compounds that are relevant for forensic sciences and traditionally analyzed by GC-MS after derivatization - a step that is time consuming in a routine work. In this paper, the use of short analytical columns (4 and 10 m) showed to decrease compound degradation in the GC oven during chromatographic separation and to allow the analysis of non-derivatized 25R-NBOH compounds by GC-MS. A shorter column demanded a higher gas flow rate, and both factors decreased residence time of the analytes in the column and their degradation. The inlet temperature (250° C or 280°C) did not impact the response of 25R-NBOH. A 25R-NBOH fragmentation pathway by electron ionization was also presented for the first time. The GC-MS method with a 4 m column was successfully applied to other compounds of forensic interest, and it can be tested in the analysis of biological samples in toxicological investigations.
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Etanolaminas/análise , Patologia Legal/métodos , Cromatografia Gasosa-Espectrometria de Massas , Toxicologia/métodos , TemperaturaRESUMO
Over the last decade, combination of drugs in all stages of pharmaceutical development has accelerated availability of promising new therapies for difficult to treat diseases. Safety assessment of combined drugs to be tested in humans can occur at a critical path prior to proceeding in clinical testing. A recent survey by The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ DruSafe) summarized member companies' approaches to combination safety strategies. In addition, feedback from Health Authorities (HAs) support a case-by-case scientific approach in assessing combination products' safety in accordance with the International Council on Harmonization (ICH) guidelines. Here, we present Pfizer's drug combination safety approach for various therapeutic areas (TA) including inflammation and immunology, metabolic, and anti-cancer products. There is no one-size-fits-all approach; rather, our main considerations include: strength of the existing clinical safety data for the individual compounds, common target organs, the potential for a synergistic effect, potential drug-drug interaction, routes of administration of each product and disease indications. No formal toxicity studies are considered necessary for anti-cancer drugs, while safety endpoints may be collected in preclinical pharmacology studies especially when the combined drugs present a novel mechanism. Combination safety studies when conducted for non-cancer indications can range from 2 to 13-weeks in duration, conducted usually in rodents, with dosages of individual molecules within clinical pharmacologic ranges. A case-by-case strategy guided by scientific rationale and in close collaboration with HAs remains the best approach to decide on the design and conduct of combination safety studies.
Assuntos
Desenvolvimento de Medicamentos , Toxicologia/métodos , Toxicologia/tendências , Animais , Biomarcadores Farmacológicos , Desenvolvimento de Medicamentos/tendências , Interações Medicamentosas , Humanos , SegurançaRESUMO
Machine perfusion (MP) is at the forefront of innovation in modern liver transplantation. Several approaches, mainly varying the temperature at which the graft is perfused, have shown benefit in preclinical models and nonrandomized clinical trials. Given the recent randomized controlled trial by Nasralla et al demonstrating the efficacy of normothermic MP over static cold storage, MP is likely here to stay for the foreseeable future. We are only beginning to explore the possibilities of this technology, including the prediction of graft function and modification of suboptimal livers. This has the potential to both increase the donor pool and improve the quality of grafts provided to recipients. Beyond transplantation, there may be a role for MP in extracorporeal liver support, cancer research and therapeutics, and pharmaceutical testing. In this review, we provide the rationale and explore the relevant preclinical studies that support the use of ex situ liver perfusion for these extended applications.
Assuntos
Transplante de Fígado/métodos , Fígado/irrigação sanguínea , Preservação de Órgãos/métodos , Perfusão/métodos , Animais , Humanos , Modelos Animais , Neoplasias/terapia , Toxicologia/métodosRESUMO
The rate of translational effort of nanomedicine requires strategic planning of nanosafety research in order to enable clinical trials and safe use of nanomedicine in patients. Herein, the experiences that have emerged based on the safety data of classic liposomal formulations in the space of oncology are discussed, along with a description of the new challenges that need to be addressed according to the rapid expansion of nanomedicine platform beyond liposomes. It is valuable to consider the combined use of predictive toxicological assessment supported by deliberate investigation on aspects such as absorption, distribution, metabolism, and excretion (ADME) and toxicokinetic profiles, the risk that may be introduced during nanomanufacture, unique nanomaterials properties, and nonobvious nanosafety endpoints, for example. These efforts will allow the generation of investigational new drug-enabling safety data that can be incorporated into a rational infrastructure for regulatory decision-making. Since the safety assessment relates to nanomaterials, the investigation should cover the important physicochemical properties of the material that may lead to hazards when the nanomedicine product is utilized in humans.
Assuntos
Nanomedicina , Neoplasias , Toxicologia , Antineoplásicos/toxicidade , Controle de Medicamentos e Entorpecentes , Humanos , Nanomedicina/normas , Nanoestruturas/toxicidade , Neoplasias/terapia , Toxicologia/métodos , Toxicologia/normas , Toxicologia/tendênciasRESUMO
The diversity and increasing prevalence of products derived from engineered nanomaterials (ENM), warrants implementation of non-animal approaches to health hazard assessment for ethical and practical reasons. Although non-animal approaches are becoming increasingly popular, there are almost no studies of side-by-side comparisons with traditional in vivo assays. Here, transcriptomics is used to investigate mechanistic similarities between healthy/asthmatic models of 3D air-liquid interface (ALI) cultures of donor-derived human bronchial epithelia cells, and mouse lung tissue, following exposure to copper oxide ENM. Only 19% of mouse lung genes with human orthologues are not expressed in the human 3D ALI model. Despite differences in taxonomy and cellular complexity between the systems, a core subset of matching genes cluster mouse and human samples strictly based on ENM dose (exposure severity). Overlapping gene orthologue pairs are highly enriched for innate immune functions, suggesting an important and maybe underestimated role of epithelial cells. In conclusion, 3D ALI models based on epithelial cells, are primed to bridge the gap between traditional 2D in vitro assays and animal models of airway exposure, and transcriptomics appears to be a unifying dose metric that links in vivo and in vitro test systems.
Assuntos
Alternativas aos Testes com Animais , Cobre , Células Epiteliais , Pulmão , Nanopartículas Metálicas , Toxicologia , Alternativas aos Testes com Animais/métodos , Alternativas aos Testes com Animais/normas , Animais , Cobre/toxicidade , Células Epiteliais/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Camundongos , Modelos Animais , Toxicologia/métodosRESUMO
Substance use is commonly associated with traumatic brain injury (TBI). We investigate associations between active substance use, peri-injury factors, and outcome after TBI across three U.S. Level I trauma centers. TBI subjects from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) with Marshall computed tomography (CT) score 1-3, no neurosurgical procedure/operation, and admission urine toxicology screen (tox+/-) were extracted. Associations between tox+/-, comorbidities, hospital variables, and six-month functional (GOSE) and neuropsychiatric (PCL-C, BSI18, RPQ-13, SWLS) outcomes were analyzed. Multivariable regression was performed for associations significant on univariate analysis with odds ratios (mOR) presented. Significance assessed at p < 0.05. In 133 subjects, tox+/tox- were 29.1%/72.9%. Tox+ was younger (35.5/43.6-years, p = 0.018), trended toward male sex (80.6%/63.9%, p = 0.067), was associated with history of seizures (27.8%/10.3%, p = 0.012), self-reported substance use (44.4%/17.5%, p = 0.001), prior TBI (58.8%/34.1%, p = 0.009), GCS < 15 (69.4%/48.4%, p = 0.031) and blood alcohol level >0.08-mg/dl (55.6%/30.8%, p = 0.022). In CT-negative subjects, tox+ was associated with increased hospital admission (95.7%/66.7%, p = 0.034). At six-months, tox+ was associated with screening positive for post-traumatic stress disorder (PCL-C: 40.0%/15.9%; mOR = 8.24, p = 0.022) and psychiatric symptoms (BSI18: 40.0%/14.3%, mOR = 11.06, p = 0.023). Active substance use in TBI may confound GCS assessment, triage to higher level of care, and be associated with increased six-month neuropsychiatric symptoms. Substance use screening should be integrated into standard emergency/acute care TBI protocols to optimize management and resource utilization. Clinicians should be vigilant in providing education, counselling, and follow-up for TBI patients with substance use.
Assuntos
Lesões Encefálicas Traumáticas/etiologia , Programas de Rastreamento/métodos , Transtornos Relacionados ao Uso de Substâncias/complicações , Toxicologia/métodos , Adulto , Fatores Etários , Concentração Alcoólica no Sangue , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores Sexuais , Tomografia Computadorizada por Raios X , Centros de Traumatologia , Resultado do TratamentoRESUMO
Genomic instability is a risk to organism health detected by methods such as the comet assay (CA). It is a highly sensitive and versatile method to detect low levels of DNA damage in a wide range of cells from humans as well as from other species as compared to other methods with the same proposal. CA is a powerful DNA damage analysis tool and its applicability extends to the genotoxicity analysis of, that is, drugs and carcinogenic substances. This study analyzed papers employing CA in the Scopus database in order to assess its scientific importance, employability, and trends by evaluating: number of articles per year, total citations and per year, country of publication and their clusters, clusters of authors, most frequently abstracts terms, name of journal, affiliations, country of publication, subject area, relevant keywords compared to citation clusters, and impact factor (IF) CiteScore. It was retrieved 13,828 articles from 1990 to 2018, with a peak in 2014 and a decline from 2015 to 2018. Four author clusters from China, United States, India, and Brazil were identified, countries presenting the greatest number of publications. China presented the most recent scientific advances in the field. It was also detected nine clusters of themes, and a positive correlation between publications, citations, and the IF. There are full employability and versatility in the use of the method. Currently, there is an advance in Chinese scientific production on the subject, and there is greater use of the method on oxidative damage researches.
Assuntos
Ensaio Cometa , Dano ao DNA , Bibliometria , Bases de Dados Factuais , Toxicologia/métodosRESUMO
A facile sol-gel route has been applied to synthesize hybrid silica-PVA-iron oxide nanocomposite materials. A step-by-step calcination (processing temperatures up to 400 °C) was applied in order to oxidize the organics together with the iron precursor. Transmission electron microscopy, X-ray diffraction, small angle neutron scattering, and nitrogen porosimetry were used to determine the temperature-induced morpho-textural modifications. In vitro cytotoxicity assay was conducted by monitoring the cell viability by the means of MTT assay to qualify the materials as MRI contrast agents or as drug carriers. Two cell lines were considered: the HaCaT (human keratinocyte cell line) and the A375 tumour cell line of human melanoma. Five concentrations of 10 µg/mL, 30 µg/mL, 50 µg/mL, 100 µg/mL, and 200 µg/mL were tested, while using DMSO (dimethylsulfoxid) and PBS (phosphate saline buffer) as solvents. The HaCaT and A375 cell lines were exposed to the prepared agent suspensions for 24 h. In the case of DMSO (dimethyl sulfoxide) suspensions, the effect on human keratinocytes migration and proliferation were also evaluated. The results indicate that only the concentrations of 100 µg/mL and 200 µg/mL of the nanocomposite in DMSO induced a slight decrease in the HaCaT cell viability. The PBS based in vitro assay showed that the nanocomposite did not present toxicity on the HaCaT cells, even at high doses (200 µg/mL agent).
Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos Férricos/farmacologia , Nanocompostos/química , Álcool de Polivinil/farmacologia , Dióxido de Silício/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Compostos Férricos/química , Humanos , Nanopartículas de Magnetita , Álcool de Polivinil/análogos & derivados , Dióxido de Silício/química , Toxicologia/métodosRESUMO
The increased concern on the consequence of exposure to multiple chemical combinations has led national regulatory authorities to develop different concepts to conduct risk assessments on chemical mixtures. Pesticide residues were identified as "problem formulation" in the respective European regulations and in this context, the European Food and Safety Authority has suggested to group pesticidal active ingredients (AIs) into cumulative assessment groups (CAGs) based on the toxicological properties of each AI. One proposed CAG, on the liver, currently consists of 15 subgroups, each representing a specific hepatotoxic effect observed in toxicity studies. Dietary cumulative risk assessments would then have to be conducted assuming dose additivity of all members of each CAG subgroup. The purpose of this publication is to group AIs based upon the knowledge of the pathogenesis of liver effects to discriminate between primary end points (direct consequence of chemical interaction with a biological target) and secondary end points (which are a consequence of, or that arise out of, a previous pathological change). Focusing on the relevant primary end points strengthens and simplifies the selection of compounds for cumulative risk assessment regarding the liver and better rationalizes the basis for chemical grouping. Relevant dose additivity is to be expected at the level of the primary/leading pathological end points and not at the level of the secondary end points. We recognize, however, that special consideration is needed for substances provoking neoplasia, and this category is included in the group of primary end points for which chemicals inducing them are grouped for risk assessment. Using the pathological basis for defining the respective CAGs, 6 liver subgroups and 2 gallbladder/bile duct groups are proposed. This approach simplifies the cumulative assessment calculation without obviously affecting consumer safety.
Assuntos
Fígado/efeitos dos fármacos , Resíduos de Praguicidas/classificação , Resíduos de Praguicidas/toxicidade , Toxicologia/métodos , Animais , Misturas Complexas/química , Misturas Complexas/classificação , Misturas Complexas/toxicidade , Humanos , Resíduos de Praguicidas/química , Medição de Risco/métodosRESUMO
Consumers are constantly exposed to trace levels of residues present in food commodities, arising from the use of pesticides. For this reason, assessing the risk caused by pesticide residues present in food requires not only identification and toxicological properties assessment of the active substance, but also of its metabolites, isomers, and degradates. This requires the use of many laboratory animals. On the other hand, currently there is an emphasis on minimizing the use of animals in toxicological research. This review article presents current activities of the European Food Safety Authority (EFSA) and the European Commission's Joint Research Centre (JRC) aiming to replace at least a part of toxicological tests on substances of unknown toxicity with the alternative methods. Quantitative Structure-Activity Relationship (QSAR) and Threshold of Toxicological Concern (TTC) can be used for this purpose in procedure of establishing residue definitions applied for dietary risk assessment.
Assuntos
Resíduos de Praguicidas/análise , Toxicologia/métodos , União Europeia , Contaminação de Alimentos/análise , Inocuidade dos Alimentos , Humanos , Medição de RiscoRESUMO
Toxicology is a broad field that requires the translation of biochemical responses to xenobiotic exposures into useable information to ensure the safety of the public. Modern techniques are improving rapidly, both quantitatively and qualitatively, to provide the tools necessary to expand available toxicological datasets and refine our ability to translate that data into relevant information via bioinformatics. These new techniques can, and do, impact many of the current critical roles in toxicology, including the environmental, forensic, preclinical/clinical, and regulatory realms. One area of rapid expansion is our understanding of bioenergetics, or the study of the transformation of energy in living organisms, and new mathematical approaches are needed to interpret these large datasets. As bioenergetics are intimately involved in the regulation of how and when a cell responds to xenobiotics, monitoring these changes (i.e., metabolic fluctuations) in cells/tissues post-exposure provides an approach to define the temporal scale of pharmacodynamic responses, which can be used to guide additional toxicological techniques (e.g., "omics"). This chapter will summarize important in vitro assays and in vivo imaging techniques to take real-time measurements. Using this information, our laboratory has utilized bioenergetics to identify significant time points of pharmacodynamic relevance as well as forecast the cell's eventual fate.
Assuntos
Bioensaio/métodos , Metabolismo Energético/fisiologia , Mitocôndrias/metabolismo , Toxicologia/métodos , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/metabolismo , 4-Cloro-7-nitrobenzofurazano/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Desoxiglucose/análogos & derivados , Desoxiglucose/metabolismo , Desoxiglucose/farmacologia , Metabolismo Energético/efeitos dos fármacos , Fluordesoxiglucose F18/metabolismo , Humanos , Técnicas In Vitro , Verde de Indocianina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , NAD/metabolismo , NADP/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluxo de Trabalho , XenobióticosRESUMO
Advances in the biological sciences have led to an ongoing paradigm shift in toxicity testing based on expanded application of high-throughput in vitro screening and in silico methods to assess potential health risks of environmental agents. This review examines progress on the vision for toxicity testing elaborated by the US National Research Council (NRC) during the decade that has passed since the 2007 NRC report on Toxicity Testing in the 21st Century (TT21C). Concomitant advances in exposure assessment, including computational approaches and high-throughput exposomics, are also documented. A vision for the next generation of risk science, incorporating risk assessment methodologies suitable for the analysis of new toxicological and exposure data, resulting in human exposure guidelines is described. Case study prototypes indicating how these new approaches to toxicity testing, exposure measurement, and risk assessment are beginning to be applied in practice are presented. Overall, progress on the 20-year transition plan laid out by the US NRC in 2007 has been substantial. Importantly, government agencies within the United States and internationally are beginning to incorporate the new approach methodologies envisaged in the original TT21C vision into regulatory practice. Future perspectives on the continued evolution of toxicity testing to strengthen regulatory risk assessment are provided.
Assuntos
Rotas de Resultados Adversos , Medição de Risco/métodos , Testes de Toxicidade/métodos , Animais , Carcinógenos/química , Carcinógenos/toxicidade , Biologia Computacional/métodos , Mineração de Dados , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Ensaios de Triagem em Larga Escala , Humanos , National Academy of Sciences, U.S. , Relação Estrutura-Atividade , Testes de Toxicidade/tendências , Toxicogenética/métodos , Toxicologia/métodos , Estados UnidosRESUMO
Exosomes are secreted membrane-bound vesicles containing a cargo of curated nucleic acids, proteins, and lipids that can alter gene expression in recipient cells. Toxic agents can alter exosome synthesis and bioactive cargo composition, thus allowing exosomes to serve as biomarkers of exposure and response. While human and animal studies have identified exosome biomarkers of organ toxicity, in vitro models are ideal to examine biological mechanisms of exosome function. Here, we discuss the importance of exosomes in toxicology research and describe applications of in vitro models in advancing our understanding of their role in exposure-associated disease. This discussion of new research frontiers is in commemoration of the invaluable contributions of Dr. Daniel Acosta to the field of in vitro biology and toxicology. Emerging studies have implicated exosomes as mediators of neurodegeneration by shuttling pollutant-induced pathogenic proteins and miRNAs from afflicted neurons to neighboring cells. Exosomes also provide a mechanistic link between inhalation exposures and airway inflammation, remodeling, and systemic effects. Exosomes provide the means for toxic agents to initiate oncogenic transformation and create favorable tumor microenvironments. Furthermore, exosome-mediated drug delivery can alter drug pharmacologic profiles. Expansion in this field using in vitro models is essential to unlock the potential applications of exosome biology in toxicology.