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1.
Medicine (Baltimore) ; 99(1): e18569, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895800

RESUMO

An adverse drug reactions avoidability tool called the Liverpool ADR avoidability assessment tool (LAAT) was recently developed (for research purposes), and subsequently validated with mixed interrater reliability (IRR). We investigated the comparative IRR of this tool in an inpatient cohort to ascertain its practical application in this setting.The patient population was comprised of 44 ADR drug pairs drawn from an observational prospective cohort of patents with ADR attending a Weill Cornell Medicine-affiliated tertiary medical Centre in Doha Qatar (Hamad General Hospital). Using the LAAT, and modified Hallas tools, 4 independent raters (2 Clinical Pharmacologists, and 2 General Physicians) assessed and scored the 44 ADR-drug pairs. Agreement proportions between the rating pairs were evaluated as well individual/overall kappa statistics and intraclass correlation coefficients. We evaluated the weight of each of the 7 questions on the LAAT tool to ascertain its determinative role.Across 44 ADR-drug pairs, the overall median Fleiss kappa using the LAAT, and modified Hallas tools were 0.67 (interquartile range (IQR) 0.55, 0.76), 0.36 (IQR, 0.23-0.71) respectively. The overall percentage pairwise agreement with the LAAT and modified Hallas tools were 78.5%, and 62.2% respectively. Exact pairwise agreement occurred in 37 out of 44 (range 0.71-1), and 27 of 44 (0.53-0.77) ADR-drug pairs using the LAAT and modified Hallas tools respectively. Using the LAAT tool, the overall intraclass correlation coefficient was 0.68 (CI 0.55, 0.79), and 0.37 (CI 0.22, 0.53) with the modified Hallas tool.We report a higher proportion of "possible" and "definite" avoidability outcomes of adverse drug reactions compared with the modified Hallas, or that reported by developers of the LAAT tool. Although initially developed for research purposes, our report has suggested for the first time a potential applicability of this tool in clinical environment as well.


Assuntos
Rotas de Resultados Adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Adulto , Algoritmos , Feminino , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Catar , Reprodutibilidade dos Testes
2.
Environ Sci Technol ; 53(18): 11002-11012, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31436975

RESUMO

Exposure to environmental contaminants can lead to adverse outcomes in both human and nonhuman receptors. The Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks can mechanistically inform cumulative risk assessment for human health and ecological end points by linking together environmental transport and transformation, external exposure, toxicokinetics, and toxicodynamics. This work presents a case study of a hypothetical contaminated site to demonstrate a quantitative approach for implementing the AEP framework and linking this framework to AOPs. We construct an AEP transport and transformation model and then quantify external exposure pathways for humans, fishes, and small herbivorous mammals at the hypothetical site. A Monte Carlo approach was used to address parameter variability. Source apportionment was quantified for each species, and published pharmacokinetic models were used to estimate internal target site exposure from external exposures. Published dose-response data for a multispecies AOP network were used to interpret AEP results in the context of species-specific effects. This work demonstrates (1) the construction, analysis, and application of a quantitative AEP model, (2) the utility of AEPs for organizing mechanistic exposure data and highlighting data gaps, and (3) the advantages provided by a source-to-outcome construct for leveraging exposure data and to aid transparency regarding assumptions.


Assuntos
Rotas de Resultados Adversos , Animais , Ecologia , Peixes , Humanos , Medição de Risco , Toxicocinética
3.
Sci Total Environ ; 686: 995-1009, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31412529

RESUMO

Chemical monitoring data were collected in surface waters from 57 Great Lakes tributaries from 2010 to 13 to identify chemicals of potential biological relevance and sites at which these chemicals occur. Traditional water-quality benchmarks for aquatic life based on in vivo toxicity data were available for 34 of 67 evaluated chemicals. To expand evaluation of potential biological effects, measured chemical concentrations were compared to chemical-specific biological activities determined in high-throughput (ToxCast) in vitro assays. Resulting exposure-activity ratios (EARs) were used to prioritize the chemicals of greatest potential concern: 4­nonylphenol, bisphenol A, metolachlor, atrazine, DEET, caffeine, tris(2­butoxyethyl) phosphate, tributyl phosphate, triphenyl phosphate, benzo(a)pyrene, fluoranthene, and benzophenone. Water-quality benchmarks were unavailable for five of these chemicals, but for the remaining seven, EAR-based prioritization was consistent with that based on toxicity quotients calculated from benchmarks. Water-quality benchmarks identified three additional PAHs (anthracene, phenanthrene, and pyrene) not prioritized using EARs. Through this analysis, an EAR of 10-3 was identified as a reasonable threshold above which a chemical might be of potential concern. To better understand apical hazards potentially associated with biological activities captured in ToxCast assays, in vitro bioactivity data were matched with available adverse outcome pathway (AOP) information. The 49 ToxCast assays prioritized via EAR analysis aligned with 23 potentially-relevant AOPs present in the AOP-Wiki. Mixture effects at monitored sites were estimated by summation of EAR values for multiple chemicals by individual assay or individual AOP. Commonly predicted adverse outcomes included impacts on reproduction and mitochondrial function. The EAR approach provided a screening-level assessment for evidence-based prioritization of chemicals and sites with potential for adverse biological effects. The approach aids prioritization of future monitoring activities and provides testable hypotheses to help focus those efforts. This also expands the fraction of detected chemicals for which biologically-based benchmark concentrations are available to help contextualize chemical monitoring results.


Assuntos
Rotas de Resultados Adversos , Monitoramento Ambiental/métodos , Ensaios de Triagem em Larga Escala/métodos , Poluentes Químicos da Água/análise , Great Lakes Region , Rios , Qualidade da Água
4.
Rev. cient. odontol ; 7(1): 132-139, ene.-jun. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1006014

RESUMO

La gingivitis es la enfermedad más prevalente, pues afecta entre un 5% y un 70% de la población mundial, y puede incluso llegar hasta un 90%. En cambio, la enfermedad periodontal (EP) alcanza un promedio del 30% al 80%, y es más frecuente a partir del segundo trimestre de embarazo. En América Latina, afecta entre un 30% y un 40% de la población. Se estima que durante el embarazo hay un mayor riesgo a contraer enfermedad periodontal en una proporción de 1 de cada 5 mujeres. La enfermedad periodontal es una enfermedad inflamatoria que perjudica a los tejidos de soporte del diente (encía, cemento radicular, ligamento periodontal y hueso alveolar).Se ha demostrado que existe una relación directa entre el agravamiento de la EP con el embarazo. Esto se debe a la variación hormonal que ocurre en este periodo, la cual promueve el crecimiento excesivo de microorganismos patógenos responsables de la inflamación gingival. Entre estos microorganismos patógenos encontramos a Prevotella intermedia y Porphyromonas gingivalis. Esta última, junto a Fusobacterium nucleatum, son capaces de atravesar la barrera placen-taria y causar infecciones y resultados adversos en el embarazo, tales como parto prematuro, preeclampsia y muerte fetal. (AU)


Gingivitis is the most prevalent disease worldwide, affecting from 5 to 70% of the population and reaching up to 90%. On the other hand, the mean prevalence of periodontal disease (PD) is 30 to 80%, being more frequent in the second trimester of pregnancy. Periodontal disease is an inflammatory disease of the tissues supporting (gingiva, root cement, periodontal ligament and alveolar bone). In Latin America, PD affects between 30 and 40% of the population, and it is estimated that 1 to 5 women will develop PD during pregnancy. It has been shown that there is a direct relationship between the aggravation of PD and pregnancy. This is due to hormonal changes during gestation, which promote the excessive growth of pathogenic microorganisms responsible for gingival inflammation.These pathogenic microorganisms include Prevotella intermedia and Porphyromonas gingivalis. The latter, together with Fusobacterium nucleatum. are able to cross the placental barrier causing infections and adverse preg-nancy outcomes, such as premature birth, preeclampsia, fetal death and metrial arteritis. (AU)


Assuntos
Humanos , Feminino , Doenças Periodontais , Gravidez , Microbiota , Rotas de Resultados Adversos , Gengivite
5.
Chemosphere ; 231: 249-255, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129406

RESUMO

Increasing concern over microplastics has recently brought increased attention to studies on microplastic toxicity. Here, we conduct a systematic review on toxicity of microplastics that focuses on identifying data gaps in the mechanisms of microplastic toxicity. We observe that microplastic toxicology research thus far has focused on ecotoxicity using apical endpoints and only a few studies deal with toxicity mechanisms. Based on this review, we propose putative Adverse Outcome Pathways (AOPs) applicable to microplastic management to understand microplastic toxicity. We matched toxicity mechanisms and apical endpoints to a key event (KE) and adverse outcome (AO) information from the AOP Wiki. Overall, our results suggest that the molecular initiating event (MIE) was reactive oxygen species (ROS) formation and the AO was increased mortality, decreased growth and feeding, and reproduction failure. However, there are a limited number of studies on toxicity mechanisms of microplastics and, therefore, evidence concerning the relationship between KEs is not sufficient. Clearly, more studies on toxicity mechanisms are required to fill these gaps in data. This study also suggests that the AOP framework is a suitable tool to integrate existing data from various literature sources and can identify data gaps in microplastic toxicity mechanisms.


Assuntos
Rotas de Resultados Adversos , Poluentes Ambientais/toxicidade , Plásticos/toxicidade
6.
Environ Res ; 175: 235-256, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31146096

RESUMO

Human biomonitoring measures the concentrations of environmental chemicals or their metabolites in body fluids or tissues. Complementing exposure biomarkers with mechanistically based effect biomarkers may further elucidate causal pathways between chemical exposure and adverse health outcomes. We combined information on effect biomarkers previously implemented in human observational studies with mechanisms of action reported in experimental studies and with information from published Adverse Outcome Pathways (AOPs), focusing on adverse reproductive effects of phthalate exposure. Phthalates constitute a group of chemicals that are ubiquitous in consumer products and have been related to a wide range of adverse health effects. As a result of a comprehensive literature search, we present an overview of effect biomarkers for reproductive toxicity that are substantiated by mechanistic information. The activation of several receptors, such as PPARα, PPARγ, and GR, may initiate events leading to impaired male and female fertility as well as other adverse effects of phthalate exposure. Therefore, these receptors appear as promising targets for the development of novel effect biomarkers. The proposed strategy connects the fields of epidemiology and toxicology and may strengthen the weight of evidence in observational studies that link chemical exposures to health outcomes.


Assuntos
Rotas de Resultados Adversos , Poluentes Ambientais/toxicidade , Ácidos Ftálicos/toxicidade , Biomarcadores/metabolismo , Exposição Ambiental , Feminino , Humanos , Masculino , Reprodução/efeitos dos fármacos
7.
Environ Health Perspect ; 127(4): 47005, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30994381

RESUMO

BACKGROUND: Available toxicity data can be optimally interpreted if they are integrated using computational approaches such as systems biology modeling. Such approaches are particularly warranted in cases where regulatory decisions have to be made rapidly. OBJECTIVES: The study aims at developing and applying a new integrative computational strategy to identify associations between bisphenol S (BPS), a substitute for bisphenol A (BPA), and components of adverse outcome pathways (AOPs). METHODS: The proposed approach combines a text mining (TM) procedure and integrative systems biology to comprehensively analyze the scientific literature to enrich AOPs related to environmental stressors. First, to identify relevant associations between BPS and different AOP components, a list of abstracts was screened using the developed text-mining tool AOP-helpFinder, which calculates scores based on the graph theory to prioritize the findings. Then, to fill gaps between BPS, biological events, and adverse outcomes (AOs), a systems biology approach was used to integrate information from the AOP-Wiki and ToxCast databases, followed by manual curation of the relevant publications. RESULTS: Links between BPS and 48 AOP key events (KEs) were identified and scored via 31 references. The main outcomes were related to reproductive health, endocrine disruption, impairments of metabolism, and obesity. We then explicitly analyzed co-mention of the terms BPS and obesity by data integration and manual curation of the full text of the publications. Several molecular and cellular pathways were identified, which allowed the proposal of a biological explanation for the association between BPS and obesity. CONCLUSIONS: By analyzing dispersed information from the literature and databases, our novel approach can identify links between stressors and AOP KEs. The findings associating BPS and obesity illustrate the use of computational tools in predictive toxicology and highlight the relevance of the approach to decision makers assessing substituents to toxic chemicals. https://doi.org/10.1289/EHP4200.


Assuntos
Rotas de Resultados Adversos , Mineração de Dados , Medição de Risco/métodos , Biologia de Sistemas , Humanos , Fenóis , Sulfonas
8.
Integr Environ Assess Manag ; 15(4): 633-647, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30908812

RESUMO

There have been increasing demands for chemical hazard and risk assessments in recent years. Chemical companies have expanded internal product stewardship initiatives, and jurisdictions have increased the regulatory requirements for the manufacture and sale of chemicals. There has also been a shift in chemical toxicity evaluations within the same time frame, with new methodologies being developed to improve chemical safety assessments for both human health and the environment. With increased needs for chemical assessments coupled with more diverse data streams from new technologies, regulators and others tasked with chemical management activities are faced with increasing workloads and more diverse types of data to consider. The Adverse Outcome Pathway (AOP) framework can be applied in different scenarios to integrate data and guide chemical assessment and management activities. In this paper, scenarios of how AOPs can be used to guide chemical management decisions during research and development, chemical registration, and subsequent regulatory activities such as prioritization and risk assessment are considered. Furthermore, specific criteria (e.g., the type and level of AOP complexity, confidence in the AOP, as well as external review and assay validation) are proposed to examine whether AOPs and associated tools are fit for purpose when applied in different contexts. Certain toxicity pathways are recommended as priority areas for AOP research and development, and the continued use of AOPs and defined approaches in regulatory activities are recommended. Furthermore, a call for increased outreach, education, and enhanced use of AOP databases is proposed to increase their utility in chemicals management. Integr Environ Assess Manag 2019;15:633-647. © 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Assuntos
Rotas de Resultados Adversos/estatística & dados numéricos , Ecotoxicologia/métodos , Política Ambiental/legislação & jurisprudência , Regulamentação Governamental , Substâncias Perigosas , Bases de Dados Factuais/estatística & dados numéricos , Tomada de Decisões , Humanos , Medição de Risco/métodos
9.
Chemosphere ; 224: 588-596, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30844590

RESUMO

Tetrabromobisphenol A (TBBPA) is ubiquitous and its contents showing an increasing trend in the coastal environment. In order to investigate the effects of TBBPA on marine bivalves, juvenile manila clams Ruditapes phillipinarum were exposed to TBBPA for 28 days. The results showed that shell growth rate of juvenile clams after exposure to 62.5-1000 µg L-1 TBBPA for 28 d were significantly inhibited (p < 0.05). Then in order to link the changes in filtration rate, mRNA expression of insulin-like growth factor homologue (IGF) and tissue thyroid hormone (TH) contents to growth, juvenile clams were exposed to 62.5 and 500 µg L-1 TBBPA for 14 days. The transcriptional levels of neuroendocrine signals (NPF and insulin homologue) associated with filter feeding regulation, and genes of TH synthesis-related enzymes were also examined. The results showed that filtration rates was significantly reduced to 44.1% and 14% of controls after 14 d of exposure. In parallel, exposure to TBBPA significantly increased the expression levels of insulin which may elicit the filter feeding inhibition. TBBPA exposure caused alterations in tissue content of THs and mRNA expression of TH synthesis-related enzymes. However, the data showed increased T3 content, T3/T4 ratio and mRNA expression of IGF. These data demonstrated that the most important key event of TBBPA could be linked to growth impairment in juveniles was the reduction of filtration rate. These results provide a robust framework towards revealing the underlying mechanism of the growth inhibition caused by TBBPA on bivalves and understanding the adverse outcome pathway across taxonomic phyla.


Assuntos
Rotas de Resultados Adversos , Bivalves/crescimento & desenvolvimento , Regulação da Expressão Gênica/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bivalves/efeitos dos fármacos , Bivalves/metabolismo , Hormônios Tireóideos/metabolismo
10.
Reprod Toxicol ; 85: 12-18, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30668982

RESUMO

There is growing concern that increased use of medical and recreational cannabis may result in increased exposure to contaminants on the cannabis, such as pesticides. Several states are moving towards implementing robust regulation of the sales, cultivation, and manufacture of cannabis products. However, there are challenges with creating health-protective regulations in an industry that, to date, has been largely unregulated. The focus of this publication is a theoretical examination of what may happen when women are exposed pre-conceptually or during pregnancy to cannabis contaminated with pesticides. We propose an adverse outcome pathway of concomitant prenatal exposure to cannabinoids and the organophosphate pesticide chlorpyrifos by curating what we consider to be the key events at the molecular, cellular, and tissue levels that result in developmental neurotoxicity. The implications of this adverse outcome pathway underscore the need to elucidate the potential developmental neurotoxicity that may result from prenatal exposure to pesticide-contaminated cannabis.


Assuntos
Rotas de Resultados Adversos , Cannabis , Síndromes Neurotóxicas/etiologia , Compostos Organofosforados/toxicidade , Resíduos de Praguicidas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Feminino , Humanos , Uso da Maconha/efeitos adversos , Troca Materno-Fetal , Gravidez
11.
ALTEX ; 36(3): 353-362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662994

RESUMO

The adverse outcome pathway (AOP) framework is a conceptual construct that mechanistically links molecular initiating events to adverse biological outcomes through a series of causal key events (KEs) that represent the perturbation of the biological system. Quantitative, predictive AOPs are necessary for screening emerging contaminants and potential substitutes to inform their prioritization for testing. In practice, they are not widely used because they can be costly to develop and validate. A modular approach for assembly of quantitative AOPs, based on existing knowledge, would allow for rapid development of biological pathway models to screen contaminants for potential hazards and prioritize them for subsequent testing and modeling. For each pair of KEs, a quantitative KE relationship (KER) can be derived as a response-response function or a conditional probability matrix describing the anticipated change in a KE based on the response of the prior KE. This transfer of response across KERs can be used to assemble a quantitative AOP. Here we demonstrate the use of proposed approach in two cases: inhibition of cytochrome P450 aromatase leading to reduced fecundity in fathead minnows and ionic glutamate receptor mediated excitotoxicity leading to memory impairment in rodents. The model created from these chains have value in characterizing the pathway and the potential or relative level of toxicological effect anticipated. This approach to simplistic, modular AOP models has wide applicability for rapid development of biological pathway models.


Assuntos
Rotas de Resultados Adversos , Pesquisa Biomédica , Toxicologia , Animais , Humanos
12.
Chemosphere ; 220: 774-782, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30611076

RESUMO

Adverse outcome pathways (AOP) have been proposed as a new method to improve the ecological risk assessment of pollutants, but it requires quantitation linkage between exposure, biomarker response and toxicity of pollutants. A toxicokinetic and toxicodynamic (TK-TD) model was used to quantify AOP of the toxicity of Cd and Pb to zebrafish, including the quantitative relationship between Cd and Pb accumulation in gill and oxidative damage level based on ROS or MDA, and LC50 values at different times. Significant relationships were found between the oxidative damage level characterized by ROS and MDA content and Cd or Pb accumulation in gill (R2 > 0.60), and the TK model could better simulate the Pb accumulation in the gills (R2 > 0.60) than Cd. The increasing of Cd or Pb concentrations induced the generation of ROS and the formation of ROS initiated the fluctuation of MDA level in the cells as compared to controls (p < 0.05). For the individual level effect, the Damage Assessment Model (DAM) could successfully explain the change of LC50-ROS and LC50-MDA values at different times (R2 > 0.99). Our findings suggested that the TK-TD model based on ROS and MDA could be used as a quantitative AOP to predict toxicity of metals to zebrafish.


Assuntos
Metais Pesados/toxicidade , Estresse Oxidativo , Toxicocinética , Peixe-Zebra/metabolismo , Rotas de Resultados Adversos , Animais , Cádmio/metabolismo , Cádmio/toxicidade , Chumbo/metabolismo , Chumbo/toxicidade , Metais Pesados/metabolismo
13.
Environ Toxicol Chem ; 38(1): 27-45, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30259559

RESUMO

Adverse outcome pathways (AOPs) link toxicity across levels of biological organization, and thereby facilitate the development of suborganismal responses predictive of whole-organism toxicity and provide the mechanistic information necessary for science-based extrapolation to population-level effects. Thus far AOPs have characterized various acute and chronic toxicity pathways; however, the potential for AOPs to explicitly characterize indirect, energy-mediated effects from toxicants has yet to be fully explored. Indeed, although exposure to contaminants can alter an organism's energy budget, energetic endpoints are rarely incorporated into ecological risk assessment because there is not an integrative framework for linking energetic effects to organismal endpoints relevant to risk assessment (e.g., survival, reproduction, growth). In the present analysis, we developed a generalized bioenergetics-AOP in an effort to make better use of energetic endpoints in risk assessment, specifically exposure scenarios that generate an energetic burden to organisms. To evaluate empirical support for a bioenergetics-AOP, we analyzed published data for links between energetic endpoints across levels of biological organization. We found correlations between 1) cellular energy allocation and whole-animal growth, and 2) metabolic rate and scope for growth. Moreover, we reviewed literature linking energy availability to nontraditional toxicological endpoints (e.g., locomotor performance), and found evidence that toxicants impair aerobic performance and activity. We conclude by highlighting current knowledge gaps that should be addressed to develop specific bioenergetics-AOPs. Environ Toxicol Chem 2019;38:27-45. © 2018 SETAC.


Assuntos
Rotas de Resultados Adversos , Metabolismo Energético , Animais , Crescimento e Desenvolvimento , Locomoção , Modelos Teóricos , Medição de Risco
14.
ALTEX ; 36(1): 91-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30332685

RESUMO

Current efforts in chemical safety are focused on utilizing human in vitro or alternative animal data in biological pathway context. However, it remains unclear how biological pathways, and toxicology data developed in that context, can be used to quantitatively facilitate decision-making.  The objective of this work is to determine if hypothesis testing using Adverse Outcome Pathways (AOPs) can provide quantitative chemical hazard predictions.  Current methods for predicting hazards of chemicals in a biological pathway context were extensively reviewed, specific case studies examined and computational modeling used to demonstrate quantitative hazard prediction based on an AOP. Since AOPs are chemically agnostic, we propose that AOPs function as hypotheses for how specific chemicals may cause adverse effects via specific pathways. Three broad approaches were identified for testing the hypothesis with AOPs, semi-quantitative weight of evidence, probabilistic, and mechanistic modeling. We then demonstrate how these approaches could be used to test hypotheses using high throughput in vitro data and alternative animal data. Finally, we discuss standards in development and documentation that would facilitate use in a regulatory context. We conclude that quantitative AOPs provide a flexible hypothesis framework for predicting chemical hazards. It accommodates a wide range of approaches that are useful at many stages and build upon one another to become increasingly quantitative.


Assuntos
Rotas de Resultados Adversos , Alternativas aos Testes com Animais , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Substâncias Perigosas/toxicidade , Animais , Tomada de Decisões , Humanos , Projetos de Pesquisa , Medição de Risco
15.
Int J Radiat Biol ; 95(2): 225-232, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30373433

RESUMO

PURPOSE: In 2012, the Organization for Economic Cooperation and Development (OECD) formally launched the Adverse Outcome Pathway (AOP) Programme. The AOP framework has the potential for predictive utility in identifying early biological endpoints linked to adverse effects. It uses the weight of correlative evidence to identify a minimal set of measurable key events that link molecular initiating events to an adverse outcome. AOPs have the capability to identify knowledge gaps and priority areas for future research based on relevance to an adverse outcome. In addition, AOPs can identify pathways that are common among multiple stressors, thereby allowing for the possibility of refined risk assessments based on co-exposure considerations. The AOP framework is increasingly being used in chemical and ecological risk assessment; however, its use in the development of radiation-specific pathways has yet to be fully explored. To bring awareness of the AOP framework to the Canadian radiation community, a workshop was held in Canada in June 2018 that brought together radiation experts from Health Canada, the Canadian Nuclear Laboratories, and the Canadian Nuclear Safety Commission. METHODS: The purpose of the workshop was to share knowledge on the AOP framework, specifically (1) to introduce the concept of the AOP framework and its possible utility to Canadian radiation experts; (2) to provide examples on how it has advanced risk assessment; (3) to discuss an illustrative example specific to ionizing radiation; and lastly (4) to identify the broad benefits and challenges of the AOP framework to the radiation community. RESULTS: The participants showed interest in the framework, case examples were described and areas of challenge were identified. Herein, we summarize the outcomes of the workshop. CONCLUSIONS: Overall, participants agreed that by building AOPs in the radiation field, a network of data-sharing initiatives will enhance our interpretation of existing knowledge where current scientific evidence is minimal. They would provide new avenues to understand effects at low-dose and dose-rates and help to quantify the combined effect of multiple stressors on shared mechanistic pathways.


Assuntos
Rotas de Resultados Adversos , Proteção Radiológica , Humanos , Doses de Radiação , Medição de Risco
16.
J Eval Clin Pract ; 25(1): 88-96, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30088321

RESUMO

RATIONALE, AIMS, AND OBJECTIVES: Medication-related problems are frequent and can lead to serious adverse events resulting in increased morbidity, mortality, and costs. Medication use in frail older patients is even more complex. The aim of this study was to investigate the effect of a pharmacist-led medicines management model among older patients at admission, during inpatient stay and at discharge on medication-related readmissions. METHOD: A randomized controlled trial conducted at the acute admission unit in a Danish hospital with acutely admitted medical patients, randomized to either a control group or one of two intervention groups. The intervention consisted of pharmacist-led medication review and patient interview upon admission (intervention ED) or pharmacist-led medication review and patient interview upon admission, medication review during inpatient stay, and medication report and patient counselling at discharge (intervention STAY). RESULTS: In total, 600 patients were included. The pharmacist identified 920 medication-related problems with 57% of the recommendations accepted by the physician. After 30 days, 25 patients had a medication-related readmission, with no statistical significant difference between the groups on either primary or secondary outcomes. CONCLUSIONS: This study showed that a clinical pharmacist can be used to identify and solve medication-related problems, but this study did not find any effect on the selected outcomes. The frequency of medication-related readmissions was low, leaving little room for improvement. Future research should consider other study designs or outcome measures.


Assuntos
Rotas de Resultados Adversos/estatística & dados numéricos , Conduta do Tratamento Medicamentoso , Readmissão do Paciente/estatística & dados numéricos , Farmacêuticos , Serviço de Farmácia Hospitalar/métodos , Idoso , Dinamarca , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Reconciliação de Medicamentos/métodos , Conduta do Tratamento Medicamentoso/organização & administração , Conduta do Tratamento Medicamentoso/normas , Alta do Paciente/estatística & dados numéricos , Papel Profissional , Melhoria de Qualidade
17.
Toxicol In Vitro ; 54: 23-32, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30196099

RESUMO

The integration of existing knowledge to support the risk assessment of chemicals is an ongoing challenge for scientists, risk assessors and risk managers. In addition, European Union regulations limiting the use of new animal testing in cosmetics makes already existing information even more valuable. Applying a previous SEURAT-1 program framework to derive predictions of in vivo toxicity responses for a compound, we selected piperonyl butoxide (PBO) as a case study for identification of knowledge and methodology gaps in understanding a compound's effects on the human liver. This is investigated through integration of data from human in vitro transcriptomics studies, biological pathway analysis, chemical and disease associations, and adverse outcome pathway (AOP) information. The outcomes of the analysis are used to generate AOPs of liver-related endpoints, identifying areas of concern for risk assessors and regulators. We demonstrate that integration of data through already existing and publicly available tools can produce outcomes comparable to those that may be found through more conventional time- and resource-intensive methods. It is also expected that, with more refinement, this approach could in the future provide evidence to support chemical risk assessment, while also identifying data gaps for which additional testing may be needed.


Assuntos
Rotas de Resultados Adversos , Fígado/efeitos dos fármacos , Sinergistas de Praguicidas/toxicidade , Butóxido de Piperonila/toxicidade , Alternativas aos Testes com Animais , Células Hep G2 , Humanos , Hepatopatias/etiologia
18.
J Toxicol Environ Health A ; 81(18): 893-912, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30230972

RESUMO

The aim of this study was to establish a process for deriving a chemical-specific mode of action (MOA) from chemical-agnostic adverse outcome pathway (AOPs), using inorganic arsenic (iAs) as a case study. The AOP developed for this case study are related to disruption of cellular signaling by chemicals that strongly bind to vicinal dithiols in cellular proteins, leading to disruption of inflammatory and oxidative stress signaling along with inhibition of the DNA damage responses. The proposed MOA for iAs incorporates this AOP, overlaid on a background of increasing oxidative stress and/or co-exposure to mutagenic chemicals or radiation. The most challenging aspect of developing a MOA from AOP is the incorporation of metabolism and dose-response, neither of which may be considered in the development of an AOP. The cellular responses to relatively low concentrations (below 100 parts per billion) of iAs in drinking water appear to be secondary to binding of trivalent arsenite and its trivalent metabolite, monomethyl arsenous acid to key cellular vicinal dithiols in target tissues, resulting in a co-carcinogenic MOA. The proposed AOP may also be applied to non-cancer endpoints, enabling an integrated approach to conducting a risk assessment for iAs.


Assuntos
Rotas de Resultados Adversos , Arsenicais/efeitos adversos , Intoxicação por Arsênico/metabolismo , Arsenicais/metabolismo , Humanos , Medição de Risco/métodos
19.
Chem Res Toxicol ; 31(8): 784-798, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29995386

RESUMO

Adverse outcome pathways (AOPs) describe causal relationships between molecular perturbation and adverse cellular effects and are being increasingly adopted for linking in vitro mechanistic toxicology to in vivo data from regulatory toxicity studies. In this work, a case study was performed by developing a bioassay toolbox to assess key events in the recently proposed AOP for chemically induced liver steatosis. The toolbox is comprised of in vitro assays to measure nuclear receptor activation, gene and protein expression, lipid accumulation, mitochondrial respiration, and formation of fatty liver cells. Assay evaluation was performed in human HepaRG hepatocarcinoma cells exposed to the model compound cyproconazole, a fungicide inducing steatosis in rodents. Cyproconazole dose-dependently activated RARα and PXR, two molecular initiating events in the steatosis AOP. Moreover, cyproconazole provoked a disruption of mitochondrial functions and induced triglyceride accumulation and the formation of fatty liver cells as described in the AOP. Gene and protein expression analysis, however, showed expression changes different from those proposed in the AOP, thus suggesting that the current version of the AOP might not fully reflect the complex mechanisms linking nuclear receptor activation and liver steatosis. Our study shows that cyproconazole induces steatosis in human liver cells in vitro and demonstrates the utility of systems-based approaches in the mechanistic assessment of molecular and cellular key events in an AOP. AOP-driven in vitro testing as demonstrated can further improve existing AOPs, provide insight regarding molecular mechanisms of toxicity, and inform predictive risk assessment.


Assuntos
Rotas de Resultados Adversos , Fígado Gorduroso/induzido quimicamente , Fungicidas Industriais/toxicidade , Triazóis/toxicidade , Bioensaio , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Fígado Gorduroso/metabolismo , Expressão Gênica , Células HEK293 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Mitocôndrias Hepáticas/efeitos dos fármacos , Modelos Biológicos , Reação em Cadeia da Polimerase , Receptores Citoplasmáticos e Nucleares/metabolismo , Medição de Risco , Triglicerídeos/metabolismo
20.
Toxicol Sci ; 165(1): 213-223, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020496

RESUMO

Molecular initiating events (MIEs) are important concepts for in silico predictions. They can be used to link chemical characteristics to biological activity through an adverse outcome pathway (AOP). In this work, we capture chemical characteristics in 2D structural alerts, which are then used as models to predict MIEs. An automated procedure has been used to identify these alerts, and the chemical categories they define have been used to provide quantitative predictions for the activity of molecules that contain them. This has been done across a diverse group of 39 important pharmacological human targets using open source data. The alerts for each target combine into a model for that target, and these models are joined into a tool for MIE prediction with high average model performance (sensitivity = 82%, specificity = 93%, overall quality = 93%, Matthews correlation coefficient = 0.57). The result is substantially improved from our previous study (Allen, T. E. H., Goodman, J. M., Gutsell, S., and Russell, P. J. 2016. A history of the molecular initiating event. Chem. Res. Toxicol. 29, 2060-2070) for which the mean sensitivity for each target was only 58%. This tool provides the first step in an AOP-based risk assessment, linking chemical structure to toxicity endpoint.


Assuntos
Rotas de Resultados Adversos , Bases de Dados de Produtos Farmacêuticos , Preparações Farmacêuticas/química , Simulação por Computador , Humanos , Estrutura Molecular , Medição de Risco , Relação Estrutura-Atividade
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