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1.
ALTEX ; 39(1): 3-29, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35034131

RESUMO

Safety sciences must cope with uncertainty of models and results as well as information gaps. Acknowledging this uncer-tainty necessitates embracing probabilities and accepting the remaining risk. Every toxicological tool delivers only probable results. Traditionally, this is taken into account by using uncertainty / assessment factors and worst-case / precautionary approaches and thresholds. Probabilistic methods and Bayesian approaches seek to characterize these uncertainties and promise to support better risk assessment and, thereby, improve risk management decisions. Actual assessments of uncertainty can be more realistic than worst-case scenarios and may allow less conservative safety margins. Most importantly, as soon as we agree on uncertainty, this defines room for improvement and allows a transition from traditional to new approach methods as an engineering exercise. The objective nature of these mathematical tools allows to assign each methodology its fair place in evidence integration, whether in the context of risk assessment, sys-tematic reviews, or in the definition of an integrated testing strategy (ITS) / defined approach (DA) / integrated approach to testing and assessment (IATA). This article gives an overview of methods for probabilistic risk assessment and their application for exposure assessment, physiologically-based kinetic modelling, probability of hazard assessment (based on quantitative and read-across based structure-activity relationships, and mechanistic alerts from in vitro studies), indi-vidual susceptibility assessment, and evidence integration. Additional aspects are opportunities for uncertainty analysis of adverse outcome pathways and their relation to thresholds of toxicological concern. In conclusion, probabilistic risk assessment will be key for constructing a new toxicology paradigm - probably!


Assuntos
Toxicologia , Teorema de Bayes , Medição de Risco , Incerteza
2.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638555

RESUMO

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 Células
3.
J Med Toxicol ; 17(4): 333-362, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34535889

RESUMO

The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology in 2010. The registry collects data from participating sites with the agreement that all bedside and telehealth medical toxicology consultation will be entered. This eleventh annual report summarizes the Registry's 2020 data and activity with its additional 6668 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from January 1 to December 31, 2020. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. Gender distribution included 50.6% cases in females, 48.4% in males, and 1.0% identifying as transgender. Non-opioid analgesics were the most commonly reported agent class, followed by opioid and antidepressant classes. Acetaminophen was once again the most common agent reported. There were 80 fatalities, comprising 1.2% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years' reports. Sub-analyses were conducted to describe race and ethnicity demographics and exposures in the registry, telemedicine encounters, and cases related to the COVID-19 pandemic.


Assuntos
Congressos como Assunto , Substâncias Perigosas/toxicidade , Envenenamento/diagnóstico , Envenenamento/terapia , Sistema de Registros/estatística & dados numéricos , Relatório de Pesquisa , Toxicologia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Canadá , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Pandemias/estatística & dados numéricos , SARS-CoV-2 , Tailândia , Estados Unidos
4.
J Chromatogr A ; 1654: 462450, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34399142

RESUMO

An Electrokinetic Chromatography method was developed for the stereoselective analysis of sulfoxaflor, a novel sulfoximine agrochemical with two chiral centers. A screening with fourteen negatively charged CDs was performed and Succinyl-ß-CD (Succ-ß-CD) was selected. A 15 mM concentration of this CD in a 100 mM borate buffer (pH 9.0), using an applied voltage of 20 kV and a temperature of 15 °C made possible the baseline separation of the four stereoisomers of sulfoxaflor in 13.8 min. The evaluation of the linearity, accuracy, precision, LODs and LOQs of the method developed showed its performance to be applied to the analysis of commercial agrochemical formulations, the evaluation of the stability of sulfoxaflor stereoisomers under biotic and abiotic conditions, and to predict, for the first time, sulfoxaflor toxicity (using real concentrations instead of nominal concentrations), on two non-target aquatic organisms, the freshwater plant, Spirodela polyrhiza, and the marine bacterium, Vibrio fischeri.


Assuntos
Cromatografia Capilar Eletrocinética Micelar , Piridinas , Compostos de Enxofre , Aliivibrio fischeri/efeitos dos fármacos , Araceae/efeitos dos fármacos , Estabilidade de Medicamentos , Piridinas/isolamento & purificação , Piridinas/toxicidade , Estereoisomerismo , Compostos de Enxofre/isolamento & purificação , Compostos de Enxofre/toxicidade , Toxicologia
5.
PLoS Comput Biol ; 17(7): e1009135, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34214078

RESUMO

There are currently 85,000 chemicals registered with the Environmental Protection Agency (EPA) under the Toxic Substances Control Act, but only a small fraction have measured toxicological data. To address this gap, high-throughput screening (HTS) and computational methods are vital. As part of one such HTS effort, embryonic zebrafish were used to examine a suite of morphological and mortality endpoints at six concentrations from over 1,000 unique chemicals found in the ToxCast library (phase 1 and 2). We hypothesized that by using a conditional generative adversarial network (cGAN) or deep neural networks (DNN), and leveraging this large set of toxicity data we could efficiently predict toxic outcomes of untested chemicals. Utilizing a novel method in this space, we converted the 3D structural information into a weighted set of points while retaining all information about the structure. In vivo toxicity and chemical data were used to train two neural network generators. The first was a DNN (Go-ZT) while the second utilized cGAN architecture (GAN-ZT) to train generators to produce toxicity data. Our results showed that Go-ZT significantly outperformed the cGAN, support vector machine, random forest and multilayer perceptron models in cross-validation, and when tested against an external test dataset. By combining both Go-ZT and GAN-ZT, our consensus model improved the SE, SP, PPV, and Kappa, to 71.4%, 95.9%, 71.4% and 0.673, respectively, resulting in an area under the receiver operating characteristic (AUROC) of 0.837. Considering their potential use as prescreening tools, these models could provide in vivo toxicity predictions and insight into the hundreds of thousands of untested chemicals to prioritize compounds for HT testing.


Assuntos
Biologia Computacional , Ensaios de Triagem em Larga Escala , Redes Neurais de Computação , Toxicologia , Animais , Embrião não Mamífero/efeitos dos fármacos , Modelos Químicos , Testes de Toxicidade , Peixe-Zebra
6.
J Anal Toxicol ; 45(8): 757, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34296274
7.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207930

RESUMO

Jacek Namiesnik, who died at the age of 69, was one of the most influential analytical chemists in Poland at the second half of the 20th century and the first two decades of the 21st century [...].


Assuntos
Técnicas de Química Analítica/métodos , Pesquisadores/história , Toxicologia/métodos , Vinho/análise , História do Século XX , História do Século XXI , Humanos , Polônia
8.
San Salvador; MINSAL; jul. 13, 2021. 14 p. ilus, graf.
Não convencional em Espanhol | LILACS, BISSAL | ID: biblio-1283710

RESUMO

El presente manual tiene como Objetivo establecer las directrices que permitan la toma de decisiones oportunas para la respuesta a brotes de intoxicaciones y/o desastres químicos, además de comunicar la información para lograr una acción de prevención y control más efectiva en los diferentes niveles del Sistema Nacional Integrado de Salud


The objective of this manual is to establish the guidelines that allow timely decision-making to respond to outbreaks of poisoning and / or chemical disasters, in addition to communicating the information to achieve a more effective prevention and control action at the different levels of the System. National Integrated Health


Assuntos
Toxicologia , Saúde , Tomada de Decisões , Desastres , Informação
9.
Yakugaku Zasshi ; 141(6): 813-816, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34078786

RESUMO

For human health and welfare, toxicology/safety science is a branch of the pharmaceutical sciences dealing with the risk or benefit of pharmaceutical products derived from organic compounds, proteins, and genes, as well as chemicals contained in cosmetics or food additives. The quality of pharmaceutical products is one of the factors that decide risk or benefit, so quality assurance based on regulatory science is an important research and education area in the field of toxicology/safety science.


Assuntos
Biofarmácia , Preparações Farmacêuticas , Garantia da Qualidade dos Cuidados de Saúde , Controle de Qualidade , Segurança , Toxicologia , Cosméticos/química , Aditivos Alimentares/química , Humanos , Preparações Farmacêuticas/química , Medição de Risco
10.
Crit Rev Toxicol ; 51(3): 264-282, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-34038674

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA that regulate the expression of messenger RNA and are implicated in almost all cellular processes. Importantly, miRNAs can be released extracellularly and are stable in these matrices where they may serve as indicators of organ or cell-specific toxicity, disease, and biological status. There has thus been great enthusiasm for developing miRNAs as biomarkers of adverse outcomes for scientific, regulatory, and clinical purposes. Despite advances in measurement capabilities for miRNAs, miRNAs are still not routinely employed as noninvasive biomarkers. This is in part due to the lack of standard approaches for sample preparation and miRNA measurement and uncertainty in their biological interpretation. Members of the microRNA Biomarkers Workgroup within the Health and Environmental Sciences Institute's (HESI) Committee on Emerging Systems Toxicology for the Assessment of Risk (eSTAR) are a consortium of private- and public-sector scientists dedicated to developing miRNAs as applied biomarkers. Here, we explore major impediments to routine acceptance and use of miRNA biomarkers and case examples of successes and deficiencies in development. Finally, we provide insight on miRNA measurement, collection, and analysis tools to provide solid footing for addressing knowledge gaps toward routine biomarker use.


Assuntos
Biomarcadores , MicroRNAs , Toxicologia , Humanos
12.
J Med Toxicol ; 17(3): 271-277, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33844171

RESUMO

INTRODUCTION: The American Board of Emergency Medicine identifies medical toxicology as an essential curricular element for emergency medicine (EM) residencies; however, access to medical toxicology education varies widely by institution. We hypothesized that EM residents are uncomfortable with core toxicology content and would be interested in  a dedicated toxicology curriculum. METHODS: An electronic needs assessment survey developed by experts in EM and medical toxicology was sent to residents and program leadership at nine EM programs participating in the Emergency Medicine Education Research Alliance (EMERA), a geographically diverse sampling of academic EM residency programs. We queried the presence of a current toxicology curriculum, interest in a dedicated toxicology curriculum, and comfort with core toxicology concepts for board examinations and in clinical practice.  RESULTS: A total of 148 residents and 8 faculty leadership completed the survey.  Only 29% of resident respondents felt comfortable with toxicology concepts, and only 66% of respondents reported access to a toxicology curriculum. Of those without a known toxicology curriculum, most were interested in a formal curriculum. Faculty respondents reported 6/8 programs offered a toxicology curriculum. Faculty at the two programs without a formal curriculum expressed interest in a dedicated curriculum. CONCLUSIONS: Emergency medicine residents remain uncomfortable with the core toxicology content in clinical practice. The majority of residents without a known toxicology curriculum would be interested in a dedicated toxicology curriculum.


Assuntos
Currículo , Educação de Pós-Graduação em Medicina/organização & administração , Medicina de Emergência/educação , Internato e Residência/organização & administração , Toxicologia/educação , Adulto , Feminino , Humanos , Masculino , Estados Unidos , Adulto Jovem
13.
Braz J Med Biol Res ; 54(5): e11177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33825779

RESUMO

Women have always played an important role in the development of toxicology all over the world. Specifically in Brazil, toxicology has had greater female representation than other countries, but women's participation at high hierarchical levels is low. Although more than 62% of the members of the Brazilian Society of Toxicology are women, only 7 out of the 22 presidents have been women throughout its 48 years of existence. This article aims to celebrate women in the field of toxicology in Brazil, based on interviews with five of these scientists who have changed the field of toxicology in Brazil as we know it today, each in their specific sub-areas. These women are: Dr. Ester de Camargo Fonseca Moraes, Dr. Silvia Berlanga de Moraes Barros, Dr. Alice Aparecida da Matta Chasin, Dr. Gisela de Aragão Umbuzeiro, and Dr. Tania Marcourakis. They are not only pioneers but they are also examples of admirable persistence in fighting the adversities presented to them. They broke the glass ceiling and opened doors for future generations of women in science. We hope that this article helps inspire women in their careers in toxicology.


Assuntos
Toxicologia , Brasil , Feminino , Humanos , Toxicologia/tendências
15.
West J Emerg Med ; 22(2): 450-453, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33856338

RESUMO

Poisoning and envenomation are a global health problem for which the mortality burden is shouldered heavily by middle- and low-income countries that often lack poison prevention programs and medical toxicology expertise. Although telehealth or teleconsult services have been used to bridge the expertise gap between countries for multiple specialties, the use of medical toxicology teleconsult services across borders has been limited. We aim to describe the use of a United States-based medical toxicology teleconsult service to support patient care at a hospital in a middle-income country that lacks this expertise. This report outlines the logistics involved in setting up such a service, including the challenges and opportunities that emerged from establishing medical toxicology teleconsult service in a low-resource setting.


Assuntos
Envenenamento , Consulta Remota , Toxicologia , Países em Desenvolvimento , Prova Pericial/métodos , Humanos , Cooperação Internacional , Líbano/epidemiologia , Envenenamento/diagnóstico , Envenenamento/epidemiologia , Envenenamento/terapia , Consulta Remota/métodos , Consulta Remota/organização & administração , Toxicologia/métodos , Toxicologia/organização & administração , Estados Unidos
16.
J Toxicol Sci ; 46(2): 83-90, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33536392

RESUMO

Epigenetic toxicity, a phenomenon in which chemicals exert epigenetic effects and produce toxicity, has been attracting attention in recent years due to advances in toxicology accompanying the development of life sciences. However, it has been difficult to identify epigenetic toxicants due to the lack of a simple experimental system to evaluate epigenetic toxicity. In this study, we developed a prototype of an in vitro reporter assay system for assessing the effects of chemicals on DNA methylation using two promoters showing different degrees of DNA methylation, Agouti IAP and Daz1 promoters, and a luciferase reporter. The system successfully detected DNA demethylating activity using 5-azacytidine, a chemical having DNA demethylation activity, as a positive control chemical, and demethylation of cytosine of CpG in the promoter was confirmed by pyrosequencing analysis. Next, in order to improve the detection sensitivity of the DNA demethylating activity of this system, we tried to increase the basal level of methylation of the Daz1 promoter by pre-methylase treatment of the reporter vectors. As a result, the detection sensitivity of the system was successfully improved in cells where the basal level of methylation was indeed increased by methylase treatment. Thus, the developed assay system here is effective for the simple evaluation of chemicals that affect DNA methylation.


Assuntos
Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Toxicologia/métodos , Azacitidina/toxicidade , Ilhas de CpG/genética , Metilação de DNA/genética , Metilases de Modificação do DNA , Luciferases/genética , Regiões Promotoras Genéticas , Sensibilidade e Especificidade
18.
Expert Opin Drug Metab Toxicol ; 17(8): 887-902, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33612039

RESUMO

INTRODUCTION: Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes is one of the most widely used cell-based models that resulted from the discovery of how non-embryonic stem cells can be differentiated into multiple cell types. In just one decade, iPSC-derived cardiomyocytes went from a research lab to widespread use in biomedical research and preclinical safety evaluation for drugs and other chemicals. AREAS COVERED: This manuscript reviews data on toxicology applications of human iPSC-derived cardiomyocytes. We detail the outcome of a systematic literature search on their use (i) in hazard assessment for cardiotoxicity liabilities, (ii) for risk characterization, (iii) as models for population variability, and (iv) in studies of personalized medicine and disease. EXPERT OPINION: iPSC-derived cardiomyocytes are useful to increase the accuracy, precision, and efficiency of cardiotoxicity hazard identification for both drugs and non-pharmaceuticals, with recent efforts beginning to demonstrate their utility for risk characterization. Notable limitations include the needs to improve the maturation of cells in culture, to better understand their potential use identifying structural cardiotoxicity, and for additional case studies involving population-wide and disease-specific risk characterization. Ultimately, the greatest future benefits are likely for non-pharmaceutical chemicals, filling a critical gap where no routine testing for cardiotoxicity is currently performed.


Assuntos
Cardiotoxicidade/diagnóstico , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Cardiotoxicidade/etiologia , Humanos , Modelos Biológicos , Miócitos Cardíacos/citologia , Testes de Toxicidade/métodos , Toxicologia/métodos
19.
Analyst ; 146(6): 1820-1834, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33605958

RESUMO

Innovative methodological approaches are needed to conduct human health and environmental risk assessments on a growing number of marketed chemicals. Metabolomics is progressively proving its value as an efficient strategy to perform toxicological evaluations of new and existing substances, and it will likely become a key tool to accelerate chemical risk assessments. However, additional guidance with widely accepted and harmonized procedures is needed before metabolomics can be routinely incorporated in decision-making for regulatory purposes. The aim of this review is to provide an overview of metabolomic strategies that have been successfully employed in toxicity assessment as well as the most promising workflows in a regulatory context. First, we provide a general view of the different steps of regulatory toxicology-oriented metabolomics. Emphasis is put on three key elements: robustness of experimental design, choice of analytical platform, and use of adapted data treatment tools. Then, examples in which metabolomics supported regulatory toxicology outputs in different scenarios are reviewed, including chemical grouping, elucidation of mechanisms of toxicity, and determination of points of departure. The overall intention is to provide insights into why and how to plan and conduct metabolomic studies for regulatory toxicology purposes.


Assuntos
Metabolômica , Toxicologia , Humanos , Medição de Risco
20.
Toxicol Sci ; 180(2): 198-211, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33555348

RESUMO

FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (U.S. Environmental Protection Agency [EPA], Strategic plan to promote the development and implementation of alternative test methods within the tsca program, 2018, https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (eg, preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (eg, neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.


Assuntos
Testes de Toxicidade , Toxicologia , Animais , Criança , Simulação por Computador , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Gravidez , Medição de Risco , Estados Unidos , United States Environmental Protection Agency
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