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1.
Ecotoxicol Environ Saf ; 203: 110991, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888602

RESUMO

The stimulant and toxicity effects of reported organic (acetic acid, propionic acid, butyric acid, formic acid, oil & grease) and inorganic (copper) by-products presented in palm oil mill effluent on anaerobic bacterial population were examined in this paper. The toxicity test had shown that acetic, propionic and butyric acids tend to stimulate the bacterial density level (survival rate more than 50%), while formic acid, copper, oil and grease were shown to have suppressed the density level (survival rate less than 50%). The highest biomass recorded was 1.66 mg/L for the concentration of acetic acid at 216 mg/L and lowest biomass concentration, 0.90 mg/L for copper at 1.40 mg/L. Biohydrogen-producing bacteria have a favourable growth rate around pH 5.5. The comparison of half maximal effective concentration (EC50) values between two test duration on the effects of organic and inorganic by-products postulate that bacteria had a higher tolerance towards volatile fatty acids. While acetic, butyric and propionic acids had exhibited higher tolerance EC50 values for bacteria, but the opposite trend was observed for formic acid, copper and oil & grease.


Assuntos
Bactérias Anaeróbias/efeitos dos fármacos , Óleo de Palmeira/toxicidade , Testes de Toxicidade/métodos , Relação Dose-Resposta a Droga , Hidrogênio/metabolismo , Resíduos Industriais/análise
2.
Chemosphere ; 254: 126905, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957298

RESUMO

With the development of modern technologies, the exploitation and application of rare earth metals (REMs) have increased parallelly. Consequently, more REMs are entering into the environment and therefore there is a pressing need to assess their potential environmental hazards. Here, a standard toxicity test with wheat (Triticum aestivum) was conducted to investigate the single and mixture toxicity of La and Ce in solutions with different levels of calcium and nitrilotriacetic acid (NTA) and results were deciphered by different modeling approaches. Both La and Ce caused adverse effect to wheat, but the presence of Ca and NTA alleviated their toxicity. The obtained EC50 for [La] or [Ce] changed by more than 28-fold and by 4-fold, respectively, with the increase of Ca or NTA. The biotic ligand model (BLM) explained approximately 93% variation of single La or Ce toxicity. The binding constants obtained were 4.14, 6.67, and 6.59 for logKCaBL, logKLaBL, and logKCeBL respectively. The electrostatic toxicity model (ETM) was proved as effective as the BLM, with R2 = 0.93 for La and R2 = 0.92 for Ce. For La-Ce mixtures, parameters from single toxicity approaches were applied successfully to predict the mixture toxicity with concentration addition (CA) model based on the BLM or ETM theory (R2 = 0.92 and RMSE = 8.56; R2 = 0.90 and RMSE = 9.6, respectively). Thus, the results obtained in this study prove that both ETM and BLM theories are appropriate to predict single and mixture REMs toxicity, providing coherent and promising tools for the risk assessment of REM pollution.


Assuntos
Cálcio/química , Cério/toxicidade , Lantânio/toxicidade , Ácido Nitrilotriacético/química , Testes de Toxicidade/métodos , Triticum/efeitos dos fármacos , Ligantes , Modelos Teóricos , Soluções , Eletricidade Estática , Triticum/crescimento & desenvolvimento
3.
Ecotoxicol Environ Saf ; 202: 110936, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800219

RESUMO

Developmental toxicity refers to the occurrence of adverse effects on a developing organism as a consequence of exposure to hazardous chemicals. The assessment of developmental toxicity has become relevant to the safety assessment process of chemicals. The zebrafish embryo developmental toxicology assay is an emerging test used to screen the teratogenic potential of chemicals and it is proposed as a promising test to replace teratogenic assays with animals. Supported by the increased availability of data from this test, the developmental toxicity assay with zebrafish has become an interesting endpoint for the in silico modelling. The purpose of this study was to build up quantitative structure-activity relationship (QSAR) models. In this work, new in silico models for the evaluation of developmental toxicity were built using a well-defined set of data from the ToxCastTM Phase I chemical library on the zebrafish embryo. Categorical and continuous QSAR models were built by gradient boosting machine learning and the Monte Carlo technique respectively, in accordance with Organization for Economic Co-operation and Development principles and their statistical quality was satisfactory. The classification model reached balanced accuracy 0.89 and Matthews correlation coefficient 0.77 on the test set. The regression model reached correlation coefficient R2 0.70 in external validation and leave-one-out cross-validated Q2 0.73 in internal validation.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Animais , Simulação por Computador , Substâncias Perigosas , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Teratogênios , Peixe-Zebra/embriologia
4.
J Environ Sci Health B ; 55(9): 803-812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602772

RESUMO

Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Clorpirifos/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Inibidores da Colinesterase/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores Sexuais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade/métodos
5.
Artigo em Inglês | MEDLINE | ID: mdl-32728873

RESUMO

Daphnia has been widely used as an indicator species in aquatic biomonitoring for decades. Traditional toxicity assays based on lethality take a long time to assess, and the effect mode of contaminants is not clear. Because of the translucency of the Daphnia body and the application of fluorescent probes in cell staining, different intoxicated parts can be visualized. In this study, a double-staining method using two fluorescent dyes, Calcein AM (cell-permeant dye) and Propidium Iodide (cell-impermeant dye), was carried out on Daphnia magna exposed to six pathogens: Salmonella spp. (four strains) and Shigella spp. (two strains). The results showed that those bacteria caused different infections on daphnia depending on the age of this organism and bacterial concentrations. In detail, S. dublin and S. sonnei are the most harmful to Daphnia when they cause damage at smaller concentrations at the younger stage (3 weeks old). Interestingly, older Daphnia can give responses to nearly 10 CFU/ml to less than 100 CFU/ml of some bacteria strains. In another experiment, S. sonnei disturbed Daphnia after just 10 min of exposure, and Daphnia adapted to S. choleraesuis, S. typhi, and S. flexneri at the early stage (3 weeks old) after 1 h of exposure. Moreover, the damaged areas of the daphnia body were directly observed via a microscope, contributing to the understanding and the prediction of toxicity mechanisms.


Assuntos
Daphnia/microbiologia , Salmonella/química , Shigella/química , Testes de Toxicidade/métodos , Animais , Corantes Fluorescentes/análise , Coloração e Rotulagem
6.
J Toxicol Sci ; 45(6): 319-325, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32493874

RESUMO

Due to finalization of the ICH S3A Q&A focusing on microsampling, application of microsampling technique to regular non-clinical animal studies is expected for non-clinical safety assessment of pharmaceuticals. In Europe, microsampling from the tail vein or saphenous vein has often been used, whereas sampling from the jugular vein is thought to be more common for non-clinical studies in Japan. Therefore, we assessed the toxicological effects of serial microsampling from the jugular vein of SD rats in a common 28-day study at 4 independent organizations. Fifty microliter sampling was performed at 6 timepoints on day 1 to 2 and 7 timepoints on day 27 to 28 and its toxicological influences on body weight, food consumption, hematological and clinical chemistry parameters, and organ weights (on day 29 for 3 and day 28 for 1 organizations) were evaluated. The serial microsampling was shown to have no or minimal influences on the assessed parameters. The observed statistical differences for the 18 parameters were sporadic and did not appear to be systemically associated with microsampling. However, the sporadic changes were more often observed in females (14/18 parameters) than in males (6/18), suggesting the possibility that female rats were more susceptible to treatment-based influences. The current results indicate that serial 50 µL sampling from the jugular vein of SD rats had no or very slight toxicological effects, suggesting that this microsampling condition is applicable for toxicokinetic evaluation of non-clinical rat toxicity studies.


Assuntos
Coleta de Amostras Sanguíneas/efeitos adversos , Veias Jugulares , Testes de Toxicidade/métodos , Toxicocinética , Animais , Coleta de Amostras Sanguíneas/métodos , Feminino , Técnicas In Vitro , Masculino , Ratos Sprague-Dawley , Fatores de Tempo
7.
Aquat Toxicol ; 225: 105543, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32585540

RESUMO

Species sensitivity distributions (SSDs) are used in chemical safety assessments to derive predicted-no-effect-concentrations (PNECs) for substances with a sufficient amount of relevant and reliable ecotoxicity data available. For engineered nanomaterials (ENMs), ecotoxicity data are often compromised by poor reproducibility and the lack of nano-specific characterization needed describe an ENM under test exposure conditions. This may influence the outcome of SSD modelling and hence the regulatory decision-making. This study investigates how the outcome of SSD modelling is influenced by: 1) Selecting input data based on the nano-specific "nanoCRED" reliability criteria, 2) Direct SSD modelling avoiding extrapolation of data by including long-term/chronic NOECs only, and 3) Weighting data according to their nano-specific quality, the number of data available for each species, and the trophic level abundance in the ecosystem. Endpoints from freshwater ecotoxicity studies were collected for the representative nanomaterials NM-300 K (silver) and NM-105 (titanium dioxide), evaluated for regulatory reliability and scored according to the level of nano-specific characterization conducted. The compiled datasets are unique in exclusively dealing with representative ENMs showing minimal batch-to-batch variation. The majority of studies were evaluated as regulatory reliable, while the degree of nano-specific characterization varied greatly. The datasets for NM-300 K and NM-105 were used as input to the nano-weighted n-SSWD model, the probabilistic PSSD+, and the conventional SSD Generator by the US EPA. The conventional SSD generally yielded the most conservative, but least precise HC5 values, with 95 % confidence intervals up to 100-fold wider than the other models. The inclusion of regulatory reliable data only, had little effect on the HC5 generated by the conventional SSD and the PSSD+, whereas the n-SSWD estimated different HC5 values based on data segregated according to reliability, especially for NM-105. The n-SSWD weighting of data significantly affected the estimated HC5 values, however in different ways for the sub-datasets of NM-300 K and NM-105. For NM-300 K, the inclusion of NOECs only in the weighted n-SSWD yielded the most conservative HC5 of all datasets and models (a HC5 based on NOECs only could not be estimated for NM-105, due to limited number of data). Overall, the estimated HC5 values of all models are within a relatively limited concentration range of 25-100 ng Ag/L for NM-300 K and 1-15 µgTiO2/L for NM-105.


Assuntos
Nanoestruturas/toxicidade , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Ecossistema , Água Doce/química , Reprodutibilidade dos Testes , Medição de Risco , Prata/toxicidade , Titânio/toxicidade
8.
Hum Cell ; 33(3): 859-867, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32449113

RESUMO

A new series of tetrahydroacridine derivatives with the fluorobenzoyl moiety was synthesized and evaluated for cytotoxic activity against lung cancer cell lines A549 and colorectal cancer HT29. The cytotoxic activity of the compounds was compared on the somatic cell line-EAhy926. Compounds showed high cytotoxic activity on A549 cells (IC50 183.26-68.07 µM) and HT29 cells (IC50 68.41-19.70 µM), higher than controls-etoposide (IC50 451.47 µM) toward A549 and 5-fluorouracil (IC50 1626.85 µM) against HT29. Derivative 4 was the most cytotoxic to A549, whereas for the cell lines HT29 compound 6. Selected compounds showed similar cytotoxicity to the EAhy926 cell line (IC50 about 50 µM). In the hyaluronidase inhibition assay, all compounds exhibited anti-inflammatory activity, including 4 exhibiting the best inhibitory activity-IC50 of 52.27 µM when the IC50 heparin was 56.41 µM. Mathematical modeling was performed to determine LD50 after intraperitoneal, oral, intravenous and subcutaneous administration and to predict potential mutagenicity and carcinogenicity of the compounds analyzed. Obtained results showed that tested derivatives are slightly toxic compounds, and LD50 values (mg/kg) ranged from 680 to 1200 (oral rat model), the analyzed compounds have low mutagenic potential, and differences between derivatives are insignificant and very low probability of carcinogenicity. To confirm mathematical calculations, an in vivo test was carried out on a laboratory mouse model for two selected compounds. It allowed to qualify compounds: 6 to category 4 of the GHS scale, and 4 to category 3 of the GHS scale.


Assuntos
Acridinas/toxicidade , Neoplasias Colorretais/patologia , Neoplasias Pulmonares/patologia , Acridinas/administração & dosagem , Acridinas/síntese química , Acridinas/química , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fluorbenzenos , Humanos , Hialuronoglucosaminidase/antagonistas & inibidores , Dose Letal Mediana , Camundongos , Ratos , Testes de Toxicidade/métodos
9.
Chemosphere ; 253: 126768, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464767

RESUMO

Humans and animals may be exposed to tens of thousands of natural and synthetic chemicals during their lifespan. It is difficult to assess risk for all the chemicals with experimental toxicity tests. An alternative approach is to use computational toxicology methods such as quantitative structure-activity relationship (QSAR) modeling. Mitochondrial toxicity is involved in many diseases such as cancer, neurodegeneration, type 2 diabetes, cardiovascular diseases and autoimmune diseases. Thus, it is important to rapidly and efficiently identify chemicals with mitochondrial toxicity. In this study, five machine learning algorithms and twelve types of molecular fingerprints were employed to generate QSAR discriminant models for mitochondrial toxicity. A threshold moving method was adopted to resolve the imbalance issue in the training data. Consensus of the models by an averaging probability strategy improved prediction performance. The best model has correct classification rates of 81.8% and 88.3% in ten-fold cross validation and external validation, respectively. Substructures such as phenol, carboxylic acid, nitro and arylchloride were found informative through analysis of information gain and frequency of substructures. The results demonstrate that resolving imbalance in training and building consensus models can improve classification rates for mitochondrial toxicity prediction.


Assuntos
Mitocôndrias/efeitos dos fármacos , Testes de Toxicidade/métodos , Algoritmos , Animais , Consenso , Humanos , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade
10.
Chemosphere ; 257: 126825, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32381281

RESUMO

Neuroactive compounds are routinely detected in surface waters at concentrations that pose potential threats to wildlife. Exposure to neurotoxicants can adversely affect exposed organism by altering ecologically-important behaviors (e.g., feeding and predator response) that are likely to have important repercussions for populations. These compounds can elicit behavioral effects at concentrations lower than those that induce overt toxicity as indicated by mortality or decreased growth. Though a wide variety of methods have been employed to assess the behavior of early life stage fish, it is unclear which assays are best suited for identifying ecologically-relevant behavioral changes following exposures to neurotoxicants. The goal of the present study was to promote the use of behavioral assays for assessing the behavioral impacts of exposure to neurotoxic compounds by comparing the performance of different behavioral assays in larval fish. To achieve this goal, the sensitivity and practicality of three behavioral assays (i.e., feeding, optomotor response, and C-start assays) were compared in larval fathead minnows exposed to a known neurotoxicant, chlorpyrifos. There were significant alterations in the performance of fathead minnow larvae in all three behavioral assays in response to a 12-d embryo-larval exposure to chlorpyrifos. However, feeding and C-start were the most practical of the selected assays, as they took less time and allowed for larger samples sizes. Further work to standardize behavioral testing methods, and to link alterations to ecologically-relevant behaviors, will help promote the use of these assays when investigating the potential environmental impacts of neurotoxic compounds.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cyprinidae/fisiologia , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Animais , Bioensaio , Substâncias Perigosas , Larva/efeitos dos fármacos
11.
Artigo em Inglês | MEDLINE | ID: mdl-32440860

RESUMO

Ecotoxicological bioassays have been widely utilized to evaluate the toxicity of substances to organisms. However, the main challenge for researchers is finding native species to assess the effects of pollutants on aquatic biota. The tropical Oligochaeta, Allonais inaequalis, can be used as a test organism in bioassays to understand the effects of toxicants on aquatic ecosystems and their impact on native aquatic biota. In this study, we tested four methodological designs to validate the use of our "Allonais inaequalis reproduction test" as an ecotoxicological bioassay. For each sample, the assay consisted of a bottle containing 10 mg of sterilized fine sand, 60 mL of dechlorinated tap water and 6 organisms, fed at the beginning of the test and again after 5 days. The assay was first established in a controlled environment and then used to evaluate a stressed environment containing one of the following three toxicants suggested by the OECD (2008) and Corbi et al. (2015): zinc chloride, copper sulfate, or potassium chloride. Our results showed that the best experimental design for reproduction analysis was a static, long-term bioassay, which lasted 10 days without aeration and allowed for the reproduction of multiple generations (10 ± 5 new organisms). The observed inhibition reproduction by toxicants (EC50 ranging between 0.2 mg L-1 and 1.36 g L-1) validated the methods used in this paper. The use of a reproduction endpoint is a new contribution to the ecotoxicological toolbox, examining responses from a native organism to predict the effects of pollutants in an aquatic environment.


Assuntos
Oligoquetos/fisiologia , Testes de Toxicidade/métodos , Animais , Bioensaio , Ecotoxicologia , Reprodução/efeitos dos fármacos
12.
J Toxicol Environ Health B Crit Rev ; 23(4): 137-176, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32321383

RESUMO

The liver is one of the most important multi-functional organs in the human body. Amongst various crucial functions, it is the main detoxification center and predominantly implicated in the clearance of xenobiotics potentially including particulates that reach this organ. It is now well established that a significant quantity of injected, ingested or inhaled nanomaterials (NMs) translocate from primary exposure sites and accumulate in liver. This review aimed to summarize and discuss the progress made in the field of hepatic nanotoxicology, and crucially highlight knowledge gaps that still exist.Key considerations include In vivo studies clearly demonstrate that low-solubility NMs predominantly accumulate in the liver macrophages the Kupffer cells (KC), rather than hepatocytes.KCs lining the liver sinusoids are the first cell type that comes in contact with NMs in vivo. Further, these macrophages govern overall inflammatory responses in a healthy liver. Therefore, interaction with of NM with KCs in vitro appears to be very important.Many acute in vivo studies demonstrated signs of toxicity induced by a variety of NMs. However, acute studies may not be that meaningful due to liver's unique and unparalleled ability to regenerate. In almost all investigations where a recovery period was included, the healthy liver was able to recover from NM challenge. This organ's ability to regenerate cannot be reproduced in vitro. However, recommendations and evidence is offered for the design of more physiologically relevant in vitro models.Models of hepatic disease enhance the NM-induced hepatotoxicity.The review offers a number of important suggestions for the future of hepatic nanotoxicology study design. This is of great significance as its findings are highly relevant due to the development of more advanced in vitro, and in silico models aiming to improve physiologically relevant toxicological testing strategies and bridging the gap between in vitro and in vivo experimentation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Nanoestruturas/toxicidade , Projetos de Pesquisa , Testes de Toxicidade/métodos , Animais , Hepatócitos/efeitos dos fármacos , Humanos , Macrófagos do Fígado/efeitos dos fármacos , Fígado/efeitos dos fármacos
13.
Crit Rev Toxicol ; 50(3): 213-218, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32228218

RESUMO

Within the European Union, various legislative acts contain specific provisions on endocrine disruption, requiring the regulation of substances with endocrine disrupting properties via a hazard-based approach. Presumably this is due to an assumed lack of thresholds for the adverse effects of such substances. Conversely, in other jurisdictions, such as USA, Canada, Australia and Japan, endocrine disruptors (EDs) are regulated using a risk-based approach. As a consequence, in recent years there has been increasing controversy on whether thresholds can be inferred for endocrine-mediated effects. There is concern that the endocrine system is too complex to allow estimation of safe levels of exposure to such chemicals. This brief review aims to evaluate the available scientific evidence in this area and offer a sound and robust conclusion supported by this analysis. It is concluded that there is nothing special or unique about endocrine disruption or greater uncertainties in its assessment compared to other non-genotoxic forms of toxicity to justify adopting a non-threshold approach by default. Biology predicts that thresholds of adversity exist and are the rule for all endpoints, including those arising from endocrine disruption. A threshold approach to the risk assessment of endocrine disrupting chemicals is scientifically justified.


Assuntos
Disruptores Endócrinos/toxicidade , Testes de Toxicidade/métodos , Ecotoxicologia , Humanos , Medição de Risco
14.
Yakugaku Zasshi ; 140(4): 491-498, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238630

RESUMO

Because the liver is the primary target organ for chemicals and pharmaceuticals, evaluation of these substances' liver toxicity is of critical importance. New evaluation methods without animal testing (i.e., in vitro and/or in silico) are eagerly anticipated, both for animal welfare and for decreasing cost. Also, the importance of mechanistic interpretation of the output derived from non-animal testing has been increasing. Accordingly, we investigated the potential for evaluating liver toxicity by applying the adverse outcome pathway (AOP) concept using gene set enrichment analysis (GSEA) from gene expression (GEx) data. A case study targeting hepatocellular fatty degeneration (HFD) is reported and discussed. We first identified the events detectable in an in vitro system by comparing the GEx data from the rat primary hepatocyte (in vitro) and rat liver (in vivo) treated with a chemical with the ability to induce HFD as one of the phenotypes in a 28-day repeated-dose toxicity test. Then, the scores based on GSEA were calculated after establishing the gene sets for each event leading to HFD. As a result, the mechanistic information leading to HFD was obtained from the score calculated based on the GSEA and the usefulness of the transcriptome-driven evaluation using AOP was demonstrated.


Assuntos
Rotas de Resultados Adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Toxicidade/métodos , Transcriptoma , Tecido Adiposo/metabolismo , Alternativas aos Testes com Animais , Bem-Estar do Animal , Animais , Simulação por Computador , Expressão Gênica , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Ratos
15.
Yakugaku Zasshi ; 140(4): 499-505, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238631

RESUMO

Toxicity testing is critical for new drug and chemical development process. A clinical study, experimental animal models, and in vitro study are performed to evaluate the safety of a new drug. The limitations of these methods include extensive time for toxicity testing, an ethical problem, and high costs of experimentation. Therefore computational methods are considered useful for estimating chemical toxicity. In silico toxicity prediction is one of the toxicity assessments that uses computational methods to predict and stimulate the toxicity of chemicals. In silico study aims to contribute to effective development of new drug and chemical design. In this study, quantitative structure-activity relationship (QSAR) models will be used to predict toxicities based on chemical structural parameters. Because toxicities are complicated physiological phenomena, a similar toxicity expression might cause a different pathway. Also, since many drugs with unknown mechanisms of actions are available, the application of artificial intelligence (AI)-which uses sophisticated algorithms- is increasingly used to predict toxicities. Recently, the QSAR model was applied to determine complex relations between chemical structures and toxicities. However, accuracy of QSAR for toxicity prediction remains an important issue. International competitions funded by public institutions can address this issue. Two important toxicity challenges were organized in the past decade; this article presents issues of toxicity based on these challenges.


Assuntos
Rotas de Resultados Adversos , Inteligência Artificial , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Relação Quantitativa Estrutura-Atividade , Alternativas aos Testes com Animais , Animais , Simulação por Computador , Modelos Animais , Testes de Toxicidade/métodos
17.
PLoS One ; 15(4): e0231634, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298350

RESUMO

The WST-1 assay is the most common test to assess the in vitro cytotoxicity of chemicals. Tetrazolium-based assays can, however, be affected by the interference of tested chemicals, including carbon nanotubes or Mg particles. Here, we report a new interference of Mn materials with the WST-1 assay. Endothelial cells exposed to Mn particles (Mn alone or Fe-Mn alloy from 50 to 1600 µg/ml) were severely damaged according to the WST-1 assay, but not the ATP content assay. Subsequent experiments revealed that Mn particles interfere with the reduction of the tetrazolium salt to formazan. Therefore, the WST-1 assay is not suitable to evaluate the in vitro cytotoxicity of Mn-containing materials, and luminescence-based assays such as CellTiter-Glo® appear more appropriate.


Assuntos
Citotoxinas/toxicidade , Células Endoteliais/efeitos dos fármacos , Manganês/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Medições Luminescentes/métodos , Oxirredução , Sais de Tetrazólio/química , Testes de Toxicidade/métodos
18.
Chemosphere ; 253: 126718, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32298908

RESUMO

High-throughput screening (HTS) using new approach methods is revolutionizing toxicology. Asexual freshwater planarians are a promising invertebrate model for neurotoxicity HTS because their diverse behaviors can be used as quantitative readouts of neuronal function. Currently, three planarian species are commonly used in toxicology research: Dugesia japonica, Schmidtea mediterranea, and Girardia tigrina. However, only D. japonica has been demonstrated to be suitable for HTS. Here, we assess the two other species for HTS suitability by direct comparison with D. japonica. Through quantitative assessments of morphology and multiple behaviors, we assayed the effects of 4 common solvents (DMSO, ethanol, methanol, ethyl acetate) and a negative control (sorbitol) on neurodevelopment. Each chemical was screened blind at 5 concentrations at two time points over a twelve-day period. We obtained two main results: First, G. tigrina and S. mediterranea planarians showed significantly reduced movement compared to D. japonica under HTS conditions, due to decreased health over time and lack of movement under red lighting, respectively. This made it difficult to obtain meaningful readouts from these species. Second, we observed species differences in sensitivity to the solvents, suggesting that care must be taken when extrapolating chemical effects across planarian species. Overall, our data show that D. japonica is best suited for behavioral HTS given the limitations of the other species. Standardizing which planarian species is used in neurotoxicity screening will facilitate data comparisons across research groups and accelerate the application of this promising invertebrate system for first-tier chemical HTS, helping streamline toxicology testing.


Assuntos
Planárias/fisiologia , Testes de Toxicidade/métodos , Animais , Neurônios , Síndromes Neurotóxicas , Planárias/efeitos dos fármacos
19.
PLoS One ; 15(4): e0231252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294131

RESUMO

Drug induced liver injury (DILI) is one of the key safety concerns in drug development. To assess the likelihood of drug candidates with potential adverse reactions of liver, we propose a compound attributes-based approach to predicting hepatobiliary disorders that are routinely reported to US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Specifically, we developed a support vector machine (SVM) model with recursive feature extraction, based on physicochemical and structural properties of compounds as model input. Cross validation demonstrates that the predictive model has a robust performance with averaged 70% of both sensitivity and specificity over 500 trials. An independent validation was performed on public benchmark drugs and the results suggest potential utility of our model for identifying safety alerts. This in silico approach, upon further validation, would ultimately be implemented, together with other in vitro safety assays, for screening compounds early in drug development.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Simulação por Computador , Testes de Toxicidade/métodos , Bases de Dados Factuais , Previsões , Humanos , Fígado/efeitos dos fármacos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/classificação , Sensibilidade e Especificidade , Máquina de Vetores de Suporte , Estados Unidos , United States Food and Drug Administration
20.
Artigo em Inglês | MEDLINE | ID: mdl-32297059

RESUMO

The main goal of this study was to perform an ecotoxicological profiling of terrestrial and aquatic cyanobacterial strains found in different soils or in toxic cyanobacterial blooms in Vojvodina region, Serbia, using the effect-directed analysis (EDA) approach. The applied procedure was based on a series of in vitro or small-scale bioassays covering multiple endpoints in combination with advanced chemical analytical protocols. Non-selective and non-target preparation techniques were used for the extraction of a broad range of chemical compounds present in three terrestrial (Anabaena C2, Anabaena C5, Nostoc S8) and three aquatic (Nostoc Z1, Phormidium Z2, Oscillatoria K3) strains. Ecotoxicological endpoints addressed included evaluation of the fish cytotoxicity in vitro (acute toxicity), algal growth inhibition (chronic toxicity), and interaction with cellular detoxification mechanisms. All cyanobacterial strains tested in the 1st tier EDA showed significant effects in terms of chronic toxicity and interaction with cellular detoxification. Three major fractions of different polarities were further tested in the 2nd tier, using bioassays which showed the strongest response: induction of CYP1A1 biotransformation enzyme and inhibition of zebrafish organic anion (Oatp1d1) and cation (Oct1) uptake transporters. Oscillatoria K3 strain was selected for a more detailed 3rd tier EDA, and the obtained results revealed that positive sub-fractions possess polar anion and cation compounds that are reactive to both uptake transporters, and compounds responsible for the strongest effects have a pronounced lipophilic character. Apart from lipophilic non-polar compounds that represent typical phase I substrates, sub-fractions that contained polar substances are also shown to significantly induce CYP1A1.


Assuntos
Ecotoxicologia , Testes de Toxicidade/métodos , Animais , Bioensaio , Cianobactérias , Sérvia , Peixe-Zebra
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