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1.
Toxicol Lett ; 314: 1-9, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295537

RESUMO

Oral administration is the preferred route of exposure for non-volatile chemicals with potential environmental exposures. For metal salts, systemic doses in such toxicity testing are often low due to limited oral bioavailability. Issues arising from the low bioavailability for toxicity testing and risk characterization are illustrated using aluminum (Al) salts as example. Al-cations have an oral bioavailability of below 1% and applicable doses are limited resulting in low systemic doses. Consequently, the low systemic doses are insufficient to induce clear adverse effects that may serve as points of departure for risk characterization.


Assuntos
Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/toxicidade , Testes de Toxicidade/métodos , Administração Oral , Compostos de Alumínio/farmacocinética , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Reprodutibilidade dos Testes , Medição de Risco , Toxicocinética
2.
Sci Total Environ ; 685: 273-279, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176214

RESUMO

The shock impact of toxic pollutants in petrochemical wastewater on the activated sludge in biological treatment system is a key factor restricting the treatment efficiency. It is necessary to evaluate the toxicity of these pollutants by appropriate methods. In this study, four test methods were used to evaluate the toxicity of characteristic organic pollutants in petrochemical wastewater including 2,4-dichlorophenol, formaldehyde and pyridine, as well as one frequently-used reference toxicant 3,5-dichlorophenol. The sensitivity, accuracy and response time were compared among these methods: the oxygen consumption rate inhibition method (OCRIM), the dehydrogenase activity inhibition method (DAIM), the nitrification rate inhibition method (NRIM) and the growth rate inhibition method (GRIM). Principal component analysis was used to evaluate the correlation among the results of different methods. The OCRIM was comprehensively outstanding with the highest correlation between concentration and inhibition ratio (R2 values were all higher than 0.9854), good sensitivity, best accuracy (error value of the effective concentrations below 0.15 mg/l) and fastest response (<40 min). The sensitivity of the NRIM was found to be the highest in this study (10% effective inhibition concentration (EC10) value of 3,5-dichlorophenol was only 0.03 mg/l). Therefore, combined tests of OCRIM and NRIM were suggested.


Assuntos
Biodegradação Ambiental/efeitos dos fármacos , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Eliminação de Resíduos Líquidos , Águas Residuárias/química
3.
Food Chem Toxicol ; 130 Suppl 1: 110564, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199993

RESUMO

2-Isobutyl-4-methyltetrahydro-2H-pyran-4-ol) was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol is not genotoxic, does not have skin sensitization potential, and provided an MOE >100 for the repeated dose, developmental, and reproductive toxicity endpoints. The local respiratory toxicity endpoint was completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class III material (0.47 mg/day). The phototoxicity/photoallergenicity endpoint was completed based on UV spectra and data on 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol. The environmental endpoints were evaluated; 2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Assuntos
Perfumes/química , Perfumes/toxicidade , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Medição de Risco
4.
Food Chem Toxicol ; 130 Suppl 1: 110588, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31216429

RESUMO

There are insufficient toxicity data on the target material propanal diethyl acetal (CAS # 4744-08-5). Hence, in silico evaluation was conducted to determine read-across analogs for this material. Based on structural similarity, reactivity, metabolism data, physical-chemical properties, and expert judgment, analogs acetal (CAS # 105-57-7) and butane, 1,1'-[methylenebis(oxy)]bis- (CAS # 2568-90-3) were identified as read-across materials with sufficient data for toxicological evaluation of genotoxicity.


Assuntos
Cetonas/química , Perfumes/química , Perfumes/toxicidade , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Medição de Risco
5.
Food Chem Toxicol ; 130 Suppl 1: 110607, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233870

RESUMO

The existing information supports the use of this material as described in this safety assessment. Isobutyl propionate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog isobutyl acetate (CAS # 110-19-0) show that isobutyl propionate is not expected to be genotoxic. Data from read-across analog isoamyl acetate (CAS # 123-92-2) show that there are no safety concerns for isobutyl propionate for skin sensitization under the current declared levels of use. The repeated dose and reproductive endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to isobutyl propionate is below the TTC (0.03 mg/kg/day and 0.03 mg/kg/day, respectively). For the local respiratory endpoint, a calculated MOE >100 was provided by read-across analog butyl acetate (CAS # 123-86-4). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; isobutyl propionate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; isobutyl propionate is not PBT as per the IFRA Environmental Standards. For the risk assessment, isobutyl propionate was not able to be risk screened as there were no reported volumes of use for North America or Europe in the 2015 IFRA Survey.


Assuntos
Perfumes/química , Perfumes/toxicidade , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Medição de Risco
6.
Food Chem Toxicol ; 130 Suppl 1: 110619, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233879

RESUMO

Butyl 10-undecenoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog methyl undec-10-enoate (CAS # 111-81-9) show that butyl 10-undecenoate is not expected to be genotoxic. Data on butyl 10-undecenoate and read-across analog methyl undec-10-enoate (CAS # 111-81-9) show that butyl 10-undecenoate is not a safety concern under the current, declared levels of use for the skin sensitization endpoint. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to butyl 10-undecenoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; butyl 10-undecenoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; butyl 10-undecenoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Assuntos
Perfumes/química , Perfumes/toxicidade , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Medição de Risco
7.
Food Chem Toxicol ; 130 Suppl 1: 110622, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31238136

RESUMO

The existing information supports the use of this material as described in this safety assessment. Methyl 2-nonenoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl trans-2,cis-4-decadienoate (CAS # 3025-30-7) show that methyl 2-nonenoate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to methyl 2-nonenoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from the target and read-across analog isobutyl-2-butenoate (CAS # 589-66-2) do not indicate the material is a sensitizer. The phototoxicity/photoallergenicity endpoints were evaluated based on data and UV spectra; methyl 2-nonenoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl 2-nonenoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Assuntos
Perfumes/química , Perfumes/toxicidade , Testes de Toxicidade/métodos , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Medição de Risco
8.
Food Chem Toxicol ; 131: 110581, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202941

RESUMO

Current global efforts are aiming to increase use of mechanistic information in regulatory testing. In tiered testing paradigms, in vitro, in silico, and in vivo studies are employed progressively to identify and classify health hazards, which are then compared against human equivalent doses. We used data from three companion papers on the brominated flame retardant hexabromocyclododecane (HBCD) to conduct a case study on tiered testing. We included ToxCast™ and in vitro-in vivo extrapolation (Tier 1), rat liver transcriptomic (Tier 2), and conventional rat (Tier 3) data. Bioactivity-exposure ratios (BERs) were derived by comparing human administered dose equivalents of the measured effects to Canadian exposure levels. Biological perturbations were highly aligned between Tiers 1/2, and consistent with apical effects in Tier 3. Tier 1 had the smallest BERs, and Tiers 2/3 were similar. The study demonstrates the promise of using physiologically-based pharmacokinetic modeling and mechanistic analyses in a tiered framework to identify pathways through which chemicals exert toxicological effects; however, they also point to some shortcomings associated with in vitro and in silico approaches. Additional case studies of chemicals from multiple classes are required to define optimal tiered screening procedures to reduce future in vivo requirements in health hazard assessments.


Assuntos
Retardadores de Chama/toxicidade , Hidrocarbonetos Bromados/toxicidade , Animais , Apoptose/efeitos dos fármacos , Feminino , Retardadores de Chama/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Humanos , Hidrocarbonetos Bromados/administração & dosagem , Masculino , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Medição de Risco , Testes de Toxicidade/métodos
9.
Chemosphere ; 232: 366-376, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31158631

RESUMO

Metals are present as mixtures in the environment, yet testing such complex mixture poses design and technical challenges. One possible solution is the use of fixed ratios, i.e. rays of increasing metal concentrations. But fixed ratios rays are compromised when soils dosed with metal salts are leached due to metal-soil selectivity rules. Two alternative metal forms, metal oxides and spinel minerals of quinary metal mixtures (Pb, Cu, Co, Ni, Zn), were evaluated for their toxicity to soil microorganisms measured by the activity of ammonia monooxygenases and acid-phosphatases in three soils. Leaching, a required step for salts, had a larger effect on ammonia monooxygenases than metals. Generally, metal salts were the most toxic form, while the spinel minerals were the least toxic form. Two extractants, CaCl2 and DTPA, were evaluated for their ability to link toxicity to metals across all three metal forms. Salt toxicity was closely linked to CaCl2 extractable concentrations but DTPA was the most appropriate for oxides. We strongly recommend combining fixed ratio rays with metal oxides for metal mixture studies, since soil ratios created using oxides were more precise and required less experimental effort compared to salts and spinel minerals. Furthermore, because DTPA and CaCl2 closely tracked the toxicity of more realistic metal forms (i.e. oxides), we recommend that field studies investigating metal mixtures use both DTPA and CaCl2.


Assuntos
Metais/toxicidade , Microbiologia do Solo , Poluentes do Solo/toxicidade , Testes de Toxicidade/métodos , Metais Pesados/análise , Solo , Poluentes do Solo/análise
10.
Chemosphere ; 229: 559-569, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100627

RESUMO

Increasingly stringent particulate matter (PM) emission standards have brought forth engine design improvements, cleaner-burning fuels, and aftertreatment technologies. Reductions in tailpipe PM mass have concomitantly reduced accumulation-mode particle emissions. However, some strategies promote the emission of nucleation-mode particles, which are typically quantified on a number (PN) basis. We previously demonstrated that PN emissions from heavy-duty diesel vehicles equipped with various aftertreatment systems were inversely correlated, and gravimetric PM mass was positively correlated, with two in vitro assays. This present work expands on the analysis of PM mass and PN with in vitro assays to also include four additional PM metrics: suspended PM mass, active particle surface area, aggregate particle surface area, and accumulation-mode particle number. This new analysis shows that like gravimetric PM mass, suspended particle mass and accumulation mode particle number are well correlated with dithiothreitol consumption rate (DTT) and macrophage reactive oxygen species consumption rate (ROS) assays (R2 = 0.61-0.96). Data suggest that PM mass emissions dominated by nucleation-mode particles induce equal or slightly greater toxicity compared to PM mass dominated by accumulation-mode particles. Data also show that among all PM metrics, those used for regulating PM in the United States and Europe, namely gravimetric mass and solid PN are overall most correlated with in vitro toxicity. Moreover, continued exploration of alternative, low-cost, and more appropriate PM metrics is warranted to better understand the reproducibility of these findings on other engine applications, fuel types, and aftertreatment platforms.


Assuntos
Testes de Toxicidade/métodos , Emissões de Veículos/toxicidade , Poluentes Atmosféricos/toxicidade , Animais , Linhagem Celular , Macrófagos/efeitos dos fármacos , Veículos Automotores , Tamanho da Partícula , Material Particulado/análise , Material Particulado/toxicidade , Ratos , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Propriedades de Superfície
11.
Adv Neurobiol ; 22: 275-297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073941

RESUMO

Neurotoxicity can be defined by the ability of a drug or chemical to alter the physiology, biochemistry, or structure of the nervous system in a manner that may negatively impact the health or function of the individual. Electrophysiological approaches have been utilized to study the mechanisms underlying neurotoxic actions of drugs and chemicals for over 50 years, and in more recent decades, high-throughput patch-clamp approaches have been utilized by the pharmaceutical industry for drug development. The use of microelectrode array recordings to study neural network electrophysiology is a relatively newer approach, with commercially available systems becoming available only in the early 2000s. However, MEAs have been rapidly adopted as a useful approach for neurotoxicity testing. In this chapter, I will review the use of MEA approaches as they have been applied to the field of neurotoxicity testing, especially as they have been applied to the need to screen large numbers of chemicals for neurotoxicity and developmental neurotoxicity. In addition, I will also identify challenges for the field that when addressed will improve the utility of MEA approaches for toxicity testing.


Assuntos
Eletrofisiologia/instrumentação , Eletrofisiologia/métodos , Microeletrodos , Síndromes Neurotóxicas/diagnóstico , Síndromes Neurotóxicas/fisiopatologia , Testes de Toxicidade/instrumentação , Testes de Toxicidade/métodos , Humanos
12.
Sci Total Environ ; 677: 108-119, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31054440

RESUMO

Ambient fine particle is a crucial indicator of air pollution brought into the air by sundry natural and public events. However, a comprehensive understanding of the PM2.5-induced cytotoxicity especially the contribution of bioaerosol part is still undiscovered. Herein, an ALI microfluidics system integrated multi-omics (iTRAQ & RNA-seq) was successfully utilized to recognize the molecular mechanisms induced by microorganisms carried bioaerosol in human lung epithelial cells. The cells viability was above 98% within 21 days on this system. Moreover, the results showed that eight microorganisms-related pathways (e.g., Salmonella, amoebiasis, HTLV-1) were activated after exposure to PM2.5 for 24 h, which played a certain proportion in contributing to inflammation reaction. In addition, multi-omics demonstrated that three inflammation-related signal transduction cascades including MAPK signaling pathway, TNF signaling pathway, and TGF signaling pathway were triggered by fine particles, ultimately leading to apoptosis-related process disorder by associated cytokines like TNF, IL6, and TGF-ß. Furthermore, flow cytometry analysis showed that the cell apoptosis rate increased from 3.8% to 66.7% between the cells exposed to PM2.5 (10 µg/cm2) for 24 h and untreated control cells, which indicated that the fine particles had the ability to activate apoptosis-related signal cascades and result in apoptosis. ELISA assay and western blot indicated that HO-1, JNK, IL6, TNF, NF-κB, and FGF14 were significantly increased after exposure to PM2.5 while Casp3 and FGFR were decreased, which were consistent with the multi-omics. Moreover, PM2.5 components (OC, EC, 16PAHs, As, Cu, Mn, Cl-, and NO3-) were significantly correlated to the inflammation related proteins and cytokines, which played a vital role in the inflammation and apoptosis related signaling pathways. These findings pointed to strong links among microorganisms infection, inflammation, and apoptosis in cell response to PM2.5 carried microorganisms. It also provided a new approach for understanding PM2.5-induced cytotoxicity and health risks.


Assuntos
Poluentes Atmosféricos/toxicidade , Microfluídica , Material Particulado/toxicidade , Testes de Toxicidade/métodos , Poluição do Ar , Apoptose , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Transdução de Sinais
13.
Toxicol Lett ; 311: 125-132, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063830

RESUMO

Toxicological data used for risk assessments must undergo an evaluation of reliability. Nevertheless, a reliability evaluation scheme for such data has yet to be established in China. A method termed TRAM (Toxicological data Reliability Assessment Method) was developed to evaluate toxicological data reliability. A questionnaire survey was performed to identify the most important criteria for reliability, and was divided into three parts: laboratory animal data (LAD), in vitro data (IVD), and human data (HD). The criteria selected from the questionnaire survey and numerical score categorization finally reached a consensus after two conferences. TRAM comprises 22 criteria for LAD, 15 for IVD, and 12 for HD. Furthermore, a combination of a quick and detailed evaluation of approaches for LAD and IVD were proposed to improve evaluation efficiency. Different weights (1-4) were assigned to each criterion, and 0-4 points were allocated according to how well each criterion was met, then a Quality score was calculated. TRAM uses three reliability categories: high (Quality score: 81-100 or met a quick evaluation approach), moderate (60-80) and low(<60). TRAM provides a transparent, easy-to-use, and quantitative method for evaluating toxicological data reliability.


Assuntos
Confiabilidade dos Dados , Inocuidade dos Alimentos/métodos , Testes de Toxicidade/métodos , Animais , Consenso , Humanos , Reprodutibilidade dos Testes , Medição de Risco , Inquéritos e Questionários
14.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052191

RESUMO

Tubulins and microtubules (MTs) represent targets for taxane-based chemotherapy. To date, several lines of evidence suggest that effectiveness of compounds binding tubulin often relies on different post-translational modifications on tubulins. Among them, methylation was recently associated to drug resistance mechanisms impairing taxanes binding. The sea urchin is recognized as a research model in several fields including fertilization, embryo development and toxicology. To date, some α- and ß-tubulin genes have been identified in P. lividus, while no data are available in echinoderms for arginine methyl transferases (PRMT). To evaluate the exploiting of the sea urchin embryo in the field of antiproliferative drug development, we carried out a survey of the expressed α- and ß-tubulin gene sets, together with a comprehensive analysis of the PRMT gene family and of the methylable arginine residues in P. lividus tubulins. Because of their specificities, the sea urchin embryo may represent an interesting tool for dissecting mechanisms of tubulin targeting drug action. Therefore, results herein reported provide evidences supporting the P. lividus embryo as animal system for testing antiproliferative drugs.


Assuntos
Citostáticos/toxicidade , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Ouriços-do-Mar/efeitos dos fármacos , Testes de Toxicidade/métodos , Moduladores de Tubulina/toxicidade , Tubulina (Proteína)/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Metilação , Processamento de Proteína Pós-Traducional , Ouriços-do-Mar/embriologia
15.
Environ Pollut ; 250: 97-106, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30986619

RESUMO

Microalgae are commonly used in ecotoxicity testing due to their ease of culturing and rapid cell division rates. These tests generally utilise a single species of algae; however, microalgae occur in the environment as complex communities of multiple species. To date, routine multispecies toxicity tests using tropical microalgae have not been available. This study investigated four tropical freshwater microalgal species for use in a chronic multispecies toxicity test based on the population growth (cell division) rate: Pediastrum duplex, Monoraphidium arcuatum, Nannochloropsis-like sp. and Chlorella sp. 12. Flow cytometric analysis identified the different fluorescence and light scattering properties of each algal species and quantified each species within multispecies mixtures. Following optimisation of test media nutrients and pH, a toxicity testing protocol was developed with P. duplex, M. arcuatum and Nannochloropsis-like sp. There were no significant differences in growth rates of each alga when tested over 72 h as single species or in multispecies mixtures. Atrazine and imazapic, two herbicides with different modes of action, were used to assess the sensitivity of the multispecies toxicity test. Atrazine was toxic to all species with 72-h IC10 values of 7.2, 63 and 280 µg/L for P. duplex, M. arcuatum and Nannochloropsis-like sp. respectively, while imazapic was not toxic to any species at concentrations up to 1100 µg/L. The toxicity of atrazine and imazapic to each microalgal species in the multispecies toxicity test was the same as that determined from single-species toxicity tests indicating that the presence of these microalgae in a mixture did not affect the toxicity of these two herbicides. This study is the first to develop a multispecies tropical microalgal toxicity test for application in freshwaters. This time- and cost-effective tool can be utilised to generate data to assist environmental decision making and to undertake risk assessments of contaminants in tropical freshwater environments.


Assuntos
Atrazina/toxicidade , Monitoramento Ambiental/métodos , Herbicidas/toxicidade , Imidazóis/toxicidade , Microalgas/efeitos dos fármacos , Ácidos Nicotínicos/toxicidade , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Chlorella/efeitos dos fármacos , Água Doce/química
16.
SAR QSAR Environ Res ; 30(5): 347-361, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31020866

RESUMO

A simple approach is introduced to assess the toxicity of nitroaromatic compounds in terms of an oral LD50 dose (50% lethal dose) for rats. Most of the presented Quantitative Structure-Activity Relationship (QSAR) models for prediction of in vivo toxicity of nitroaromatics are calculated by quantum computing descriptors which are more difficult to interpret and apply, while the new model requires only the molecular structure of a desirable nitroaromatic compound. The novel model is based on the constitutional descriptors, such as the number of oxygen, sulphur, phosphorous and molecular fragments. Experimental data of 90 nitroaromatics are used to derive and test the new model as the logarithm of LD50 values, i.e. -log (LD50). Although it is based on only simple structural parameters, the reliability of the new model is also higher than the complex QSAR model because the values of the root-mean-square deviation (RMSD) of -log (LD50) for the new and the outputs of the latest QSAR method are 0.342 and 0.377, respectively.


Assuntos
Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/toxicidade , Nitrocompostos/química , Nitrocompostos/toxicidade , Testes de Toxicidade/métodos , Animais , Dose Letal Mediana , Modelos Químicos , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Reprodutibilidade dos Testes
17.
Regul Toxicol Pharmacol ; 105: 15-29, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30930176

RESUMO

Despite a major role of experimental animals in development of biomedical research, there has been historical controversy surrounding animal research. Along with a strategy of 3Rs, various in vitro methods have been suggested to replace potentially painful animal experiments. In this review, we summarize the use of stem cells as an alternative of animal experimentation in predictive toxicology. There have been continuing researches on stem cells and stem cell-derived tissue-specific cells to develop alternative methods/biomarkers for animal toxicity testing including developmental toxicity, genotoxicity, and tissue-specific toxicity. Along with unique abilities of stem cells including self-renewal, infinite proliferation, and differentiation into multiple lineages, human stem cell-based in vitro systems have been proven valuable to increase predictive power of toxicology through providing with better scientific information related to toxic risks in humans without inter-species variability. In particular, stem cells including induced pluripotent stem cell-based system for personalized toxicological assessment could be a better option as an in vitro model system in comparison with immortalized cells with abnormal phenotype or primary cells with small quantity and batch-to-batch variation. This review will be useful for understanding the current status and future direction in using stem cells as an alternative non-animal method for predictive toxicology.


Assuntos
Células-Tronco/efeitos dos fármacos , Testes de Toxicidade/métodos , Toxicologia/métodos , Experimentação Animal , Alternativas aos Testes com Animais/métodos , Animais , Diferenciação Celular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Especificidade da Espécie , Células-Tronco/citologia
18.
Regul Toxicol Pharmacol ; 105: 62-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30981719

RESUMO

The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics. With regards to human risk assessment practices for developmental toxicity, the analysis showed that, after excluding lenalidomide and pomalidomide data in rats, all available AUC margins at the NOAEL for the induction of malformations or embryofetal lethality were <4-fold of the exposure at the MRHD for all 22 therapeutics. These data support the proposed general approach of increased level of concern for human risk when exposure margins of the NOAEL to the MRHD are <10-fold, reduced concern when the exposure margins are 10- to 25-fold, and minimal concern when the exposure margin is > 25-fold.


Assuntos
Embrião de Mamíferos/efeitos dos fármacos , Medição de Risco/métodos , Teratogênios/toxicidade , Testes de Toxicidade/métodos , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Humanos , Nível de Efeito Adverso não Observado , Gravidez , Coelhos , Ratos , Estudos Retrospectivos , Especificidade da Espécie
19.
J Vet Sci ; 20(2): e14, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944536

RESUMO

With the increased use of cell therapy in the veterinary sector, there is a growing demand for the development of cell-based medicinal products and the determination of their safety. Currently, the Korean Animal and Plant Quarantine Agency has established a guideline for evaluating the safety of cell-based medicinal products for animal use. The guideline includes items related to definition, classification, management, manufacturing procedure and quality control (standard and test method), stability testing, toxicity testing, pharmacological testing, and performance of clinical trials. In addition, testing protocols related to safety assessment of animal cell-based products such as chromosome karyotyping, tumorigenicity testing, confirmatory testing of biodistribution and kinetics, and target animal safety testing are described in detail. Moreover, because cell-based medicinal products are novel therapies, deviations from traditional designs may be justified in order to obtain relevant safety information on the treatment. Additionally, this guideline can be amended on the basis of new scientific findings.


Assuntos
Produtos Biológicos/normas , Testes de Toxicidade/veterinária , Animais , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Ensaios Clínicos Veterinários como Assunto , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
20.
Zygote ; 27(2): 55-63, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30871647

RESUMO

SummaryStudies have shown that daily exposure to different products, whether chemical or natural, can cause irreversible damage to women's reproductive health. Therefore it is necessary to use tests that evaluate the safety and efficacy of these products. Most reproductive toxicology tests are performed in vivo. However, in recent years, various cell culture methods, including embryonic stem cells and tissues have been developed with the aim of reducing the use of animals in toxicological tests. This is a major advance in the area of toxicology, as these systems have the potential to become a widely used tool compared with in vivo tests routinely used in reproductive biology and toxicology. The present review describes and highlights data on in vitro culture processes used to evaluate reproductive toxicity as an alternative to traditional methods using in vivo tests.


Assuntos
Técnicas de Cultura de Órgãos/métodos , Folículo Ovariano/citologia , Ovário/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Linhagem Celular , Feminino , Humanos , Oócitos/citologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ovário/fisiologia
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