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1.
Sci Total Environ ; 857(Pt 3): 159518, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36270350

RESUMO

Understanding the frequency of non-additive effects of pesticides (synergism and antagonism) is important in the context of risk assessment. The goal of this study was to investigate the prevalence of non-additive effects of pesticides to honey bees (Apis mellifera). We investigated a large set of mixtures including insecticides and fungicides of different chemical modes of action and classes. The mixtures included represent a relevant sample of pesticides that are currently used globally. We investigated whether the experimental toxicity of the mixtures could be predicted based on the Concentration Addition (CA) model for acute contact and oral adult bee toxicity tests. We measured the degree of deviation from the additivity predictions of the experimental toxicity based on the well-known Mixture Deviation Ratio (MDR). Further, we investigated the appropriate MDR thresholds that should be used for the identification of non-additive effects based on acceptable rates for false positive (alpha) and true positive (beta) findings. We found that a deviation factor of MDR = 5 is a sound reference for labeling potential non-additive effects in acute adult bee experimental designs when assuming a typical Coefficient of Variation (CV%) = 100 in the determination of the LD50 of a pesticide (a factor of 2× deviation in the LD 50 resulting from inter-experimental variability). We found that only 2.4 % and 9 % of the mixtures evaluated had an MDR > 5 and MDR < 0.2, respectively. The frequency and magnitude of deviation from additivity found for bees in this study are consistent with those of other terrestrial and aquatic taxa. Our findings suggest that additivity is a good baseline for predicting the toxicity of pesticide mixtures to bees, and that the rare cases of synergy of pesticide mixtures to bees are not random but have a mechanistic basis.


Assuntos
Fungicidas Industriais , Inseticidas , Praguicidas , Abelhas , Animais , Praguicidas/toxicidade , Inseticidas/farmacologia , Dose Letal Mediana
2.
Toxins (Basel) ; 14(11)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36355985

RESUMO

The present study aimed to evaluate the acute and subacute toxicity profiles of Erodium guttatum extracts in mice using the methods described in the guidelines of the OECD. In the acute toxicity study, the LD50 value was greater than 2000 mg/kg. The subacute toxicity study of E. guttatum extracts showed no significant changes in body or organ weights. The administration of E. guttatum extracts to mice at a dose of 200 mg/kg led to an increase in white blood cells, platelets and hemoglobin. Moreover, the aqueous extract of E. guttatum only decreased liver aspartate aminotransferase (ASAT) levels at a dose of 200 mg/kg, and creatinine and urea levels did not show any significant alterations compared to the control group. Our results showed that the extracts of E. guttatum caused a slight increase in alanine aminotransferase (ALAT) and triglycerides. The histological study showed that mice treated with E. guttatum extracts experienced some histopathological changes in the liver, particularly with the methanolic extract, and slight changes in the kidneys and pancreas. Regarding the renal profile, no toxicity was observed. These results provide basic information on the toxicological profile of E. guttatum used in traditional medicine.


Assuntos
Extratos Vegetais , Roedores , Animais , Camundongos , Testes de Toxicidade Aguda , Extratos Vegetais/toxicidade , Dose Letal Mediana , Administração Oral
3.
Ecotoxicol Environ Saf ; 246: 114198, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36272173

RESUMO

Pomacea canaliculata, as an invasive snail in China, can adversely affect agricultural crop yields, ecological environment, and human health. In this paper, we studied the molluscicidal activity and mechanisms of arecoline against P. canaliculata. The molluscicidal activity tests showed that arecoline exhibits strong toxicity against P. canaliculata, and the LC50 value (72 h) was 1.05 mg/L (15 ± 2 mm shell diameter). Additionally, Molluscicidal toxicity were negatively correlated with the size of snails. Snails (25 ± 2 mm shell diameter) were choosed for mechanisms research and the result of microstructure and biochemistry showed that arecoline (4 mg/L, 20 â„ƒ) had strong toxic effect on the gill, and the main signs were the loss of cilia in the gill filaments. Moreover, arecoline significantly decreased the oxygen consumption rate, ammonia excretion rate and inhibited acetylcholinesterase (AChE). Then, the changes in protein expression were studied by iTRAQ, and 526 downregulated proteins were found. Among these, cilia and flagella-associated 157-like (PcCFP) and rootletin-like (PcRoo) were selected as candidate target proteins through bioinformatics analysis, and then RNA interference (RNAi) was adopted to verify the function of PcCFP and PcRoo. The results showed that after arecoline treated, the mortality and the cilia shedding rate of PcRoo RNAi treated group was significantly lower than control group. The above results indicate that arecoline can bind well with protein PcRoo, and then leads to the drop of gill cilia, affect respiratory metabolism, accelerate its entry into hemolymph, inhibit AChE and finally leads to the death of P. canaliculata.


Assuntos
Gastrópodes , Moluscocidas , Animais , Humanos , Arecolina , Acetilcolinesterase , Moluscocidas/toxicidade , Dose Letal Mediana
4.
Bull Environ Contam Toxicol ; 109(6): 996-1000, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36074128

RESUMO

The toxicity of the insecticide chlorantraniliprole and its formulated product Altacor® was determined for the Cladoceran, Ceriodaphnia dubia Richard. Acute toxicity (48 h) and 21 d population studies were conducted. The hypothesis of this study was that these two compounds would have different toxicities. We conducted acute and chronic toxicity studies for each compound and compared the results to test this hypothesis. 48 h LC50s (95% CL) for chlorantraniliprole and Altacor® were 8.5 (6.6-11.5) and 6.0 (3.7-9.0) µg chlorantraniliprole/L water, respectively. Therefore, chlorantraniliprole and Altacor® were equitoxic to C. dubia at LC50 based on overlap of the 95% CL. In the population study, chlorantraniliprole and Altacor® concentrations equivalent to the acute LC5, 10, 25, and 50 for each product were evaluated on populations of C. dubia. Number of individuals after 21 d was the endpoint evaluated. T-tests conducted at each LC value indicated that there was no significant difference in population size between these two products at each LC value evaluated. Previous studies show that toxicity can vary greatly between formulated and technical grade pesticides. However, our results show that chlorantraniliprole and its formulated product, Altacor® were equally toxic to C. dubia. Therefore, making assumptions about the toxicity of formulated and unformulated products is ill advised.


Assuntos
Cladóceros , Inseticidas , Poluentes Químicos da Água , Humanos , Animais , ortoaminobenzoatos/toxicidade , Inseticidas/toxicidade , Dose Letal Mediana , Poluentes Químicos da Água/toxicidade
5.
Toxicol Lett ; 367: 48-58, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35868497

RESUMO

Sarin was used as a chemical weapon due to its high neurotoxicity and mortality. Subacute sarin induced cognitive and behavioral disorder. However, the underlying mechanism is still unclear. Here we offered a multi-omic approach for the analysis of altered metabolites, lipids, and proteins to explore the neurotoxicity of subacute sarin. Guinea pigs were administered between the shoulder blades 16.8 µg/kg of sarin in a volume of 1.0 ml/kg body weight by subcutaneous injection once daily for 14 days. At the end of the final injection, guinea pigs were sacrificed, and striatum were dissected for analysis. A total of 138 different metabolites were identified in the metabolome analysis. Lipids and lipid-like molecules is the largest group (38.41%). For lipidomic analysis, a total of 216 lipids were identified. In proteomic study, over 4300 proteins were identified and quantified. By integrating these enriched components, we demonstrated that the joint pathways disturbed by subacute sarin mainly involving lipid, purine and pyrimidine metabolism in guinea pig striatum. Overall, this study highlights the powerfulness of omics platforms to deepen the understanding of nerve agents caused neurotoxicity.


Assuntos
Substâncias para a Guerra Química , Síndromes Neurotóxicas , Animais , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Cobaias , Homeostase , Dose Letal Mediana , Lipidômica , Lipídeos , Síndromes Neurotóxicas/metabolismo , Proteômica , Purinas , Pirimidinas/toxicidade , Sarina/toxicidade
6.
Environ Pollut ; 308: 119691, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35792294

RESUMO

The glass clover snail, Monacha cartusiana (M. cartusiana) is one of the most seriously impacting economic animal pests spreading across Egypt which inflicts severe damages to the agriculture. A green route is developed by deploying an abundant Rosemary plant leaves aqueous extract to synthesize ZnO and F-doped ZnO (F-ZnO) nanoparticles (NPs) that display high molluscicidal activities against the M. cartusiana land snails via leaf dipping and contact techniques. The effect of lethal concentrations, that kills 50% of exposed snails (LC50) value of the treatments, is examined on the activity of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), enzymes, total protein (TP), total lipids (TL) and cholesterol level of snails, including the histopathological evaluation of the digestive gland and foot of M. Cartusiana. Their molluscicidal activity as poisonous baits under field conditions is also evaluated and compared to the recommended molluscicide, Neomyl. The results show that F- doping dramatically improves the snail control capability of ZnO NPs, and promotes a considerable increase in both ALT and AST enzymes with an enhancement of TL and Cholesterol levels, but a significant decrease in TP content and ALP activity in treated snails compared to the control group. The LC50 values are found to be 1381.55 and 2197.59 ppm using the leaf dipping for F-ZnO and ZnO, while 237.51 and 245.90 ppm can be achieved using the contact technique, respectively. The greenly synthesized F-ZnO and ZnO NPs induce severe histological alterations in the digestive gland and foot of M. cartusiana, including a complete destruction of the digestive tubules. The histological evaluation of the foot of M. cartusiana exposed to ZnO, shows a rupture of the epithelial layer of the foot sole, while F- ZnO NPs causes the folds of the foot becoming deeper and the rupture of epithelial layer. Our field experiments further demonstrate that F-ZnO achieves 60.08% reduction, while ZnO attains 56.39% diminution in snail population compared to the commercial, Neomyl (69.55%), exhibiting great potentials in controlling the harmful land snail populations.


Assuntos
Moluscocidas , Óxido de Zinco , Animais , Colesterol , Dose Letal Mediana , Moluscocidas/toxicidade , Extratos Vegetais/química , Folhas de Planta , Óxido de Zinco/toxicidade
7.
Ecotoxicology ; 31(6): 1035-1043, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35831720

RESUMO

Chloroquine (CQ) has been widely used for many years against malaria and various viral diseases. Its important use and high potential to being persistent make it of particular concern for ecotoxicological studies. Here, we evaluated the toxicity of CQ alone and in combination with copper (Cu) to the euryhaline rotifer Proales similis. All experiments were carried out using chronic toxicity reproductive five-day tests and an application factor (AF) of 0.05, 0.1, 0.3, and 0.5 by multiplying the 24-h LC50 values of CQ (4250 µg/L) and Cu (68 µg/L), which were administered in solution. The rate of population increase (r, d-1) ranged from 0.50 to 52 (controls); 0.20 to 0.40 (CQ); 0.09 to 0.43 (Cu); and -0.03 to 0.30 (CQ-Cu) and showed significant decrease as the concentration of both chemicals in the medium increased. Almost all tested mixtures induced synergistic effects, mainly as the AF increased. We found that the presence of Cu intensifies the vulnerability of organisms to CQ and vice versa. These results stress the potential hazard that these combined chemicals may have on the aquatic systems. This research suggests that P. similis is sensitive to CQ as other standardized zooplankton species and may serve as a potential test species in the risk assessment of emerging pollutants in marine environments.


Assuntos
Cobre , Rotíferos , Animais , Cloroquina/toxicidade , Cobre/toxicidade , Dose Letal Mediana , Testes de Toxicidade Crônica
8.
Ecotoxicol Environ Saf ; 242: 113907, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35901590

RESUMO

Copper is both an essential trace element and a potent pesticide. The use of copper as an antifoulant has increased in the last decades in line with the expanding aquaculture and shipping industries. In aquatic environments, it also affects non-target taxa. One of which are copepods, which constitute the central link in the marine food web. Despite their ecological importance, there are no systematic reviews of the lethal concentration range and drivers of copper toxicity in this taxon. Here, we combined literature data from 31 peer-reviewed articles recording the Lethal Concentration 50 (LC50) for copper in copepods and the experiments' respective environmental, developmental, and taxonomic parameters. The LC50 is a traditional endpoint for toxicity testing used in standardized toxicity testing and many ecological studies. In total, we were able to extract 166 LC50 entries. The variability in the metadata allowed for a general analysis of the drivers of copper sensitivity in copepods. Using a generalized additive modeling approach, we find that temperature increases copper toxicity when above approximately 25℃. Counter to our expectations; salinity does not influence copper sensitivity across copepod species. Unsurprisingly, nauplii are more susceptible to copper exposure than adult copepods, and benthos-associated harpacticoids are less sensitive to copper than pelagic calanoids. Our final model can predict sensible specific-specific copper concentrations for future experiments, thus giving an informed analytical approach to range testing in future dose-response experiments. Our model can also potentially improve ecological risk assessment by accounting for environmental differences. The approach can be applied to other toxicants and taxa, which may reveal underlying patterns otherwise obscured by taxonomic and experimental variability.


Assuntos
Copépodes , Poluentes Químicos da Água , Animais , Copépodes/fisiologia , Cobre/toxicidade , Dose Letal Mediana , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade
9.
Food Chem Toxicol ; 168: 113301, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35868606

RESUMO

A battery of studies was conducted to examine the toxicological potential of dihydroberberine (DHBBR), a derivative of berberine (BBR). The genotoxicity studies conducted on DHBBR, including the bacterial reverse mutation test, the mouse lymphoma assay, and the in vivo micronucleus test, showed that DHBBR is non-mutagenic and non-clastogenic. An acute oral toxicity study revealed that the LD50 of DHBBR in female Sprague Dawley rats was greater than 2000 mg/kg bw. In a 14-day oral dose range finding study, the maximum tolerated dose was the high dose, 120 mg/kg bw/day. Based on a 90-day oral toxicity study in male and female Sprague Dawley rats, it was concluded that the NOAEL for DHBBR is 100 mg/kg bw/day, the highest dose tested.


Assuntos
Berberina , Animais , Berberina/análogos & derivados , Berberina/toxicidade , Feminino , Dose Letal Mediana , Masculino , Camundongos , Testes para Micronúcleos , Nível de Efeito Adverso não Observado , Ratos , Ratos Sprague-Dawley
10.
Environ Sci Pollut Res Int ; 29(58): 87319-87333, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35802337

RESUMO

Lactic and formic acid are two commonly found monocarboxylic organic acids. Lactic acid is discharged into the water bodies as acidic industrial effluent from the food, cosmetic, chemical, and pharmaceutical industries, whereas formic acid is discharged from various paper, leather tanning, and textile processing industries. The present study investigated the toxicity of both organic acids upon the benthic oligochaete worm Tubifex tubifex. The 96-h median lethal concentration (LC50) values for lactic and formic acid are determined as 143.81 mg/l and 57.99 mg/l respectively. The effects of two sublethal concentrations (10% and 30% of 96 h LC50) of these acids on differential expression of oxidative stress enzymes are investigated. The comparative analysis of acute toxicity demonstrates that formic acid exposure is more detrimental to T. tubifex than lactic acid. The in silico structural analysis predicts that formic acid can interact with cytochrome c oxidase of the electron transport system and thereby inhibits its functionality and induces reactive oxygen species production. Integrated biomarker response (IBR) analysis illustrates that overall oxidative stress of formic acid to T. tubifex is significantly higher than that of lactic acid, which supports the structural analysis. It is concluded from this study that toxicokinetic-toxicodynamic and species sensitivity distributions studies are helpful for ecological risk management of environmental toxicants.


Assuntos
Oligoquetos , Poluentes Químicos da Água , Animais , Poluentes Químicos da Água/análise , Dose Letal Mediana , Formiatos , Ácido Láctico
11.
Toxicon ; 215: 6-10, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35660626

RESUMO

Foothill death camas (Zigadenus paniculatus) is a native, cool-season, bulbous perennial forb found throughout the western U.S. The toxins in death camas are steroidal alkaloids. Zygacine is often the most abundant alkaloid in death camas and is believed to be the primary toxic component. A population of death camas with plants consisting of two different chemical profiles (chemotypes) growing within the same location were identified. The objective of this study was to determine the percentage of a death camas population represented by each of the different chemotypes and to determine if there was a difference in toxicity between the two chemotypes. One third of the population sampled consisted of chemotype 1, while two-thirds of the population consisted of chemotype 2. The zygacine concentration of chemotype 1 was three times higher than chemotype 2. Chemotype 2 contained higher concentrations of several other steroidal alkaloids than chemotype 1. We hypothesized that chemotype 1, which consisted of higher concentrations of zygacine, would be more toxic than chemotype 2. The acute toxicity of each chemotype was determined in mice and sheep. In the mouse LD50 study, the acute toxicity of the chemotype 1 alkaloids (2.3 mg/kg BW) was different than the chemotype 2 alkaloids (3.2 mg/kg BW). However, in the sheep study there were no differences in the adverse effects between chemotypes. Based upon the results of this study, caution should be taken when livestock are grazing death camas, as both chemotypes of death camas appear to pose a similar risk to grazing livestock.


Assuntos
Alcaloides , Zigadenus , Alcaloides/toxicidade , Animais , Dose Letal Mediana , Gado , Camundongos , Raízes de Plantas , Ovinos
12.
Environ Toxicol Chem ; 41(8): 2003-2007, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35661245

RESUMO

Long-chain per- and poly-fluoroalkyl substances (PFAS) have been the active ingredients in firefighting foams for more than 50 years. Due to their extreme persistence, regulatory agencies are concerned about their potential adverse environmental and health impacts. Recently, nonfluorinated chemical constituents have been proposed for use in fire-fighting foams in an effort to reduce the potential negative impacts of PFAS on terrestrial and aquatic flora and fauna. However, it is important to also determine the potential ecotoxicity of these nonfluorinated foam products, because we have little toxicological information for many of them. In preparation for a chronic study, we conducted an acute (24-h) oral toxicity test in northern bobwhite quail (Colinus virginianus) using six different fluorine-free foams; five were commercial foams (BioEx ECOPOL A, Fomtec Enviro USP, National Foam Avio Green KHC, National Foam NFD 20-391, and Solberg Re-Healing Foam), and one was an experimental foam (NRL 502W). A short-chain PFAS-based foam (Buckeye Platinum Plus C6) was also evaluated for comparative purposes. Groups of five birds were initially pseudogavaged with a volume of each product corresponding to a "limit" (the highest exposure concentration expected to occur environmentally). Only one bird (1 of 35) died during the limit test, indicating that all seven products have an acute median lethal dose in adult quail at or above the limit (~1500 mg/kg body wt). Environ Toxicol Chem 2022;41:2003-2007. © 2022 SETAC.


Assuntos
Colinus , Fluorcarbonetos , Animais , Fluorcarbonetos/toxicidade , Dose Letal Mediana , Codorniz , Testes de Toxicidade
13.
J Appl Toxicol ; 42(11): 1766-1776, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35653511

RESUMO

Fish is one of the model animals used to evaluate the adverse effects of a chemical exposed to the ecosystem. However, its low throughput and relevantly high expense make it impossible to test all new chemicals in manufacture. Hence, using in silico models to prioritize compounds to be tested has been widely applied in environmental risk assessment and drug discovery. In this study, we constructed the local predictive models for four fish species, including bluegill sunfish, rainbow trout, fathead minnow, and sheepshead minnow, and the global models with all four fish data. A total of 1874 unique compounds with their labels, that is, toxic (LC50 < 10 ppm) or nontoxic, were collected from ECOTOX and literature. Both conventional machine learning methods and the deep learning architecture, graph convolutional network (GCN), were used to build predictive models. The classification accuracy of the best local model for each fish species was higher than 0.83. For the global models, two strategies including consistency prediction and probability threshold were adopted to improve the predictive capability at the cost of limiting applicability domain. For 63% of compounds in domain, the accuracy was around 0.97. By comparison of the deep learning and machine learning methods, we found that the single-task GCN showed specific advantages in performance, and multitask GCN showed no advantages over the conventional machine learning methods. The data and models are available on GitHub (https://github.com/ChemPredict/ChemicalAquaticToxicity).


Assuntos
Cyprinidae , Aprendizado Profundo , Animais , Ecossistema , Dose Letal Mediana , Aprendizado de Máquina
14.
Regul Toxicol Pharmacol ; 133: 105188, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35636684

RESUMO

MPTA is a novel extract product derived from Macleaya cordata (Willd.) R. Br., which has good anti-inflammatory and antioxidant activity. The aim of this study was to investigate the acute oral toxicity and 90-day sub-chronic oral toxicity of MPTA. In the acute toxicity study, 50 SD rats of both sexes were randomly divided into 5 groups and dosed in a gradient from 197.53 mg/kg to 1000.00 mg/kg bw. Toxic effects were observed up to 14 days and LD50 was calculated. In a subchronic toxicity test, male and female SD rats were orally dosed repeatedly with 96.40, 19.28, 3.86 mg/kg bw of MPTA for 90 days. In addition, a control group was set up in the subchronic study. The acute toxicity test showed that the oral LD50 of MPTA was 481.99 mg/kg with a 95% confidence interval of 404.24-574.70 mg/kg. MPTA did not appear to induce toxic effects in the longer term in terms of food and water consumption, weight gain, haematological and clinical biochemical parameters and pathological examination. The first data on the potential toxicity of MPTA was provided to highlight the safety of short-term to longer-term oral administration of MPTA, and the experimental results yield and establish a NOEAL of 96.40 mg/kg/d for MPTA.


Assuntos
Extratos Vegetais , Compostos de Amônio Quaternário , Administração Oral , Animais , Feminino , Dose Letal Mediana , Masculino , Extratos Vegetais/toxicidade , Compostos de Amônio Quaternário/toxicidade , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica
15.
Appl Biochem Biotechnol ; 194(9): 3890-3900, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35556209

RESUMO

Cadmium chloride is a metal salt used in industries in a large scale. Trichogaster (Colisa) fasciata (common name banded gourami) is an air-breathing fresh water fish with both nutritional and ornamental values. In this present study, as per EPA guidelines, acute toxicity bioassay was performed in a 96-h static test method in four replicates, each replicate having one control and five concentrations (25, 50, 75, 100 and 125 mg/L, respectively) of the metal salt. A total of 192 fish was used in the study in four series with each replicate containing 8 fish per concentration. The water temperature was maintained at 20-22℃ during the study. The data observed were analysed statistically on the basis of Finney's Probit Analysis method using SPSS software. The estimated 96-h LC50 value of cadmium chloride for the fish was 49.5 mg/L.


Assuntos
Perciformes , Poluentes Químicos da Água , Animais , Bioensaio , Cádmio/toxicidade , Cloreto de Cádmio/toxicidade , Peixes , Água Doce , Dose Letal Mediana , Testes de Toxicidade Aguda
16.
Sci Rep ; 12(1): 8880, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35614210

RESUMO

The chemical risk assessment paradigm is shifting from "substance-based" to "product/mixture-based" and from "animal testing" to "alternative testing" under chemical regulations. Organisms and the environment may be exposed to mixtures rather than a single substance. Conducting toxicity tests for all possible combinations is impractical due to the enormous combinatorial complexity. This study highlights the development and application case studies of Mixture Risk Assessment Toolbox, a novel web-based platform that supports mixture risk assessment through the use of different prediction models and public databases. This integrated framework provides new functional values for assessors to easily screen and compare the toxicity of mixture products using different computational techniques and find strategic solutions to reduce the mixture toxicity in the product development process. The toolbox ( https://www.mratoolbox.org ) includes four additive toxicity models: two conventional (Concentration Addition; and Independent Action) and two advanced (Generalized Concentration Addition; and Quantitative Structure-Activity Relationship-based Two-Stage Prediction) models. We demonstrated the multiple functions of the toolbox using three cases: (i) how it can be used to calculate the mixture toxicity, (ii) those for which safety data sheet (SDS) only indicating representative toxicity values (EC50; and LC50), and (iii) those comprising chemicals with low toxic effects.


Assuntos
Relação Quantitativa Estrutura-Atividade , Testes de Toxicidade , Animais , Internet , Dose Letal Mediana , Medição de Risco/métodos
17.
Aquat Toxicol ; 248: 106175, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35523058

RESUMO

Risk assessment of chemicals is still primarily focusing on single compound evaluation, even if environmental contamination consists of a mixture of pollutants. The concentration addition (CA) and independent action (IA) models have been developed to predict mixture toxicity. Both models assume no interaction between the components, resulting in an additive mixture effect. In the present study, the embryo toxicity test (OECD TG no. 236) with zebrafish embryos (Danio rerio) was performed to investigate whether the toxicity caused by binary, ternary, and quaternary mixtures of organic (Benzo[a]pyrene, perfluorooctanesulfonate, and 3,3´,4,4´,5-pentachlorobiphenyl 126) and inorganic (arsenate) pollutants can be predicted by CA and IA. The acute toxicity and sub-lethal alterations such as lack of blood circulation were investigated. The models estimated the mixture toxicity well and most of the mixtures were additive. However, the binary mixture of PFOS and PCB126 caused a synergistic effect, with almost a ten-fold difference between the observed and predicted LC50-value. For most of the mixtures, the CA model was better in predicting the mixture toxicity than the IA model, which was not expected due to the chemicals' different modes of action. In addition, some of the mixtures caused sub-lethal effects not observed in the single compound toxicity tests. The mixture of PFOS and BaP caused a division of the yolk and imbalance was caused by the combination of PFOS and As and the ternary mixture of PFOS, As, and BaP. Interestingly, PFOS was part of all three mixtures causing the mixture specific sub-lethal effects. In conclusion, the present study shows that CA and IA are mostly resulting in good estimations of the risks that mixtures with few components are posing. However, for a more reliable assessment and a better understanding of mixture toxicity, further investigations are required to study the underlying mechanisms.


Assuntos
Poluentes Ambientais , Poluentes Químicos da Água , Animais , Poluentes Ambientais/toxicidade , Dose Letal Mediana , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
18.
PLoS One ; 17(4): e0265962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35390011

RESUMO

Current USEPA ecological risk assessments for pesticide registration include a determination of potential risks to bees. Toxicity data are submitted to support these assessments and the USEPA maintains a large database containing acute and chronic toxicity data on adult and larval honey bees (Apis mellifera), which USEPA considers a surrogate for Apis and non-Apis bees. We compared these toxicity data to explore possible trends. This analysis indicated a significant correlation between acute contact and oral median lethal dose (LD50) values for adult honey bees (ρ = 0.74, p <0.0001). Using default EPA modeling assumptions, where exposure for an individual bee is roughly 12x lower through contact than through ingestion, the analysis indicates that the oral LD50 is similarly if not more protective of the contact LD50 for the majority of pesticides and modes of action evaluated. The analysis also provided evidence that compounds with a lower acute toxicity for adults through contact and oral exposure pathways may still be acutely toxic for larvae. The acute toxicity of herbicides and fungicides was higher for larvae relative to oral and contact toxicity for adult honey bees for the same compounds and the no observed adverse effect level (NOAEL) from chronic toxicity studies were lower for larvae relative to adults, indicating increased sensitivity of larvae. When comparing 8-day LD50 values between single dose larval acute studies to those derived from repeat dose 22-day larval chronic toxicity studies, the LD50 values derived from chronic studies were significantly lower than those from acute toxicity tests (Z = -37, p = 0.03).


Assuntos
Praguicidas , Animais , Abelhas , Larva , Dose Letal Mediana , Praguicidas/toxicidade , Estudos Retrospectivos , Testes de Toxicidade Aguda
19.
Molecules ; 27(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35268738

RESUMO

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and ß-sitosterol (4).


Assuntos
Artemisia/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Flavonoides/química , SARS-CoV-2/enzimologia , Animais , Artemisia/metabolismo , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Proteases 3C de Coronavírus/metabolismo , Teoria da Densidade Funcional , Flavonoides/isolamento & purificação , Flavonoides/metabolismo , Flavonoides/farmacologia , Humanos , Dose Letal Mediana , Masculino , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ratos , SARS-CoV-2/isolamento & purificação , Pele/efeitos dos fármacos , Pele/patologia
20.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35269835

RESUMO

The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till-McCulloch's test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated ß-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12-1/8 LD10), both parenterally and intragastrically. In this case, its therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses (ED84-98-141-224 mg/kg) are an order less than the maximum tolerated doses-1/16-1/10 LD10. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) ß-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.


Assuntos
Proteção Radiológica , Protetores contra Radiação , Animais , Raios gama , Dose Letal Mediana , Camundongos , Fosfatos , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Ratos
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