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1.
Zhongguo Zhong Yao Za Zhi ; 47(15): 4183-4189, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046909

RESUMO

This study aims to establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method for determining the concentrations of triptolide(TP) in plasma and liver, and to explore the toxicokinetics of TP and the relationship between TP exposure and liver injury in C57 BL/6 mice, so as to provide reference for dissecting the toxicity mechanism of TP. The liquid chromatography was conducted with ZORBAX SB-C_(18) column(3.0 mm×100 mm, 3.5 µm) and the mobile phase of methanol-0.05 mmol·L~(-1) ammonium acetate. Electrospray ionization(ESI) and multiple reaction monitoring(MRM) mode were employed for mass spectrometry. After oral administration of TP(toxic dose 600 µg·kg~(-1)), the blood and liver tissues of the C57 BL/6 mice were collected at different time points to measure the TP concentrations in plasma and liver tissues. Furthermore, the blood biochemical indexes, including alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), and total bile acid(TBA), were determined. After being processed by DAS 2.0, the experiment data showed that the TP in mice had the toxicokinetic parameters of T_(max)=5 min, C_(max)=14.38 ng·mL~(-1), t_(1/2)=0.76 h, AUC_(0-t)=5.63 h·ng·mL~(-1), MRT_(0-t)=0.56 h, and CL_(Z/F)=103.19 L·h~(-1)·kg~(-1). The trend of TP concentration in mouse liver tissue was consistent with that in plasma. The concentration of TP peaked at the time point of 5 min and then decreased until TP was completely metabolized. The plasma biochemical indexes(ALT, AST, ALP, and TBA) showed no significant changes within 3 h after TP administration. TP had high clearance rate and short residence time and did not significantly increase the blood biochemical indexes in mice. The results suggested that the exposure amount of free TP in vivo cannot directly cause liver injury, which might be caused by the binding of TP to some substances or the stimulation of inflammation and immune response.


Assuntos
Fígado , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão/métodos , Diterpenos , Compostos de Epóxi , Camundongos , Fenantrenos , Espectrometria de Massas em Tandem/métodos , Toxicocinética
2.
Zhongguo Zhong Yao Za Zhi ; 47(15): 4214-4220, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046912

RESUMO

This study aims to establish an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) method for the determination of emodin-8-O-ß-D-glucoside(EG) and its metabolites in plasma, and to investigate the toxicokinetics(TK) behavior of them in rats. To be specific, the TK of EG and its metabolites from the first to the last administration in the repeated dose toxicity study was determined, and the kinetic parameters were calculated. The exposure of EG prototype and metabolites in rat plasma after oral administration of different doses of EG was evaluated. The result showed that the prototype of EG and its metabolites aloe-emodin-8-O-ß-D-glucoside, emodin, aloe-emodin, and hydroxyemodin could be detected in rats after oral administration of high-, medium-, and low-dose EG. The area under the curve(AUC) of the prototype and metabolites after the first and last administration was in positive correlation with the dose. The time to the maximum concentration(T_(max)) of EG and metabolites in the three administration groups was <6 h, and the longest in vivo residence time was 12 h. The T_(max) and in vivo residence time of EG were prolonged with the increase in the dose. The metabolites emodin, aloe-emodin, and hydroxyemodin all had two peaks. Both hydroxyemodin and aloe-emodin exhibited increased plasma exposure, slow metabolism, and accumulation in vivo. In addition, aloe-emodin-8-O-ß-D-glucoside and emodin disappeared with the increase in dose, suggesting the change of the metabolic pathway of EG in vivo in the case of high-dose administration. The mechanism of high-dose EG in vivo needs to be further explored. This study preliminarily elucidates the TK behavior of EG in rats, which is expected to support clinical drug use.


Assuntos
Emodina , Animais , Antraquinonas , Cromatografia Líquida de Alta Pressão/métodos , Emodina/toxicidade , Glucosídeos/toxicidade , Espectrometria de Massas , Ratos , Toxicocinética
3.
Environ Sci Technol ; 56(18): 13189-13199, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36055240

RESUMO

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental contaminants, and their relative stability and high bioaccumulation potential create a challenging risk assessment problem. Zebrafish (Danio rerio) data, in principle, can be synthesized within a quantitative adverse outcome pathway (qAOP) framework to link molecular activity with individual or population level hazards. However, even as qAOP models are still in their infancy, there is a need to link internal dose and toxicity endpoints in a more rigorous way to further not only qAOP models but adverse outcome pathway frameworks in general. We address this problem by suggesting refinements to the current state of toxicokinetic modeling for the early development zebrafish exposed to PFAS up to 120 h post-fertilization. Our approach describes two key physiological transformation phenomena of the developing zebrafish: dynamic volume of an individual and dynamic hatching of a population. We then explore two different modeling strategies to describe the mass transfer, with one strategy relying on classical kinetic rates and the other incorporating mechanisms of membrane transport and adsorption/binding potential. Moving forward, we discuss the challenges of extending this model in both timeframe and chemical class, in conjunction with providing a conceptual framework for its integration with ongoing qAOP modeling efforts.


Assuntos
Fluorcarbonetos , Poluentes Químicos da Água , Animais , Fluorcarbonetos/toxicidade , Cinética , Toxicocinética , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
4.
Int J Mol Sci ; 23(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36012484

RESUMO

Phytochemicals like pyrrolizidine alkaloids (PAs) can affect the health of humans and animals. PAs can occur for example in tea, honey or herbs. Some PAs are known to be cytotoxic, genotoxic, and carcinogenic. Upon intake of high amounts, hepatotoxic and pneumotoxic effects were observed in humans. This study aims to elucidate different toxicokinetic parameters like the uptake of PAs and their metabolism with in vitro models. We examined the transport rates of differently structured PAs (monoester, open-chained diester, cyclic diester) over a model of the intestinal barrier. After passing the intestinal barrier, PAs reach the liver, where they are metabolized into partially instable electrophilic metabolites interacting with nucleophilic centers. We investigated this process by the usage of human liver, intestinal, and lung microsomal preparations for incubation with different PAs. These results are completed with the detection of apoptosis as indicator for bioactivation of the PAs. Our results show a structure-dependent passage of PAs over the intestinal barrier. PAs are structure-dependently metabolized by liver microsomes and, to a smaller extent, by lung microsomes. The detection of apoptosis of A549 cells treated with lasiocarpine and monocrotaline following bioactivation by human liver or lung microsomes underlines this result. Conclusively, our results help to shape the picture of PA toxicokinetics which could further improve the knowledge of molecular processes leading to observed effects of PAs in vivo.


Assuntos
Alcaloides de Pirrolizidina , Animais , Carcinógenos/farmacologia , Humanos , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Alcaloides de Pirrolizidina/química , Toxicocinética
5.
Regul Toxicol Pharmacol ; 134: 105238, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35931234

RESUMO

Physiologically based pharmacokinetic (PBPK) models are a means of making important linkages between exposure assessment and in vitro toxicity. A key constraint on rapid application of PBPK models in risk assessment is traditional reliance on substance-specific in vivo toxicokinetic data to evaluate model quality. Bounding conditions, in silico, in vitro, and chemical read-across approaches have been proposed as alternative sources for metabolic clearance estimates. A case study to test consistency of predictive ability across these approaches was conducted using trimethylbenzenes (TMB) as prototype chemicals. Substantial concordance was found among TMB isomers with respect to accuracy (or inaccuracy) of approaches to estimating metabolism; for example, the bounding conditions never reproduced the human in vivo toxicokinetic data within two-fold. Using only approaches that gave acceptable prediction of in vivo toxicokinetics for the source compound (1,2,4-TMB) substantially narrowed the range of plausible internal doses for a given external dose for occupational, emergency response, and environmental/community health risk assessment scenarios for TMB isomers. Thus, risk assessments developed using the target compound models with a constrained subset of metabolism estimates (determined for source chemical models) can be used with greater confidence that internal dosimetry will be estimated with accuracy sufficient for the purpose at hand.


Assuntos
Modelos Biológicos , Exposição Ocupacional , Humanos , Cinética , Exposição Ocupacional/efeitos adversos , Medição de Risco/métodos , Toxicocinética
6.
Biosens Bioelectron ; 215: 114489, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35961129

RESUMO

Due to the technical barriers and complexity of biological detection equipment, the intensive study of the toxicokinetics of uranium has been limited. In other words, efficient biodetection system for accurately and conveniently uranium analysis is the core demand. In this study, an efficient monitoring system was developed for rapid visual detection of trace UO22+ in biological samples by using electrochemiluminescence (ECL) imaging technology. In detail, poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-(1-cyanovinylene-1,4-phenylene)] (CN-PPV) was prepared as polymer dots (Pdots), which give a low background signal and notable visual UO22+ response in accurate monitoring as well as high selectivity. This sensor was successfully applied to visual UO22+ detection in blood and urine in an oral uranyl metabolism rat model. The results showed that UO22+ concentration in rat blood reached the maximum 30 min after administration and then decreased rapidly. Even after 48 h, trace UO22+ could still be detected with the developed method, demonstrating its ultrahigh sensitivity and selectivity. This work is the first visualized UO22+ detection via ECL in biological samples. This ECL method for accurate trace UO22+ monitoring in biological samples indicates its wide field of application with good prospects such as nuclear forensics, evidence-based medicine, and toxicological research.


Assuntos
Técnicas Biossensoriais , Urânio , Animais , Técnicas Biossensoriais/métodos , Fotometria , Ratos , Toxicocinética , Urânio/análise , Urânio/toxicidade
7.
Ecotoxicol Environ Saf ; 243: 113971, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35981482

RESUMO

Anticoagulant rodenticides have been widely used to eliminate wild rodents, which as invasive species on remote islands can disturb ecosystems. Since rodenticides can cause wildlife poisoning, it is necessary to evaluate the sensitivity of local mammals and birds to the poisons to ensure the rodenticides are used effectively. The Bonin Islands are an archipelago located 1000 km southeast of the Japanese mainland and are famous for the unique ecosystems. Here the first-generation anticoagulant rodenticide diphacinone has been used against introduced black rats (Rattus rattus). The only land mammal native to the archipelago is the Bonin fruit bat (Pteropus pselaphon), but little is known regarding its sensitivity to rodenticides. In this study, the Egyptian fruit bats (Rousettus aegyptiacus) was used as a model animal for in vivo pharmacokinetics and pharmacodynamics analysis and in vitro enzyme kinetics using their hepatic microsomal fractions. The structure of vitamin K epoxide reductase (VKORC1), the target protein of the rodenticide in the Bonin fruit bat, was predicted from its genome and its binding affinity to rodenticides was evaluated. The Egyptian fruit bats excreted diphacinone slowly and showed similar sensitivity to rats. In contrast, they excreted warfarin, another first-generation rodenticide, faster than rats and recovered from the toxic effect faster. An in silico binding study also indicated that the VKORC1 of fruit bats is relatively tolerant to warfarin, but binds strongly to diphacinone. These results suggest that even chemicals with the same mode of action display different sensitivities in different species: fruit bat species are relatively resistant to warfarin, but vulnerable to diphacinone.


Assuntos
Quirópteros , Rodenticidas , Animais , Anticoagulantes/toxicidade , Quirópteros/metabolismo , Ecossistema , Mamíferos/metabolismo , Fenindiona/análogos & derivados , Ratos , Rodenticidas/toxicidade , Toxicocinética , Vitamina K Epóxido Redutases/genética , Vitamina K Epóxido Redutases/metabolismo , Varfarina/toxicidade
8.
BMC Complement Med Ther ; 22(1): 220, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35971113

RESUMO

BACKGROUND: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms. METHODS: Sprague-Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms. RESULTS: Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female). CONCLUSIONS: TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF.


Assuntos
Alcaloides , Berberina , Coptis , Medicamentos de Ervas Chinesas , Alcaloides/farmacologia , Animais , Peso Corporal , Coptis/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Etanol , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Toxicocinética , Aumento de Peso
9.
Environ Sci Technol ; 56(16): 11547-11558, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35896009

RESUMO

Chemicals with elevated bioaccumulation profiles present potential hazards to public health and the environment. Ionizable organic compounds (IOCs) increasingly represent a large proportion of commercial chemicals; however, historical approaches for bioaccumulation determinations are mainly developed for neutral chemicals, which were not appropriate for IOCs. Herein, we employed the zebrafish embryo, a common vertebrate model in environmental and biomedical studies, to elucidate toxicokinetics and bioconcentration of eight IOCs with diverse physicochemical properties and pharmacokinetic parameters. At an environmentally relevant pH (7.5), most IOCs exhibited rapid uptake and depuration in zebrafish, suggesting the ionized forms of IOCs are readily bioavailable. Bioconcentration factors (BCF) of these IOCs ranged from 0.0530 to 250 L·kg-1 wet weight. The human pharmacokinetic proportionality factor, apparent volume of distribution (VD), better predicted the BCF of selected IOCs than more commonly used hydrophobicity-based parameters (e.g., pH-dependent octanol-water distribution ratio, Dow). Predictive bioaccumulation models for IOCs were constructed and validated using VD alone or with Dow. Significant relationships between fish BCF and human VD, which is readily available for pharmaceuticals, highlighted the utility of biologically based "read-across" approaches for predicting bioaccumulative potential of IOCs. Our novel findings thus provided an understanding of the partitioning behavior and improved predictive bioconcentration modeling for IOCs.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Bioacumulação , Humanos , Compostos Orgânicos/química , Toxicocinética , Poluentes Químicos da Água/química
10.
Sci Total Environ ; 843: 157048, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35779734

RESUMO

The assessment of chemical mixture toxicity is one of the major challenges in ecotoxicology. Chemicals can interact, leading to more or less effects than expected, commonly named synergism and antagonism respectively. The classic ad hoc approach for the assessment of mixture effects is based on dose-response curves at a single time point, and is limited to identifying a mixture interaction but cannot provide predictions for untested exposure durations, nor for scenarios where exposure varies in time. We here propose a new approach using toxicokinetic-toxicodynamic modelling: The General Unified Threshold model of Survival (GUTS) framework, recently extended for mixture toxicity assessment. We designed a dedicated mechanistic interaction module coupled with the GUTS mixture model to i) identify interactions, ii) test hypotheses to identify which chemical is likely responsible for the interaction, and finally iii) simulate and predict the effect of synergistic and antagonistic mixtures. We tested the modelling approach experimentally with two species (Enchytraeus crypticus and Mamestra brassicae) exposed to different potentially synergistic mixtures (composed of: prochloraz, imidacloprid, cypermethrin, azoxystrobin, chlorothalonil, and chlorpyrifos). Furthermore, we also tested the model with previously published experimental data on two other species (Bombus terrestris and Daphnia magna) exposed to pesticide mixtures (clothianidin, propiconazole, dimethoate, imidacloprid and thiacloprid) found to be synergistic or antagonistic with the classic approach. The results showed an accurate simulation of synergistic and antagonistic effects for the different tested species and mixtures. This modelling approach can identify interactions accounting for the entire time of exposure, and not only at one time point as in the classic approach, and provides predictions of the mixture effect for untested mixture exposure scenarios, including those with time-variable mixture composition.


Assuntos
Clorpirifos , Inseticidas , Oligoquetos , Animais , Clorpirifos/toxicidade , Daphnia , Inseticidas/química , Toxicocinética
11.
Front Public Health ; 10: 909247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35801236

RESUMO

Various synthetic powders with primary particle sizes at the nanoscale and a high commercial impact have been studied using Wistar rats. The test materials were metal oxides, i.e., TiO2, ZnO and amorphous silica, and carbon black (technical soot). Dosing schemes were in the regular ranges typically used in subacute rat studies to simulate occupational exposure scenarios (mg range). Nanoscaled particle agglomerates have the potential to disintegrate and translocate as individual nanoparticles to remote locations following deposition in the lungs. The toxicokinetic fate of metal oxides post-inhalation in lungs/organs was investigated (i) by chemical analysis of the retained particulate/dissolved matter and (ii) by visualization of particles in various remote organs using transmission electron microscopy (TEM). The three titanium dioxides (NM-103, NM-104, NM-105; JRC coding) showed a very slow dissolution in lung fluids. In contrast, the coated ZnO (NM-111) dissolved quickly and was eliminated from the body within approximately 1 day. The precipitated amorphous silica (NM-200) showed a partial dissolution. Chemical analysis in lungs (particulate and soluble TiO2) and in remote organs (liver and brain) showed a small solubility effect under physiological conditions. The translocation to remote organs was negligible. This confirms that for poorly soluble TiO2 particles there was no considerable translocation to the liver and brain. The chemical analysis of zinc demonstrated a very rapid dissolution of ZnO particles after deposition in the lungs. Statistically significant increases in Zn levels in the lungs were detectable only on day 1 post-exposure (NM-111). Overall, no relevant amounts of increased NM-111 in the ionic or particulate matter were detected in any body compartment. Amorphous silica (NM-200) particles were found in the cytoplasm of intraalveolar macrophages in the lung and the cytoplasm of macrophages in the lung associated lymph node. Interestingly, these particles were found in a few animals of all treatment groups (1, 2.5, and 5 mg/m3 NM-200) even after 91 days post-exposure. In all other organs of the NM-200 treated animals such as the nasal epithelium, trachea, larynx, liver, spleen, kidney, and mesenteric lymph node no particles were found at any time point investigated. Carbon black was tagged internally ("intrinsically") with a γ tracer (7beryllium; half-time: 53.3 days). Due to limited amounts, the test item (0.3 mg per rat lung) was intratracheally instilled into the lungs. This dose avoided a particle overload effect, meaning that the toxicokinetic fate of carbon black could be followed under the approximated physiological conditions of lung clearance. Analysis of the γ labeled carbon black confirmed conclusively that there was no evidence for the translocation of carbon black beyond the lung into the blood or other body compartments. Very small amounts were only detected in lung-associated lymph nodes (LALN). On day 20 post-treatment, upon necropsy, both carbon black samples were practically exclusively found in lungs (75.1% and 91.0%, respectively) and in very small amounts in the lung-associated lymph nodes (LALN), i.e., ~0.5%. In the other organs/tissues, the test item was not significantly detectable. Separation of leukocytes and cell-free supernatant of a bronchoalveolar lavagate by centrifugation revealed that carbon black was completely located in the cell sediment, indicating total engulfment by alveolar macrophages. In conclusion, in occupational settings the nanomaterials titanium dioxide, zinc oxide, amorphous silica, and carbon black acted as microscaled agglomerates, not as individual nanoparticles. They displayed no potential to translocate beyond the lung into the blood compartment. Besides lungs, very small particulate amounts were detected only in LALN. This finding is consistent with the behavior of microscaled poorly soluble particles. Overall, there was no evidence of translocation of the nanomaterials following pulmonary exposures.


Assuntos
Nanopartículas , Exposição Ocupacional , Óxido de Zinco , Animais , Pulmão , Nanopartículas/toxicidade , Óxidos/farmacologia , Material Particulado , Ratos , Ratos Wistar , Dióxido de Silício/toxicidade , Fuligem/toxicidade , Toxicocinética , Óxido de Zinco/toxicidade
12.
Arch Toxicol ; 96(10): 2755-2766, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35788413

RESUMO

Synthetic cannabinoids (SC) are new psychoactive substances known to cause intoxications and fatalities. One reason may be the limited data available concerning the toxicokinetics of SC, but toxicity mechanisms are insufficiently understood so far. Human carboxylesterases (hCES) are widely known to play a crucial role in the catalytic hydrolysis of drugs (of abuse). The aim of this study was to investigate the in vitro contribution of hCES to the metabolism of the 13 SC 3,5-AB-5F-FUPPYCA, AB-5F-P7AICA, A-CHMINACA, DMBA-CHMINACA, MBA-CHMINACA, MDMB-4F-BINACA, MDMB-4en-PINACA, MDMB-FUBICA, MDMB-5F-PICA, MMB-CHMICA, MMB-4en-PICA, MMB-FUBINACA, and MPhP-5F-PICA. The SC were incubated with recombinant hCES1b, hCES1c, or hCES2 and analyzed by liquid chromatography-ion trap mass spectrometry to assess amide or ester hydrolysis in an initial activity screening. Enzyme kinetic studies were performed if sufficient hydrolysis was observed. No hydrolysis of the amide linker was observed using those experimental conditions. Except for MDMB-5F-PICA, ester hydrolysis was always detected if an ester group was present in the head group. In general, SC with a terminal ester bearing a small alcohol part and a larger acyl part showed higher affinity to hCES1 isozymes. Due to the low hydrolysis rates, enzyme kinetics could not be modeled for the SC with a tert-leucine-derived moiety, but hydrolysis reactions of MPhP-5F-PICA and of those containing a valine-derived moiety followed classic Michaelis-Menten kinetics. In conclusion, drug-drug/drug-food interactions or hCES polymorphisms may prolong the half-life of SC and the current results help to estimate the risk of toxicity in the future after combining them with activity and clinical data.


Assuntos
Canabinoides , Drogas Ilícitas , Amidas , Canabinoides/metabolismo , Canabinoides/toxicidade , Hidrolases de Éster Carboxílico/metabolismo , Ésteres , Humanos , Cinética , Toxicocinética
13.
Arch Toxicol ; 96(10): 2639-2654, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35900469

RESUMO

Deoxynivalenol (DON) is the most widespread mycotoxin in food and feedstuffs, posing a persistent health threat to humans and farm animals. The susceptibilities of DON vary significantly among animals, following the order of pigs, mice/rats and poultry from the most to least susceptible. However, no study comprehensively disentangles factors shaping species-specific sensitivity. In this review, the toxicokinetics and metabolism of DON are summarized in animals and humans. Generally, DON is fast-absorbed and widely distributed in multiple organs. DON is first enriched in the plasma, liver and kidney and subsequently accumulates in the intestine. There are also key variations among animals. Pigs and humans are highly sensitive to DON, and they have similar absorption rates (1 h < tmax < 4 h), high bioavailability (> 55%) and long clearance time (2 h < t1/2 < 4 h). Also, both species lack detoxification microorganisms and mainly depend on liver glucuronidation and urine excretion. Mice and rats have similar toxicokinetics (tmax < 0.5 h, t1/2 < 1 h). However, a higher proportion of DON is excreted by feces as DOM-1 in rats than in mice, suggesting an important role of gut microbiota in rats. Poultry is least sensitive to DON due to their fast absorption rate (tmax < 1 h), low oral bioavailability (5-30%), broadly available detoxification gut microorganisms and short clearance time (t1/2 < 1 h). Aquatic animals have significantly slower plasma clearance of DON than land animals. Overall, studies on toxicokinetics provide valuable information for risk assessment, prevention and control of DON contamination.


Assuntos
Micotoxinas , Animais , Disponibilidade Biológica , Fezes , Humanos , Camundongos , Micotoxinas/metabolismo , Ratos , Suínos , Toxicocinética , Tricotecenos
14.
Environ Sci Technol ; 56(14): 10216-10228, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35797464

RESUMO

Bisphenol A (BPA) is an industrial chemical, which has raised human health and environmental concerns due to its endocrine-disrupting properties. BPA analogues are less well-studied despite their wide use in consumer products. These analogues have been detected in water and aquatic organisms around the world, with some analogues showing toxic effects in various species including fish. Here, we present novel organ-specific time-course distribution data of bisphenol Z (BPZ) in female zebrafish (Danio rerio), including concentrations in the ovaries, liver, and brain, a rarely sampled organ with high toxicological relevance. Furthermore, fish-specific in vitro biotransformation rates were determined for 11 selected bisphenols. A physiologically based toxicokinetic (PBTK) model was adapted for four of these bisphenols, which was able to predict levels in the gonads, liver, and brain as well as the whole body within a 2-5-fold error with respect to experimental data, covering several important target organs of toxicity. In particular, predicted liver concentrations improved compared to currently available PBTK models. Predicted data indicate that studied bisphenols mainly distribute to the carcass and gonads and less to the brain. Our model provides a tool to increase our understanding on the distribution and kinetics of a group of emerging pollutants.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Compostos Benzidrílicos/toxicidade , Encéfalo , Feminino , Humanos , Fígado/metabolismo , Fenóis , Toxicocinética , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
15.
Ecotoxicol Environ Saf ; 242: 113875, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35843108

RESUMO

The R-package rbioacc allows to analyse experimental data from bioaccumulation tests where organisms are exposed to a chemical (exposure) then put into clean media (depuration). Internal concentrations are measured over time during the experiment. rbioacc provides turnkey functions to visualise and analyse such data. Under a Bayesian framework, rbioacc fits a generic one-compartment toxicokinetic model built from the data. It provides TK parameter estimates (uptake and elimination rates) and standard bioaccumulation metrics. All parameter estimates, bioaccumulation metrics and predictions of internal concentrations are delivered with their uncertainty. Bioaccumulation metrics are provided in support of environmental risk assessment, in full compliance with regulatory requirements required to approve market release of chemical substances. This paper provides worked examples of the use of rbioacc from data collected through standard bioaccumulation tests, publicly available within the scientific literature. These examples constitute step-by-step user-guides to analyse any new data set, uploaded in the right format.


Assuntos
Poluentes Químicos da Água , Teorema de Bayes , Bioacumulação , Toxicocinética
16.
Environ Toxicol Chem ; 41(9): 2193-2201, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35770718

RESUMO

Understanding the survival of honey bees after pesticide exposure is key for environmental risk assessment. Currently, effects on adult honey bees are assessed by Organisation for Economic Co-operation and Development standardized guidelines, such as the acute and chronic oral exposure and acute contact exposure tests. The three different tests are interpreted individually, without consideration that the same compound is investigated in the same species, which should allow for an integrative assessment. In the present study we developed, calibrated, and validated a toxicokinetic-toxicodynamic model with 17 existing data sets on acute and chronic effects for honey bees. The model is based on the generalized unified threshold model for survival (GUTS), which is able to integrate the different exposure regimes, taking into account the physiology of the honey bee: the BeeGUTS model. The model is able to accurately describe the effects over time for all three exposure routes combined within one consistent framework. The model can also be used as a validity check for toxicity values used in honey bee risk assessment and to conduct effect assessments for real-life exposure scenarios. This new integrative approach, moving from single-point estimates of toxicity and exposure to a holistic link between exposure and effect, will allow for a higher confidence of honey bee toxicity assessment in the future. Environ Toxicol Chem 2022;41:2193-2201. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Assuntos
Praguicidas , Animais , Abelhas , Praguicidas/toxicidade , Medição de Risco , Toxicocinética
17.
Sci Total Environ ; 839: 156388, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35654180

RESUMO

The increasing use of perfluorooctanesulfonate (PFOS) alternatives has led to their release into the aquatic environment. This study sought to determine the effects of exposure concentration on the toxicokinetics of PFOS and its alternatives, including perfluorobutanesulfonic acid (PFBS), perfluorohexanesulfonic acid (PFHxS), chlorinated polyfluorinated ether sulfonate (F-53B) and sodium p-perfluorous nonenoxybenzenesulfonate (OBS) in adult zebrafish by exposure to mixtures of the five per- and polyfluoroalkyl substances (PFAS) at 1, 10, and 100 ng/mL for 28-day, followed by a 14-day depuration. PFAS predominantly accumulated in the blood and liver, and the bioconcentration factor (BCF) decreased in the order of F-53B > PFOS > OBS ≫ PFHxS > PFBS in whole-fish homogenates. The uptake rate constants and BCF of the short-chain PFAS (≤C6) positively correlated with increasing exposure concentration, while the long-chain PFAS (≥C8) exhibited a pattern of first increasing and then decreasing. A consistent increase in the elimination rate constants of short- and long-chain PFAS was observed with increasing exposure concentration. All PFAS form tight conformations with ZSA and ZL-FABP via hydrogen bonding as revealed by molecular docking analysis. Furthermore, chronic combined exposure to PFAS induced the occurrence of vacuolation and oxidative stress in the zebrafish liver. Our findings uniquely inform the concentration-dependent bioconcentration potential and health risks to aquatic organisms of these PFOS alternatives in the environment.


Assuntos
Ácidos Alcanossulfônicos , Fluorcarbonetos , Poluentes Químicos da Água , Ácidos Alcanossulfônicos/toxicidade , Animais , Fluorcarbonetos/análise , Fluorcarbonetos/toxicidade , Simulação de Acoplamento Molecular , Toxicocinética , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
18.
Ecotoxicol Environ Saf ; 241: 113751, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35691199

RESUMO

Pyrethroids pesticides (PPs) are the widely adopted synthetic pesticides for agriculture and fishery. The frequent use of these pesticides leads to the accumulation of residues in the freshwater environments in China, subsequently affecting aquatic organisms and ecosystems. However, there are few reports on the toxicological and risk assessment of aquaculture aquatic products. In this study, the uptake, depuration kinetics and potential risk to human health and ecology of fenpropathrin, cypermethrin, fenvalerate, and deltamethrin were assessed using tilapia. The results indicated that four PPs were readily accumulated by tilapia. The bioconcentration factors (BCF) of the PPs in plasma and muscle were between 71.3 and 2112.1 L/kg and 23.9-295.3 L/kg, respectively. The half-lives (t1/2) of muscle and plasma were 2.90-9.20 d and 2.57-8.15 d. The risks of PPs residues in the muscle of tilapia and exposed water were evaluated by hazard quotient (HQ) and risk quotient (RQ). Although PPs residues in tilapia had a low dietary risk to human health, the residues in the exposed water had a high ecological risk to fish, daphnia, and green algae. Therefore, assessing the PPs content in freshwater aquaculture and monitoring their dosages and frequencies are highly necessitated to avoid their adverse effect on the aquaculture environment.


Assuntos
Praguicidas , Piretrinas , Tilápia , Poluentes Químicos da Água , Animais , Ecossistema , Humanos , Piretrinas/toxicidade , Medição de Risco , Toxicocinética , Água , Poluentes Químicos da Água/farmacocinética , Poluentes Químicos da Água/toxicidade
19.
Environ Pollut ; 308: 119681, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35764184

RESUMO

Along the South Carolina coast (U.S.) where the ecologically and economically important eastern oyster (Crassostrea virginica) forms extensive intertidal reefs, recent surface water surveys found that fibers, fragments, and microscopic tire particles represented 43.6%, 30.9%, and 17.7% of the total microplastics, respectively. The aim of this study was to characterize accumulation and depuration of these particles in eastern oysters. Oysters were exposed to purple polyethylene fibers, green nylon fragments, or micronized crumb rubber at a concentration of 5000 microplastics/L, and sacrificed after 0, 24, 48, and 96 h to characterize uptake. Following 96 h, remaining oysters were transferred to microplastic-free brackish water and sacrificed at 24, 48, and 96 h to characterize depuration. For fibers and fragments, levels increased in a nonlinear fashion reaching 1.61 ± 0.6 particles/g w. w. (mean ± SE) and 0.46 ± 0.1 particles/g w. w. after 96 h, respectively. Conditional uptake clearance rate constants (ku) were estimated to be 0.0084 and 0.0025 mL/g*h for fibers and fragments, respectively. For crumb rubber, levels increased in a linear fashion reaching 3.62 ± 0.8 particles/g w. w. after 96 h, and the ku value was estimated to be 0.0077 mL/g*h. Depuration was best described using a two-compartment (double exponential) model suggesting the presence of fast and slow compartments. Conditional depuration rate constants (kd) for the slow compartments were 0.0084, 0.0205, and 0.0048/h for fibers, fragments, and crumb rubber, respectively. These results demonstrate accumulation and depuration of microplastics in eastern oysters is size-and shape-dependent. Depuration, which is a common practice for shellfish safety, is an effective way to reduce microplastic loads in eastern oysters, but the minimum recommended time of 44 h would only reduce loads of these particles by 55.5-67.6%.


Assuntos
Crassostrea , Microplásticos , Animais , Plásticos/toxicidade , Borracha , Toxicocinética
20.
NanoImpact ; 25: 100368, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35559876

RESUMO

The increasing application of zinc oxide nanoparticles (ZnO NPs) in consumer products has raised concerns about the potential health risks in human. It is crucial to understand the toxicokinetic information of ZnO NPs, especially the differences between NPs and non-nano form material. This study investigated the toxicokinetic profile of ZnO NPs and food grade bulk-sized ZnO in rats after single or repeated oral dosages. For single oral administration of ZnO suspensions at 350 mg/kgbw, the Zn content in blood and tissues showed no elevation, the majority of ZnO particles were eliminated via feces within 48 h. For repeated oral exposure to ZnO suspensions at 350 mg/kgbw or ZnSO4 solution at 700 mg/kgbw for 90 days, elevated Zn levels were observed in liver, kidney, and bone in all three treatment groups, the Zn level recovered to normal level in liver and kidney, but not in bone, after a recovery period. ZnO NPs and bulk-sized ZnO showed similarity in toxicokinetics in rats, regardless of exposure duration or gender. ZnO particles shared a similar biodistribution profile with ZnSO4, and were likely to be absorbed mostly in ionic forms.


Assuntos
Nanopartículas , Óxido de Zinco , Animais , Fígado/metabolismo , Nanopartículas/toxicidade , Ratos , Distribuição Tecidual , Toxicocinética , Óxido de Zinco/toxicidade
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