| Nano science and technology are rapidly developing and form to many branches such as nanotoxicology, nanobiotechnology, nanopharmacology and nanoelectronics. Nanomaterials have been applied in various fields for the unique optical, electrical, thermal, mechanical, or chemical properties. Silver nanoparticle is one of the most used nano products. It is widely used in biomedicine and health. However, because of the small size, nano materials could be liable to cross the barriers like blood-brain barrier, blood-testis barrier and blood-eye barrier, and functioned with the biomacromolecule. The health effects of nanomaterials were concerned due to the latent health hazards.Silver nanoparticles toxicity studies have focused in vitro which couldn’t exactly reflect the the change process and toxic effect of silver nanoparticles. There is few research on the biological effect of silver nanoparticles which entered the body through various routes. Biological effects and kinetics research of silver nanoparticles in vivo are necessary for the toxicity.Physiologically based toxicokinetic model is based on physiology and anatomy. Bloodstream was used to contact each organ and tissue. The model reflected the process of poison distribution, conversion, metabolism and excretion. Differential equations were used to describe changing process according to the mass conservation rule. The change of target dose could be described after solving system of equations over time. PBTK model is a new kind of method to predict the dose. It could effectively predict the internal dose and quantitatively evaluate the relation between external dose and internal dose.Two kinds of different silver nanoparticles, AgNPs-20(20nm, PVP caoted,25% silver content), AgNPs-100(100nm,99.5% silver content), were used to expose rats by one-time intravenous injection. The doses were respectively 120 mg/kg and 30 mg/kg, which were all 30 mg/kg in terms of silver content. Control group was exposed PVP and AgNO3 by the dose of 90 mg/kg and 5 mg/kg. Acute toxicity, hemodynamics, viscera distribution and excretion were under study. Based on overviews of former researchers, PBTK model was established by Acsl software. Then the distribution data in vivo was used to test and.optimize the model to provide the basis for health effects and safety evaluation of silver nanoparticles.MethodsCharacterization of silver nanoparticle TEM and SEM was used to observe morphological characteristics of silver nanoparticles and measure the particle size of both silver nanoparticles. Malvern Mastersizer was used to measured hydrated particle size of silver nanoparticles. ICP-MS was used to detect the actual silver content of the silver nanoparticles.Acute toxicity of silver nanoparticles in rats Rats were single exposed by tail intravenous injection and sacrificed after exposed for 1 d,7 d,14 d. Serum, organ, and urine samples were taken. Changes of the general state and relative organ weight was observed. Changes of serum and urine biochemical parameters was observed including liver function index (TP, ALB, ALT, AST, ALP), cardiac function (CK, CK-MB), renal function (BUN, UP, UA, Cre). Pathology watch was observed.Rats hemodynamic and biodistribution research Research of hemodynamic: After anesthesia rats were under emoral vein surgery. Blood was collected from femoral vein over time (5min,10 min,20 min,30 min,1 h,2 h,4 h,6 h) after exposed by tail vein. ICP-MS was used to detect the silver content in blood. DAS was used to calculate related kinetic parameters. Research of tissue distribution:Rats were single exposed by tail intravenous injection and sacrificed after exposed for 1 d,7 d,14 d. Brain, heart, lungs, liver, spleen, kidney and blood samples were taken. ICP-MS was used to detect the silver content in these visceral organ. Research of excretion pathway:Rine and feces were collected over time. ICP-MS was used to detect the silver content.Construction and validation of PBTK model Physiological parameters of rats and biochemical parameters of silver nanoparticles were collected by reviewing literature to establishing the structure of model and building differential equations. The PBTK model was built by the application of Acsl software. The existing data of silver nanoparticles in rats was applied to validate and optimize the model.ResultsCharacterization of silver nanoparticles AgNPs-20 showed spherical, better dispersibility. The average particle size and hydrated particle size were respectively 21.54 nm and 43.76 nm. Silver content of the material was 29.08%. AgNPs-100 showed ellipsoid. The average particle size and hydrated particle size were respectively 79.04 nm and 952.10 nm. Silver content of the material was 99.84%.Acute toxicity of silver nanoparticles in rats:The influence of the ordinary index and relative organ weight showed that compared with PVP group, the rats of the groups with AgNPs-20, AgNPs-100 and AgNO3 became grey and showed reduction of drinking and eating, recovered in 3 d after exposed. When exposed for 1 d, compared with PVP group, the liver viscera coefficient of AgNO3 group increased with that of AgNPs-20 and AgNPs-100 group decreased (P<0.05). Serum and urine biochemical index:When the rats exposed for 1 d, compared with PVP group.the TP of AgNO3 group decreased, the AST of AgNPs-20 group increased, the AST and ALT of AgNPs-100 group increased (P<0.01,P<0.05). When exposed for 7 d, compared with PVP group, the AST of AgNPs-20 and AgNPs-100 group increased (P<0.01). There was no significant difference compared other indicators with PVP group. Pathology watch:When the rats exposed for 7 d, compared with PVP group the rats’ of AgNPs-20 and AgNPs-100 groups had slightly liver injury. When the rats exposed for 7 d or 14 d, there was no significant difference compared other organs in any groups with PVP group.Rats hemodynamic and biodistribution research:Research of hemodynamic: Silver concentration of AgNPs-20 and AgNPs-100 groups were in rapid decline in 1 h and became stable in 1 h to 6 h after exposure. Silver concentration of AgNO3 group drop off quickly and became stable in 10 min after exposure. The parameters of AgNPs-20, AgNPs-100 and AgNO3 groups were AUC (mg/L*h,57.41±28.21, 106.99±11.60,55.88±9.26), MRT (h,0.54±0.27,1.88±0.11,2.57±0.11), t1/2 (h,0 0.80±0.30,1.88±0.23,6.06±4.67), CL (L/h*kg,0.63±0.35,0.25±0.03,0.04±0.02) Vd (L/kg,0.79±0.70,0.69±0.07,0.23±0.04). Silver nanoparticle could widely distribute in various organs. AgNPs-20 mainly distributed in the liver and spleen. AgNPs-100 mainly distributed in the lung. The concentration gradually reduced over time. Total excretion rate respectively were AgNPs-20(6.97%,0.15%), AgNPs-100(4.40%, 0.11%), AgNO3 (22.06%,7.60%).Construction and validation of PBTK model The PBTK model was built preliminarily. The model of actual data fitting is good. The AgNPs-20 and AgNPs-100 groups fitting data of blood Pearson correlation coefficient were 0.774 and 0.754.ConclusionWeight, viscera coefficient, serum biochemical and histopathological changes indicate the slight acute toxicity after exposed AgNPs-20 and AgNPs-100 with 30 mg/kg by tail vein. In vivo kinetics indicates that silver nanoparticles widely distribute in the body. AgNPs-20 major accumulate in the liver and spleen. AgNPs-100 mainly accumulate in the lung, liver and spleen. Parameters of kinetics indicates that compared with the AgNPs-20 group, AgNPs-100 distribute in rats and metabolic more quickly. The possible reasons is that silver nanoparticles enter into the lungs in the first place. The MPS have interception functions to AgNPs-100.Particle size influence the distribution of intravenous silver nanoparticles in the body. Excretion shows that silver nanoparticles mainly excrete through feces. The PBTK model has initial built by collecting Parameter and building differential equations. It can preliminary simulate the metabolism of silver nanoparticles in rats and contribute to analyze metabolic rule. The model also provides the basis for human safety evaluation of silver nanoparticles... |
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