According to the requirements of ISO10993-11.2006 and ISO10993-6:r2007 standards, we used SD rats for evaluating the subchronic systemic toxicity and local implantation response of two kinds of sodium hyaluronan gels with different application. The results of 90d subchronic toxicity study by intraperitoneal route showed that the animals of the tested group and control group grew normally. There were no differences in the increases of the body weight, haematological index and clinical biochemistry indexes. The examination of gross pathology and histopathology revealed no abnormal changes caused by the test substance during the process. But there was different degree test article residual in the body of the animals at the end of the experiment. It was observed in the local subcutaneous implantation that at the early stage, gel A had mild inflammatory response, cysts were seen clearly, and new blood capillaries were visible at local area. Later, the wall got thinner and dense with little tissue reaction. Gel B also had mild inflammatory response earlier, but it totally disappeared after 14 days of implantation. It can be concluded that the gel products with different characteristics decided its degradation and metabolic process in the body of the test animals and therefore the areas of application of the products clinically. Meanwhile, we compared the evaluation method of subchronic systemic toxicity and local implantation response in risk assessment, providing reference for the choice of biological safe testing.
Animals ; Female ; Gels ; toxicity ; Hyaluronic Acid ; toxicity ; Implants, Experimental ; Male ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Subchronic

As the new type cornea ulcer renovation material, the biological amnion is to be implanted into the human body for a long time, a subchronic toxicity study in rats is made to evaluate its possibility of subchronic toxicity. The study is based on the requirements of "Biological Evaluation of Medical Devices, Part 11: Tests for systemic toxicity and Part 6: Tests for local effects after implantation". After the implantation of examples to be tested, animals were observed daily for mortality and 92 days later the possible subchronic toxicity was evaluated. And a necropsy was conducted and the selected organs were excised, weighed, and processed histologically. Body weights, organ weights, organ/body weight ratios, hematology values and clinical chemistry values were analyzed statistically. Results show that daily clinical observation, body weights, necropsy findings, organ weights and organ/body weight ratios were within acceptable limits in test and control treatment groups. There were no obvious changes in histopathology, hematology values or clinical chemistry values in either male or female rats and no notable differences between the biological amnion and the control amnion. This study proves that, the cornea ulcer renovation material, the biological amnion does not induce subchronic toxicity.
Amnion ; transplantation ; Animals ; Biological Products ; toxicity ; Corneal Ulcer ; surgery ; Female ; Male ; Materials Testing ; Rats ; Rats, Wistar ; Toxicity Tests, Subchronic

Animals ; Body Weight ; Feeding Behavior ; Female ; Lactobacillus fermentum ; Male ; Probiotics ; toxicity ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Subchronic

OBJECTIVETo investigate the subchronic oral toxicity of silica nanoparticles (NPs) and silica microparticles (MPs) in rats and to compare the difference in toxicity between two particle sizes.

METHODSSprague-Dawley rats were randomly divided into seven groups: the control group; the silica NPs low-, middle-, and high-dose groups; and the silica MPs low-, middle-, and high-dose groups [166.7, 500, and 1,500 mg/(kg•bw•day)]. All rats were gavaged daily for 90 days, and deionized water was administered to the control group. Clinical observations were made daily, and body weights and food consumption were determined weekly. Blood samples were collected on day 91 for measurement of hematology and clinical biochemistry. Animals were euthanized for necropsy, and selected organs were weighed and fixed for histological examination. The tissue distribution of silicon in the blood, liver, kidneys, and testis were determined.

RESULTSThere were no toxicologically significant changes in mortality, clinical signs, body weight, food consumption, necropsy findings, and organ weights. Differences between the silica groups and the control group in some hematological and clinical biochemical values and histopathological findings were not considered treatment related. The tissue distribution of silicon was comparable across all groups.

CONCLUSIONOur study demonstrated that neither silica NPs nor silica MPs induced toxicological effects after subchronic oral exposure in rats.

Administration, Oral ; Animals ; Dose-Response Relationship, Drug ; Female ; Male ; Nanoparticles ; toxicity ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Silicon Dioxide ; toxicity ; Toxicity Tests, Subchronic

OBJECTIVETo study the activity, protein and gene expression of renal HK-ATPase (HKA) in rats subchronic exposed to trimethyltin chloride (TMT).

METHODSIn subchronic toxic test (14-week), 55 female SD rats (age, 6 weeks) were divided randomly into 5 groups: control, low, medium, high and super high dosage, respectively, which drank water with TMT of 0, 8.20, 32.81, 131.25 and 262.50 microg x kg(-1) x d(-1) for 14 weeks. Then serum K+ levels were measured; the activities of HK-ATPase (HKA) in kidneys were detected by the method of determinated phosphorus content; Western Blot assay and real-time PCR were used to exam the protein and mRNA expression levels of HKA in kidneys, respectively.

RESULTSThe serum K+ level in super-high dosage group was (5.6 +/- 0.4) mmol/L, which was significantly lower than that [(6.9 +/- 0.3) mmol/L] in control group (P < 0.01). The HKA enzymatic activity of kidneys in low and super high dosage groups was 4.50 +/- 1.45 and 4.55 +/- 0.72 micromolPi x mg prot(-1)h(-1), respectively, which were significantly lower than that (6.55 +/- 0.77 micromol Pi x mg prot(-1) h(-1)) in control group (P < 0.05).

CONCLUSIONWhen rats were exposed subchronic to TMT, the renal HKA activity could reduce, but the expression levels of HKA protein and mRNA did not decrease.

Animals ; Female ; Gene Expression ; H(+)-K(+)-Exchanging ATPase ; genetics ; metabolism ; Kidney ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Subchronic ; Trimethyltin Compounds ; toxicity

OBJECTIVE: The aim of this study is to investigate the effects of oral cadmium (Cd) ingestion on the pulmonary immune response. METHODS: Determination of Cd content in lungs and histopathological evaluation of the tissue was performed in rats following 30-day oral Cd administration (5 and 50 mg/L). Antioxidant enzyme defense (superoxide dismutase and catalase), cell infiltration, and production of tumor necrosis factor (TNF) and interferon (IFN)-γ, as well as the activity of myeloperoxidase (MPO), nitric oxide (NO), and various cytokines [interleukin (IL)-1β, IL-6, IL-10, and IL-17] were investigated. RESULTS: Cd caused tissue damage and cell infiltration in the lungs, and this damage was more pronounced at higher doses. Cd deposition resulted in lung inflammation characterized by a dose-dependent IL-1β increase in lung homogenates, increased TNF levels at both doses, and IL-6 stimulation at low doses with inhibition observed at higher doses. Cd exerted differential effects on lung leukocytes isolated by enzyme digestion, and these effects were characterized by a lack of change in the production of reactive oxygen and nitrogen species, an inhibition of IL-1β and TNF, and stimulation of MPO and IFN-γ. The higher capacity of Cd-exposed lung cells to respond to the opportunistic pathogen Staphylococcus epidermidis was demonstrated in vitro. CONCLUSION The potential of ingested Cd to exert both proinflammatory and immunosuppressive effects on pulmonary tissue inflammation and immune reactivity highlights the complex immunomodulatory actions of this metal.
Administration, Oral ; Animals ; Cadmium ; administration & dosage ; toxicity ; Leukocytes ; metabolism ; Lung ; drug effects ; immunology ; pathology ; Male ; Rats ; Staphylococcus epidermidis ; Toxicity Tests, Subchronic

OBJECTIVE: To explore the possible long-term health effects of the defoamer used in seawater desalination by sub-chronic toxicity testing. METHODS: Blood analysis, internal organ assessment, and histopathological examination were carried out in rats exposed to low, medium, and high (0.5, 1.0, and 2.0 g/kg BW, respectively) doses of defoamer for 90 days through oral administration. RESULTS: The high dose group showed decreased blood alanine aminotransferase and aspartate aminotransferase (P < 0.05). All doses resulted in a significant increase in albumin and decrease in globulin (P < 0.05). The direct bilirubin and indirect bilirubin were decreased in the medium and high dose groups (P < 0.05). All dose groups showed significant induction of alkaline phosphatase (P < 0.05). Pathological examination revealed a case of liver mononuclear cell infiltration in the medium dose group and three cases of liver congestion, steatosis of hepatic cells around the central vein, and punctate necrosis with multiple focal mononuclear cell infiltration in male rats administered the high dose. The No Observed Adverse Effect Level was 0.5 g/kg BW in rats, with albumin and total bilirubin as health effect indices. CONCLUSION Long-term defoamer exposure may cause liver injury but has no significant impact on renal function in rats. The effect on blood cells in female rats was more prominent than that in male rats.
Administration, Oral ; Animals ; Antifoaming Agents ; toxicity ; Blood Chemical Analysis ; Body Weight ; drug effects ; Eating ; drug effects ; Female ; Male ; Rats, Wistar ; Toxicity Tests, Subchronic

OBJECTIVETo study the acute, subacute and subchronic toxicity induced by ammonium dinitramide (ADN), and to ascertain the gradation and target organs of acute toxicity induced by AND.

METHODSAccording to technical specifications for toxicity determination of chemicals, the oral tests for acute, subacute and subchronic toxicity induced by AND were performed for 90 days.

RESULTSThe oral LDx for mouse and rat was 568.9 mg/kg and 616.6 mg/kg ADN respectively. The gradation of acute toxicity induced by AND was low level. The results of oral subacute and subchronic toxicity tests (for 28 and 90 days) showed that a gain in weight in group exposed to 123 mg/kg AND was significantly lower than that in control group (P<0.05), the TBIL and ALT in group exposed to 61.6 and 123 mg/kg AND significantly increased and the ratio of liver weight to body weight obviously decreased, as compared with control group, the number of animals with hepatic pathological changes in group exposed to 61.6 and 123 mg/kg AND was significantly higher than that in control group (P<0.05).

CONCLUSIONThe gradation of acute toxicity induced by ADN was low level. When the exposure dose of AND was 30.8 mg/kg, the adverse effect was not observed, and the target organ was liver.

Animals ; Body Weight ; Female ; Liver ; drug effects ; pathology ; Male ; Mice ; Mice, Inbred Strains ; Nitrites ; toxicity ; Quaternary Ammonium Compounds ; toxicity ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Acute ; Toxicity Tests, Subchronic

OBJECTIVETo investigate the spatial learning and exploration along with the CNS excitatory amino acid neurotransmitters profiles in adult rats subchronically exposed to the anticholinesterase organophosphorus insecticide dimethoate.

METHODSRats were gavaged daily with dimethoate (0, 5, 10 or 20 mg/kg via oral) in NS. for 90 days. Morris water maze tasks were used to test the spatial learning and memory in the rats after the dimethoate exposure. Simultaneously, rats were decapitated for the determination of brain cholinesterase AChE activities, glutamate concentrations, and the NMDA receptor NMDA-R densities and affinities in hippocampus.

RESULTSLatencies to find a hidden escape platform were significantly longer in dimethoate dosed groups than that of the control group in the place navigation tests. Subsequently, the times of crossing the location of platform which had been removed obviously decreased in the highest dose group compared with that of the control in the spatial probe tests (P < 0.05). AChE activity was significantly reduced 42% approximately 78% by all three doses of dimethoate (P < 0.05). Glutamate concentrations were increased significantly 132.9% approximately 134.5% by the two highest doses of dimethoate (P < 0.05). In addition, the NMDA receptor bindings were reduced 21.2% approximately 23.2% with the statistical significance at the same two highest doses (P < 0.05). Furthermore, the receptor affinities was reduced 33.1% by the highest dose group (P < 0.05). The lesions of spatial memory were statistically corrected with the decrease of the NMDA-R affinities (P < 0.05).

CONCLUSIONThe cholinergic lesion as well as the excitatory amino acid system alteration might attribute to the inferior ability in spatial learning and memory in dimethoate subchronically exposed rats.

Acetylcholinesterase ; metabolism ; Animals ; Chronic Disease ; Dimethoate ; toxicity ; Disease Models, Animal ; Glutamic Acid ; metabolism ; Insecticides ; toxicity ; Learning ; drug effects ; Male ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Toxicity Tests, Subchronic

OBJECTIVETo observe the effects of subchronic benzo[a]pyrene (B[a]P) exposure on the neurobehavior and hippocampal acetylcholine (Ach) level, acetylcholinesterase (AChE) activity, and mRNA and protein expression of nicotinic acetylcholine receptor α7 subtype (nAChR α7) in rats, and to investigate the neurotoxic mechanism of B[a]P.

METHODSSixty healthy male SD rats were randomly divided into blank control group, solvent control group, and B [a]P exposure groups. Each rat in the exposure groups was intraperitoneally injected with B[a]P at 1.0, 2.5, or 6.25 mg/kg once every other day for 90 days. The learning and memory ability of the rats was examined by Morris water maze test and step-down test; the hippocampal Ach level was measured by alkaline hydroxylamine method; the AChE activity was measured by DNTB method; the mRNA and protein expression levels of hippocampal nAChR α7 were measured by quantitative PCR and Western blot.

RESULTSThe 2.5 and 6.25 mg/kg B[a]P exposure groups showed significantly lower learning and memory abilities than the blank control group and solvent control group (P < 0.05); also, the two groups had significantly lower hippocampal Ach levels than the blank control group, solvent control group, and 1.0 mg/kg B[a]P exposure group (P < 0.05). The 6.25 mg/kg B[a]P exposure group showed significantly lower hippocampal AChE activity than the blank control group, solvent control group, and 1.0 mg/kg B[a]P exposure group (P < 0.05). There were no significant differences in the mRNA and protein expression levels of nAChR α7 among all groups (P > 0.05). The hippocampal Ach level was negatively correlated with the mean escape latency period and total distance travelled (r = -0.567, P < 0.01; r = -0.503, P < 0.01) but positively correlated with the time in platform quadrant (r = 0.800, P < 0.01).

CONCLUSIONSubchronic B[a]P exposure may impair the learning and memory ability in rats, which is related to the downregulation of hippocampal Ach level.

Acetylcholine ; metabolism ; Acetylcholinesterase ; metabolism ; Animals ; Benzo(a)pyrene ; toxicity ; Hippocampus ; drug effects ; metabolism ; Male ; Maze Learning ; drug effects ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Cholinergic ; metabolism ; Toxicity Tests, Subchronic ; alpha7 Nicotinic Acetylcholine Receptor ; metabolism