Animals ; Cyanides ; toxicity ; Mice ; Random Allocation ; Toxicity Tests, Chronic

PURPOSE: To perform biological safety test of the Seoul-type keratoprosthesis (SKpro) according to the international standards. METHODS: Mouse fibroblasts were used to assess the cellular toxicity, and albino rabbits were used for the irritation test, intradermal test, ocular toxicity test, pyrogenic test and transplantation test. Albino guinea pigs were used for the sensitization test, and rats were used for the acute toxicity test and chronic toxicity test. All tests were performed using the SKpro extracts, which was extracted under 121degrees C for 1 hour using a 0.9% normal saline as the solvent. RESULTS: For the cellular toxicity test, all the rat fibroblasts showed cell proliferation inhibition of less than 29%, which proved to be non-cellular toxic. For the irritation test and the intradermal reaction test, none of the albino rabbits showed skin rash, crust or edema. On the ocular irritation test, there were no conjunctival, corneal or iris abnormalities among the albino rabbits. On the sensitization test, none of the guinea pigs showed skin rash, crust or edema. On the acute systemic toxicity test, there were no signs of lethargy or coma among rats. On the pyrogenic test, no temperature increase was observed in the albino rabbits. On the transplantation test, there was no evidence of graft reaction around the cornea. On the chronic toxicity test, complete blood analysis, urinalysis and histological findings 6 month after exposure showed no signs of abnormalities. CONCLUSIONS: The result of this study shows that SKpro is non-toxic and biologically safe.
Animals ; Cell Proliferation ; Coma ; Cornea ; Edema ; Exanthema ; Fibroblasts ; Guinea Pigs ; Intradermal Tests ; Iris ; Lethargy ; Mice ; Rabbits ; Rats ; Toxicity Tests ; Toxicity Tests, Acute ; Toxicity Tests, Chronic ; Transplants ; Urinalysis

OBJECTIVETo evaluate the acute and sub-chronic toxicity of intravenously administered tetrandrine (TET) in female BALB/c mice.

METHODSThe median lethal dose (LD) of intravenously administered TET was calculated in mice using Dixon's up-and-down method. In the acute toxicity study, mice were intravenously administered with TET at a single dose of 20, 100, 180, 260 and 340 mg/kg, respectively and were evaluated at 14 days after administration. In the sub-acute toxicity study, mice were intravenously administered various doses of TET (30, 90 and 150 mg/kg) each day for 14 consecutive days. Clinical symptoms, mortality, body weight, serum biochemistry, organ weight and histopathology were examined at the end of the experiment, as well as after a 1-week recovery period.

RESULTLDwas found to be 444.67±35.76 mg/kg. In the acute toxicity study, no statistically signifificant differences in body weight, blood biochemistry, or organ histology were observed between the administration and control groups when mice were intravenously administered with single dose at 20, 100, 180, 260 and 340 mg/kg of TET (P >0.05). In the sub-acute toxicity study, no signifificant changes in body weight, biochemistry and organ histology were observed with up to 90 mg/kg of TET compared with the control group (P >0.05), however, in the 150 mg/kg administered group, TET induced transient toxicity to liver, lungs and kidneys, but withdrawal of TET can lead to reversal of the pathological conditions.

CONCLUSIONSThe overall fifindings of this study indicate that TET is relatively non-toxic from a single dose of 20, 100, 180, 260 or 340 mg/kg, and that up to 90 mg/kg daily for 14 consecutive days can be considered a safe application dose.

Administration, Intravenous ; Animals ; Benzylisoquinolines ; administration & dosage ; toxicity ; Body Weight ; drug effects ; Female ; Mice, Inbred BALB C ; Organ Specificity ; drug effects ; Toxicity Tests, Acute ; Toxicity Tests, Chronic

OBJECTIVETo study the oral chronic toxicity of 97% isopropyl thioxanthone (97% ITX) in rats, determine the no-observed adverse effect levels (NOAEL).

METHODSFour groups of rats were fed with foodstuff containing 97% ITX in the dosage of 1000.0, 250.0, 62.5 mg/kg respectively for 2 years. The general behavior, body weight, food availability ect. were observed during the experiment. At the end of the experiment, blood and urine samples were collected for routine and biochemical assays. The internal organs were taken for calculating their organ coefficients and histopathological examinations.

RESULTSDuring the experimental period, no obvious abnormality were found in the experimental animals. The body weight and the total food availability rate in the high dosage group of male were lower than that of control (P < 0.05). Hematology examination showed that the quantity of Hb and RBC in high dosage groups of both the male and female and Hb in the male middle group were all lower than the control group (P < 0.01 or P < 0.05). Analysis of correlation indicated that r = -0.433, P < 0.01 in male, r = -0.337, P < 0.01 in female of Hb; r = -0.266, P < 0.05 in male, r = -0.317, P < 0.01 in female of RBC. There were obviously negative correlation. Serum biochemistry examination showed the concentration of CHO in the high and middle dosage treated rats of male and female were higher than that of the control (P < 0.01 or P < 0.05). Analysis of correlation indicated that r = 0.497, P < 0.01 in male, r = 0.417, P < 0.01 in female. No abnormality were found in urine examination. The organ weight and organ coefficient such as liver, were higher than control group (P < 0.01). The result of histopathological examinations displayed that the renal tubule Cast and the tubulointerstitial nephritis in the treated groups were higher than that of control group (P < 0.01).

CONCLUSION97% ITX could obviously interfere with the animals' physical condition, and reduce the number of RBC and the concentration of Hb in the blood, interact metabolism of lipoid and induce the concentration of CHO in the serum. The livers of the treated rats are compensatory enlarged. And kidneys of the poisoning animals are damaged. The 2 years oral NOAEL of 97% ITX in rats are more than 4.63 mg/kg for female rats, and larger than 4.06 mg/kg for male rats.

Administration, Oral ; Animals ; Female ; Male ; No-Observed-Adverse-Effect Level ; Rats ; Rats, Wistar ; Toxicity Tests, Chronic ; Xanthones ; toxicity

BACKGROUND: The industrial revolution has resulted in increased synthesis and the introduction of a variety of compounds into the environment and their potentially hazardous effects have been observed in the biota. The present study was aimed to evaluate the potential endocrine-disrupting effects of chronic exposure to the low concentrations of bisphenol S (BPS) in male rats. METHODS: Weaning male Sprague-Dawley rats (22 days old) were either exposed to water containing 0.1% ethanol for control or different concentrations of BPS (0.5, 5, and 50 μg/L) in drinking water for 48 weeks in the chronic exposure study. After completion of the experimental period, animals were dissected and different parameters (hormone concentrations, histology of testis and epididymis, oxidative stress and level of antioxidant enzymes in the testis, daily sperm production (DSP), and sperm parameters) were determined. RESULTS: Results of the present study showed a significant alteration in the gonadosomatic index (GSI) and relative reproductive organ weights. Oxidative stress in the testis was significantly elevated while sperm motility, daily sperm production, and the number of sperm in epididymis were reduced. Plasma testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) concentrations were reduced and estradiol levels were high in the 50 μg/L-exposed group. Histological observations involved a significant reduction in the epithelial height of the testis along with disrupted spermatogenesis, an empty lumen of the seminiferous tubules, and the caput region of the epididymis. CONCLUSION These results suggest that exposure to 5 and 50 μg/L of BPS for the chronic duration started from an early age can induce structural changes in testicular tissue architecture and endocrine alterations in the male reproductive system which may lead to infertility in males.
Animals ; Biomarkers ; Endocrine Disruptors/toxicity* ; Environmental Exposure/adverse effects* ; Environmental Pollutants/toxicity* ; Hypothalamo-Hypophyseal System/physiopathology* ; Infertility, Male/physiopathology* ; Male ; Phenols/toxicity* ; Rats ; Rats, Sprague-Dawley ; Sulfones/toxicity* ; Testis/physiopathology* ; Toxicity Tests, Chronic

OBJECTIVETo investigate the toxicity of realgar and provide the scientific basis for safety use of realgar in clinic.

METHODAcute toxicity was tested by single oral administration. Chronic toxicity of realgar was tested at different dose levels (5, 10, 20, 80, 160 mg x kg(-1) x d(-1)) which correspond to 1/2, 1, 2, 8, 16 times of human dose levels. The rats were treated with the test substances through oral administration once daily for successively 90 days. Urinary qualitative test, blood routine examination, serum chemistry measurement, and histomorphologic observation were conducted at day 30, 60 and 90. Toxic changes related to the treatment of realgar and no-observed adverse effect level (NOAEL) was evaluated.

RESULTWith the content of 90% total arsenic and 1.696 mg x g(-1) soluble asenic, LD50 of Realgar with oral administration was 20.5 g x kg(-1) (corresponding to 34.8 mg x kg(-1) soluble arsenic), equivalent to 12 812 times of clinical daily dose for an adult. Realgar can cause kidney toxicity or/and liver toxicity after administration for over 30, 60 or 90 days respectively. The kidney was more sensitive to realgar than liver. Based on repeated dose toxicity study, NOAELs were 160 mg x kg(-1) x d(-1) for 30 day's administration, 20 mg x kg(-1) x d(-1) for 60 day's administration, 10 mg x kg(-1) x d(-1) mg x kg(-1) x d(-1) for 90 day's administration respectively. Thus, for safety use of realgar, it is recommended that the daily doses of realgar (with soluble arsenic < or = 1.7 mg x g(-1)) for an adult of the body weight about 60 kg could be 10-160 mg depending on the variation of the treatment duration.

CONCLUSIONLong term use of realgar can cause kidney and liver pathological change, so the doses and administration duration should be limited. The suggestion is as follows: realgar which contains soluble arsenic < or = 1.7 mg x g(-1) should be used less than 2 weeks at daily dose 160 mg, less than 4 weeks at the dose of 20 mg and less than 6 weeks at the dose of 10 mg.

Administration, Oral ; Animals ; Arsenicals ; administration & dosage ; chemistry ; Dose-Response Relationship, Drug ; Female ; Kidney ; drug effects ; Liver ; drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Solubility ; Sulfides ; administration & dosage ; chemistry ; toxicity ; Time Factors ; Toxicity Tests, Acute ; methods ; Toxicity Tests, Chronic ; methods

OBJECTIVETo explore the effects of chronic exposure to trace chromium (VI) as a result of metal-on-metal hip arthroplasty on oxidative stress in mouse liver cells.

METHODSEighty NIH mice were randomly divided into 4 groups and subject to intraperitoneal injection of CrO(3) at the dose of 0, 5, 10 or 20 mg/kg every other day for 16 weeks. Five mice from each group were selected every 4 weeks for determining the content of chromium (VI) in the whole blood and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), glutathione reductase (GR) activity, and glutamate cysteine ligase (GCL) expression in the liver cells. The ultrastructural changes of the liver cells were also observed using transmission electron microscopy.

RESULTSExposure to 5 and 10 mg/kg CrO(3) caused significantly increased blood chromium concentration and ROS level, which reached the peak level at 8 weeks and became stabilized, whereas at the dose of 20 mg/kg, CrO(3) exposure resulted in progressive, time-dependent increase of blood chromium concentration and ROS level. MDA showed no significant changes in the 4 groups. With the prolongation of the exposure time, GSH content and GR activity were decreased in these groups. In 5 and 10 mg/kg CrO(3) groups, GCL expression increased at each time point of measurement, but in 20 mg/kg group, GCL expression decreased gradually with a prolonged exposure. Transmission electron microscopy revealed apoptotic changes of the liver cells in 20 mg/kg group.

CONCLUSIONThe slow accumulation of trace chromium (VI) after metal-on-metal hip arthroplasty may cause oxidative stress and changes in the oxidative stress system in the liver cells.

Animals ; Apoptosis ; Chromium ; administration & dosage ; toxicity ; Environmental Exposure ; Glutathione ; metabolism ; Hepatocytes ; metabolism ; pathology ; Malondialdehyde ; metabolism ; Mice ; Oxidative Stress ; Reactive Oxygen Species ; metabolism ; Superoxide Dismutase ; metabolism ; Toxicity Tests, Chronic

OBJECTIVETo investigate the effects of chronic aluminum exposure on the learning and memory abilities and brain-derived nerve growth factor (BDNF) in Sprague-Dawley (SD) rats.

METHODSThirty-two male SD rats were randomly and equally divided into 4 groups: control group and high-, middle-, and low-dose exposure groups. The rats in high-, middle-, and low-dose exposure groups were fed with the feed mixed with AlCl(3) (120.0, 12.0, and 1.2 mg/kg, respectively), while the rats in control group were fed conventionally. After 6 months of feeding, brain aluminum levels were determined by inductively coupled plasma mass spectrometry; Morris water maze was employed to test the learning and memory abilities; the expression and content of BDNF in brain tissue were measured by Western blot and enzyme-linked immuno sorbent assay (ELISA).

RESULTSThe high- and middle-dose exposure groups had significantly higher brain aluminum levels than the control group (P<0.05). The Morris water maze test showed that the high- and middle-dose exposure groups had significantly prolonged escape latency (P<0.05), significantly prolonged time taken to first reach the target quadrant (P<0.01), and significantly decreased number of platform crossings and time spent in the target quadrant (P<0.05), as compared with the control group. The Western blot and ELISA showed that the expression and content of BDNF in brain tissue decreased as the dose of AlCl(3) increased, and they were significantly lower in the high- and middle-dose exposure groups than in the control group (P<0.05).

CONCLUSIONChronic aluminum exposure (12.0 and 120.0 mg/kg) can lead to cognitive dysfunction in rats, and the decreased expression of BDNF may be one of the mechanisms of learning and memory deficits induced by aluminum.

Aluminum ; toxicity ; Animals ; Brain ; metabolism ; Brain-Derived Neurotrophic Factor ; metabolism ; Male ; Maze Learning ; drug effects ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Chronic

AIMTo investigate the effect of chronic lead exposure on rat hippocampal CA1 LTP and alpha-Ca2+ /calmodulin-dependent protein kinase II (alpha-CaM K II) activity in vivo.

METHODSA stimulus bipolar electrode was placed on the Schaffer/Commissural fibers, with extra cellular microelectrode technique to record the population spike (PS) in the CA1 pyramidal, and we observed the changes of PS amplitude before and after the high frequency stimulation (HFS) of lower, mid and higher level lead exposure groups and the control group, respectively. The hippocampal CA1 alpha-CaM K II activity was determined by Western blots by using phosphorylation antibody.

RESULTSThe average changes of PS after HFS of the control group, the lower, mid and higher level lead exposure groups were 162.5%, 105.2%, 86.8%, 83.0%, respectively (P < 0.01 vs. control). Defined control a-CaM K II activity as 100, that the lower, mid and higher level lead exposure groups were 62.0 +/- 3.7, 50.8 +/- 4.0, 43.3 +/- 4.1 (P < 0.01).

CONCLUSIONChronic lead exposure can inhibit CA1 LTP in vivo, and the decrease of alpha-CaMK II activity may play an important role in this mechanism.

Animals ; CA1 Region, Hippocampal ; metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; metabolism ; Lead ; toxicity ; Long-Term Potentiation ; Rats ; Rats, Wistar ; Toxicity Tests, Chronic

OBJECTIVETo observe the expression of Clara cell secretory protein(CCSP) in the Kunming mouse model of n-hexane long-term inhalation, and to discuss the functions of Clara cell in injury lung induced by n-hexane.

METHODS24 healthy mice were randomly divided into 4 groups: one control group and three n-hexane groups (4 w, 8 w and 12 w), 6 each group. Primary concentration of n-hexane was 17.6 g/m3, 8 hours per day, 6 d per week. After inhalation, n-hexane concentration of blood from celiac artery was detected. The lungs were embedded with paraffin and HE staining in the routine. The ratio of Clara cells with CCSP reaction in bronchiole and the number of macrophage cells with lysozyme reaction were determined by immuno-histochemistry.

RESULTSIn the poisoning groups, the average n-hexane concentration of blood was significantly higher than that of the control group (P < 0.01). There were apparent pathologic damages in lungs of the poisoning mice. In poisoning 4 w, 8 w and 12 w groups, the ratio of Clara cells was significantly decreased [(73.33 +/- 4.21)%, (60.98 +/- 4.94)%, (34.04 +/- 2.33)% in terminal bronchiole, and (75.44 +/- 7.91)%, (58.54 +/- 4.86)%, (33.35 +/- 2.67)% in respiratory bronchiole] as compared with the control mice [(80.26 +/- 6.43)% and (81.74 +/- 7.75)%, P < 0.05 or P < 0.01], meanwhile the numbers of macrophage cells were gradually increased [(21.39 +/- 7.41), (28.54 +/- 10.73), (48.97 +/- 19.55) per microscopic field at 200x] in poisoning mice than those in control mice [(7.84 +/- 3.12) per microscopic field at 200x, P < 0.05 or P < 0.01].

CONCLUSIONIn injury lungs after n-hexane inhalation, Clara cells are the target cells of n-hexane toxicity effect. Clara cells play an extensive protective role in lung inflammation.

Animals ; Epithelial Cells ; metabolism ; Hexanes ; toxicity ; Inhalation Exposure ; Lung Injury ; etiology ; metabolism ; Mice ; Mice, Inbred Strains ; Toxicity Tests, Chronic ; Uteroglobin ; metabolism