As the development of a pharmaceutical product is a dynamic process which involves continuousfeed-back between non-clinical and clinical studies, the integration of pharmacokinetics into toxicity testing became increasingly important in recent years. Toxicokinetic measurements in the toxicity studies is considered to be an important scientific approach in the interpretation of the toxicology findings and the promotion of rational study design development. Primarily this research project was conducted to determine the systemic exposure achieved in acute toxicity test and its relationship to dose level and the time course of the toxicity study. Acute hepatotoxicity study and its relevant toxicokinetic study in mice were performed using acetarninophen (AA) as a model compound. The correlation between acute hepatotoxicity indices and toxicokinetic parameters following intraperitoneally administration of various dosages of AA in mice was evaluated and discussed minutely in the text. Based on these studies, single-dose toxicity testing of AA including kinetic studies was evaluated in ICR mice for 7 days and interpreted in the text. Our results from the integration of toxicokinetic monitoring into single-dose toxicity study enable to elucidate the relation of the exposure achieved in toxicity study to toxicological findings and assist in the selection of appropriate dose levels for use in repeated-dose toxicity or later studies.
Acute and subacute oral toxicity of $HELIKIT^{TM}$ ($^{13}C-urea$) were carried out in Sprague-Dawley rats of both sex. The toxicity of $HELIKIT^{TM}$ was compared with urea($^{12}C-urea$ which is used for control). In acute toxicity studies, we daily examined number of deaths, clinical signs, body weights and pathological examination for 14 days after single oral administration of HELIKIT or urea($^{12}C-urea$) at a dose of 5000 mg/kg. The subacute oral toxicity was investigated in Sprague-Dawley rats treated with $HELIKIT^{TM}$ at a dose of 40, 200 and 1,000 mg/kg/day or $^{12}C-urea$ at a dose of 1,000 mg/kg/day for 4 weeks. In acute toxicity studies, $HELIKIT^{TM}$ and urea did not show any toxic effect in rats and oral LD50 value was over 5,000 mg/kg rats. In subacute toxicity studies, no death occured and no drug-related changes were found in clinical observations; body weight, food consumption, opthalmoscopy. auditory test, urinalysis, hematology, blood chemistry, gross pathological examination or organ weight between $HELIKIT^{TM}$, urea and control groups. In histopathological examinations, the slight thickening of mucosa of the limiting ridge in the stomach was noted in the animals treated with $HELIKIT^{TM}$ at a dose of 1,000 mg/kg/day and also the changes in urea group at a dose of 1,000 mg/kg/day was found, but all of these changes in the changes in ures group at a dose of 1,000 mg/kg/days was found, but all of these changes in the stomach regressed after withdrawal of the test article for 2 weeks and reversibility of the effect was revealed. These results indicate that the non toxic dose level of $HELIKIT^{TM}$ was 1,000 mg/kg/day in the 4 weeks-repeated dose study, suggesting that the substitution of $^{13}C$ for carbon in urea molecule has no effect on the toxicity of urea and changes in stomach are reversible.
There are concerns that chemical residues could harm the consumer on the environment, although 50 to 80% of the crops would be destroyed by pests and others without agrochemicals. Environmental fate and ecotoxicity studies are usually carried out to assess the impact on the human and the environment. A comparision of the Daphnia magnia and Simocephalus mixtus toxicity was performed to study the relative sensitivities and discrimination abilities to agriculture chemicals. The species of Simocephalus mixtus was more sensitive to agriculture chemicals than Daphnia magnia. Simocephalus mixtus was approved to be a water flea in determining insecticide and pesticide toxicity by heart-beat rate in a consistency and repeatability. The order of acute toxicity to water flea Daphnia magnia for ecotoxicity test was carbaryl>benomyl>amtirole with both Daphnia magnia and Simocephalus mixtus. The heartbeat pattern after the exposure to agrochemicals was different from that of exposure to heavy metals. Agrochemical leathal concentration test with heartbeat rate measurement was found to be more appropriate than inhibition concentration test with respect to toxicological endpoint.
Proficiency testing by interlaboratory comparisons is used to determine the performance of individual laboratories. In order to verify the quality of acute toxicity testing with Daphnia magna, National Institute of Environmental Research in South Korea is regularly organizing interlaboratory comparisons to estimate the analytical accuracy of different laboratories. Total 58 laboratories located in South Korea took part in interlaboratory proficiency testing scheme with three proficiency testing samples. TU(Toxic Unit) values of each laboratory were determined and robust z-score was calculated in order to evaluate the proficiency levels. Based on the robust z-score classification, 74% of the participant laboratories showed a satisfactory performance (43 laboratories). The main reason of 'unsatisfactory' performance seemed to be considered that the unsuitable management of test organism incubation system and the lack of experience on the identification of the test organism condition by effect of toxicity.
Perfluorooctane sulfonic acid (PFOS) and Perfluorooctanoic acid (PFOA) are the principal chemicals known as perfluoroalkyl acids (PFAs). Despite the widespread use of these compounds, relatively little is known about their fate and effects. The purpose of this study was to determine the toxic effects of PFOS and PFOA on Daphnia magna. In the acute toxicity test, D. magna were exposed for 48 hours at concentrations of 0, 30, 45, 67.5, 101.25 and 151.88 mg/L PFOS, and 0, 100, 160, 225, 337.5 and 506.25 mg/L PFOA, respectively. In the case of chronic toxicity test, D. magna were exposed through water for 21 days at concentrations of 0, 0.375, 0.75, 1.5, 3 and 6 mg/L PFOS, and 0, 1.25, 2.5, 5, 10 and 20 mg/L PFOA, respectively. Acute toxicity was assessed on the basis of immobility, while chronic toxicity was assessed on the basis of fecundity. The acute toxicity test on PFOS and PFOA showed that the values of $EC_{50}$ were 50.90 mg/L and 253.47 mg/L, respectively. In the chronic test, fecundity was reduced significantly at 1.5 mg/L of PFOS and 10 mg/L of PFOA, respectively. These results indicated that PFOS is more toxic to zooplankton than PFOA, and both chemicals have some hazard demonstrates risk for acute or chronic toxicity to freshwater organism.
Objectives : Taglisodog-eum(TSE), a poly herbal formula, has been widely used to improve carbuncles by removing inflammation of the lymphatic channels in Traditional Korean Medicine. We previousely reported the action mechanism of TSE on experimental atopic dermatitis and the establishment of formulation for TSE ointment. In this study, we examined the toxicity test on skin and eye irritation by TSE ointment to prove the safety of Taglisodog-eum ointment in clinical use. Methods : Acute skin toxicity of the TSE ointment was evaluated in Sprague-Dawley(SD) rats. After dermal administration of TSE ointment(2,000mg/kg), body weight, mortality, and clinical signs of the rats were observed for 14days. Primary skin irritation and ocular irritation tests for TSE ointment were performed in male New Zealand White Rabbits. In dermal and ocular irritation test, body weight, mortality, clinical signs, Primary Irritation Index(P.I.I.), and The Index of Acute Ocular Irritaion(I.A.O.I.) of rabbit were observed after applying at abraded skin and eye balls with Taglisodog-eum ointment. Results : In the results of acute skin toxicity, no significant differences were found in body weight, the clinical sign and the mortality between control and TSE ointment treated group. In primary dermal irritation test, body weight, the clinical sign and the mortality were not significantly changed and Primary Irritation Index(P.I.I.) was 0.8, indicating TSE ointment as weak irritant material. In ocular irritation test, The Index of Acute Ocular Irritaion was 0.0, indicating TSE ointment as non-irritating to the eye of the rabbits. To evaluate toxicity of the TSE ointment in animal test, body weight, the clinical signs, the skin and eye irritation check were conducted; TSE ointment was considered to be weak dermal irritant in test animals. The no response of eye irritation test was observed in this experimental condition. Conclusions : According to the above toxicity test, We consider that this results is helpful for saying about the safety of TSE ointment in clinical use.
Objective: The purpose of this study was to investigate the acute and subacute toxicity and sarcoma- 180 anti-cancer effects of Herbal acupuncture with Triglii Semen in mice and rats. Method: Balble mice were injected intraperitoneally with Triglii semen Herbal acupuncture for $LD_{50}$ and acute toxicity test. Sprague Dawley rats were injected intraperitoneally with Triglii semen Herbal acupuncture for subacute toxicity test. The Triglii semen Herbal acupuncture was injected on Chung-wan(CV12) of mice with S-180 cancer cell line. Results: 1. In acute toxicity test, the $LD_{50}$ value was $7.49{\times}10^3$ml, 0.30ml/kg.2. The body weights of mice treated with Triglii semen Herbal acupuncture increased during the acute toxicity test. 3. In acute toxicity test of serum biochenrical values of mice, total protein was decreased in treatment groups I, 2 and 3, albunrin was decreased in treatment groups 2 and 3 compared to the control group. GOT was increased in treatment group I and Alk. Phosphatase was increased in treatment groups 1,2 and 3 compared to the normal group(p<0.05). 4.ln subacute toxicity test, severe tissue injury was found in lung and liver. 5. In subacute toxicity test, the body weight was decreased in treatment groups I and 2 compared to the normal group and the weight of liver. lung and kidney were increased in treatment groups 1, 2 and 3 compared to the normal group.(p<0.05) 6. In subacute toxicity test, RBC, HGB and HCT were decreased in treatment groups 1 and 2 compared to the normal group. MCV was increased in treatment group1 compared to the normal group, MCH was increased in treatment groups 1 and 2 compared to the control group in complete blood count test.(p<0.05) 7. In subacute toxicity test, total protein was decreased in treatment groups 1 and 2 compared to the nonnal group, BUN was increased in treatment groups 1 and 2 compared to the nonnal group, creatinine and uric acid were decreased in treatment groups 1 and 2 compared to the normal group, glucose was increased in treatment group 2 compared to the nonnal group, triglycelide was decreased in treatment groups I and 2 compared to the normal group, total cholesterol was increased in treatment groups 1 and 2 compared to the control group. GOT was decreased in treatment group 2 compared to the normal and control group, AIk. Phosphatase was increased in treatment group 1 compared to the normal and control group.(p<0.05) 8. Median survival time was 17days in treatment group 2 for S- 180 cancer cell treated with Triglii semen Herbal acupuncture. 9. Natural killer cell activity was insignificant for S-180 cell treated with Triglii semen Herbal acupuncture.(p<0.05) 10. lnterieukin-2 productivity was decreased for S-180 cell treated with Triglii semen Herbal acupuncture compared to the normal and control group.(p<0.05) Conclusion: According to the results, we can conclude Herbal-acupuncture with Triglii semen caused toxicity, and caused no effects in S-180 cancer cell.
This study was carriet out to evaluate the acute intravenous toxicity and antigenicity of Guamerin, newly developed by Mogam Biotechnology Research Institute (MBRI). In acute intravenous toxicity test, ICR mice were administered intravenously with single dose of 1,000mg/kg, and body weights and clinical signs were observed for 14 days. No dead animal, clinical signs, body weight change and abnormal autopsy findings were found in control and Gumerin treated group. Therefore, the 50% lethoal dose (LD50) of Guamerin for ICR mice was more than 1,000mg/kg on intravenous route for male and female. And the antigenic potential of Guamerin was examined by active systemic anaphylaxis(ASA) and passive cutaneous anaphylaxis(PCA) tests. In the ASA test, low and high doses (10 and 100ug/animal, respectiwely) of Guamerin were administed subcutaneously to guinea pigs for 9 times 3 weeks. All experimental groups showed negative responses whereas the positive control group given ovalbumin plus Freunds complete adjuvant (FCA) showed severe anaphylactic responses. PCA test using rats with mice anti-serum against Guamerin, low and high doses(10 and 100 ug/animal, respectively) of Guamerin were administered to mice for 9 times in 3 weeks. The anti-serum against Guamerin was administed intradermally at the back of rats, however, any positive responses were not detected in the experimental groups. These results strongly indicate that Guamerin does not induce IgE production and is not a PCA reaction inducer under these experimental conditions.
This experiment was carried out to study on the safety assessment of Pinus densiflora Siebold et Zuccarini for Hebal-acupuncture. SD rats and ICR mice were used for acute toxicity test, the results were summerized as follows; 1. In rats and mice, $LD_{50}$ value could not be measured. 2. There were no abnormal finding in acute toxicity test treated Pinus densiflora Siebold et Zuccarini for Hebal-acupuncture.
The acute toxicity effect of triorganotin of trioganotin on the growth of microalgae and shellfish was investigated through flask culture. The value of 120 hr-LC$_{50}$ that is the median lethal concentration of TBTO on the shellfish (R. philipinarum) was found to be 6 $\mu$g/L. The acute toxicity effect of TBTO on T. suecica was obviously shown even at the concentration of 0.5 $\mu$g/L, and the effect diminished as the initial cell density increased. The effect also diminished less in the experiment done under aeration than in that done under non-aeration. To design a chemostat system for the test of chronic toxicity, the culture of T. suecica was executed in photobioreactor. In batch culture, the profiles of chlorophyII a and D.C.W. showed the growth of T. suecica very well, and the maximum specific growth rate was estimated to be 0.54 d$^{-1}$. with this value, as a dilution rate in contimuous culture, pH was nicely maintained between 7 and 9 when air was supplied with 3% CO$_{2}$. From all results and the natural environment of clam, a novel chemostat system was invented. Through this system, we can observe each independent toxicity effect of TBTO and plankton and combined toxicity effect as well.
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