1.Application of the Threshold of Toxicological Concern (TTC) to Biological Evaluation of Medical Devices.
Chenghu LIU ; Yanping SHI ; Xiaodan DU ; Xiaoxia SUN ; Jia LIU
Chinese Journal of Medical Instrumentation 2019;43(4):282-285
The threshold of toxicological concern (TTC), a risk estimation method based on compound structurally-related toxicity data, has been widely used by many countries and regions for the safety risk assessment of food packaging materials and additives etc. Toxicological risk estimation is of importance in the biological evaluation of medical devices. Application of the TTC approach to leachable from medical devices may reduce or replace some unnecessary biocompatibility tests, but consideration should be taken for contact duration and route differences, which could affect the applicability of TTC. We herein focused on analyzing the eligibility of TTC for its further application in biological evaluation of medical devices.
Equipment and Supplies
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standards
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Food Packaging
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standards
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Risk Assessment
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Toxicological Phenomena
2.In silico design of novel proton-pump inhibitors with reduced adverse effects.
Xiaoyi LI ; Hong KANG ; Wensheng LIU ; Sarita SINGHAL ; Na JIAO ; Yong WANG ; Lixin ZHU ; Ruixin ZHU
Frontiers of Medicine 2019;13(2):277-284
The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features: (1) number of ring II = number of ring I + 1; (2) preferably five, six, or seven-membered heteroatomic ring for stability; and (3) 1 < pKa1 < 4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.
Computer Simulation
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Drug Design
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Humans
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Proton Pump Inhibitors
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toxicity
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Toxicological Phenomena
3.Reversal effect of aloe emodin liposomes on cisplatin resistance line A549/DDP human lung adenocarcinoma cells.
Rong ZENG ; Zhi-wu ZHOU ; Cui-fang WU ; Yu-lu ZHOU
China Journal of Chinese Materia Medica 2008;33(12):1443-1445
OBJECTIVETo determine the reversal effect of aloe emodin liposomes (AE-L) on cisplatin resistance human lung adenocarcinoma cell line A549/DDP.
METHODThe un-cytotoxic and cytotoxic concentration of AE-L, and un-cytotoxic concentration of E-L were determined by MTT. The sensitivity of cisplatin were determined by MTT assay in above 3 groups. The intracellular concentration of cisplatin was detected by inductively coupled plasma mass spectrometry (ICP-MS).
RESULTThe maximum non-toxic concentration group of AE-L (2.0 mg x L(-1)) increased the sensitivity of cisplatin in A549/DDP, decreased IC50 of cisplatin in A549/DDP from 16.81 mg x L(-1) to 5.86 mg x L(-1), and the hyp-cytotoxic concentration (7.0 mg x L(-1) ) group's IC50 decreased to 4.34 mg x L(-1); AE-L groups significantly increased intracellular concentration of cisplatin in A549/DDP cells.
CONCLUSIONThe results showed that aloe emodin can reverse multidrug resistance (MDR) of A549/DDP cells and the mechanism might be associated with the increase of intracellular concentration of cisplatin.
Adenocarcinoma ; pathology ; Animals ; Anthraquinones ; adverse effects ; chemistry ; pharmacology ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Inhibitory Concentration 50 ; Lethal Dose 50 ; Liposomes ; Lung Neoplasms ; pathology
4.Acute Oral or Dermal and Repeated Dose 90-Day Oral Toxicity of Tetrasodium Pyrophosphate in Spraque Dawley (SD) Rats.
Dong Seok SEO ; Min KWON ; Ha Jung SUNG ; Cheol Beom PARK
Environmental Health and Toxicology 2011;26(1):e2011014-
OBJECTIVES: Tetrasodium pyrophosphate (TSP) is used in processed meat products, as an emulsifier in cheese, and as a color preservative in soybean paste. However, little is known about its toxicity. This study was conducted to investigate the potential acute and repeated dose toxicity of TSP in Spraque Dawley (SD) rats. METHODS: In the acute study, animals were administered with oral or dermal doses of 2,000 mg/kg TSP. In the repeated dose study, animals were administered doses of 0, 250, 500, and 1,000 mg/kg by oral gavage five times a week for 90 days. RESULTS: In acute toxicity studies, no dead animals or abnormal necropsy findings were found in the control or treated group. In the repeated dose toxicity study, there were no significant changes in body weight in the 1,000 mg/kg treatment group, or food consumption, urinalysis, and hematology in any group. With regards serum biochemistry, the levels of total protein, albumin, A/G ratio, triglyceride, calcium and inorganic phosphate were altered at doses of 500 and 1,000 mg/kg. However, no changes were observed at the dose of 250 mg/kg. With regards histopathological findings, cortical tubular basophilia of the kidney increased at the dose of 1,000 mg/kg, but not at doses of 250 and 500 mg/kg. No significant changes were observed in other organs at doses of 250, 500, and 1,000 mg/kg. CONCLUSIONS: Based on the results, TSP is unclassified according to the Globally Harmonization System, with an LD50 value of over 2,000 mg/kg. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) were 250 and 500 mg/kg /day respectively and the target organ appears to be the kidney.
Animals
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Biochemistry
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Body Weight
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Calcium
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Cheese
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Diphosphates
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Hematology
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Kidney
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Lethal Dose 50
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Meat Products
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No-Observed-Adverse-Effect Level
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Rats
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Soybeans
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Urinalysis
5.The activity of blood cholinesterase in rats exposed to dimehypo.
Weiguo WAN ; Mailing XU ; Hejian ZOU ; Ailing LU ; Xinyu SHEN ; Yuming CHEN
Chinese Journal of Industrial Hygiene and Occupational Diseases 2002;20(6):416-418
OBJECTIVETo determine whether and to what degree the activity of cholinesterase(ChE) is inhibited by dimehypo at different doses of dimehypo [scientific name: 2-dimethylamine-1,3-bi(sodium hyposulfit)].
METHODRats were dosed with dimehypo or methamidophos orally, and were randomly divided into four subgroups according to the pesticide doses, which were 1/16, 1/8, 1/4 and 1/2 of LD50 respectively(the LD50 of dimethypo and methamidophos is 342 mg/kg and 20 mg/kg respectively). The activity of ChE in blood was determined before and 30 min, 1, 2, 4 and 24 h after exposure. The modified Ellman Method was employed to measure the activity of ChE.
RESULT1/16 LD50 dose of dimehypo did not affect the activity of ChE. When the dose increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of dimehypo inhibited the activity of ChE by 35.9% compared with that of control group(P < 0.01). In rats dosed with methamidophos, even 1/16 LD50 dose inhibited the activity of ChE by 42.4% compared with that of control group. When the dose of methamidophos increased, the activity of ChE decreased accordingly. 1/2 LD50 dose of methamidophos inhibited the activity of ChE by 52.9%. The activity of ChE in the rats dosed with dimehypo at various doses was significantly lower than that in the rats dosed with corresponding doses of methamidophos(P < 0.01).
CONCLUSIONHigher doses of dimehypo may inhibit the activity of ChE. However, as compared with methamidophos, dimehypo is a weaker inhibitor of ChE.
Animals ; Cholinesterase Inhibitors ; toxicity ; Cholinesterases ; blood ; Dose-Response Relationship, Drug ; Insecticides ; toxicity ; Lethal Dose 50 ; Organothiophosphorus Compounds ; toxicity ; Rats
6.Study on the acute toxicity experiment of mice and anti-tumor function in vitro of the qinglongyi.
Wei LIU ; Wen-han LIN ; Yu-bin JI
China Journal of Chinese Materia Medica 2004;29(9):887-890
OBJECTIVETo study the anti-tumor effect and acute toxicity in vitro of the separation compositions from qinglongyi.
METHODThe conventional acute toxicity experiments of mice, the MTT [3-(4,5-dimethylthiazol-2 yl)-2,5-diphenylterazolium bromide, MTT] and the SRB (sulforhodamin B) were used to make preliminary selection to qinglongyi and its separation compositions.
RESULTThe half-deadly dose (LD50, the half-lethiferous dose) of the chloroform separation composition in qinglongyi was 575.38 mg x kg(-1) (i.g.), and of the acetic ether separation compositions in qinglongyi was 1303.59 mg x kg(-1) (i.g.). From the other parts of separation compositions in qinglongyi, the LD50 were more than 5 g x kg(-1). When acetic ether separation composition of qinglongyi was at 100 microg x mL(-1) the growth inhibitory rate (GIR) was < 50% to the leukaemia cell HL-60 of human. When chloroform separation composition and the acetic ether separation compositions of qinglongyi was at 100 mg x mL(-1), GIR was 52% to the leukaemia cell HL-60, the gastric carcinoma cell BGC-823 and the cervical carcinoma cell Hela of human.
CONCLUSIONThe separation composition of the chloroform and the acetic ether from qinglongyi have obvious, anti-tumor effect.
Animals ; Antineoplastic Agents, Phytogenic ; isolation & purification ; pharmacology ; toxicity ; Behavior, Animal ; drug effects ; Cell Line, Tumor ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; toxicity ; Female ; Fruit ; chemistry ; HL-60 Cells ; drug effects ; HeLa Cells ; drug effects ; Humans ; Inhibitory Concentration 50 ; Juglans ; chemistry ; Lethal Dose 50 ; Male ; Mice ; Plants, Medicinal ; chemistry ; Stomach Neoplasms ; pathology
7.In vivo toxicity study of Lantana camara.
Badakhshan Mahdi POUR ; Sreenivasan SASIDHARAN
Asian Pacific Journal of Tropical Biomedicine 2011;1(3):230-232
OBJECTIVETo investigate the toxicity of methanol extract of various parts (Root, Stem, Leaf, Flower and Fruit) of Lantana camara (L. Camara) in Artemia salina.
METHODSThe methanol extracts of L. camara were tested for in vivo brine shrimp lethality assay.
RESULTSAll the tested extract exhibited very low toxicity on brine shrimp larva. The results showed that the root extract was the most toxic part of L. camara and may have potential as anticancer agent.
CONCLUSIONSMethanolic extract of L. camara is relatively safe on short-term exposure.
Animals ; Artemia ; drug effects ; Dose-Response Relationship, Drug ; Lantana ; chemistry ; Lethal Dose 50 ; Plant Components, Aerial ; chemistry ; Plant Extracts ; toxicity ; Plant Roots ; chemistry
8.Study on alternative methods for the acute oral toxicity in detection of chemicals.
Jian-Bin TAN ; Min ZHAO ; Xing-Fen YANG ; Yi-Lin ZHOU ; Bi-Feng CHEN ; Rui-Yi CHEN ; Jian-Kang HUANG
Chinese Journal of Industrial Hygiene and Occupational Diseases 2011;29(6):431-434
OBJECTIVETo evaluate three alternative methods for LD50 test-Fixed Dose Procedure (FDP), the Acute Toxic Class Method (ATC) and Up and Down Procedure (UDP).
METHODSFemale SD rats (8-12 weeks of age, 160-200 g) were used. Three alternative methods from OECD were applied to assess 22 chemicals (10 cosmetic raw materials and 12 raw materials of personal and home care products). The toxicity ranking for tested chemicals was established according to Globally Harmonized System (GSH). The results LD50 test were compared for the consistency and correlation between alternative methods and traditional test.
RESULTSFor cosmetic raw materials, the concordance rate of the three alternative methods was 80% (8/10); for raw material of personal and home care products, the concordance rates of FDP, ATC and UDP was 91.7% (11/12), 75.0% (9/12) and 83.0% (10/12), respectively. The number of animals required in three alternative methods was significantly lower than that in traditional test (P < 0.05), but the time required in three alternative methods was significantly higher than that in traditional test (P < 0.05).
CONCLUSIONSHigh consistency and correlation were found between each alternative method and LD50 test. FDP may be more potential when applied to assess acute oral toxicity of cosmetic raw materials.
Administration, Oral ; Animals ; Cosmetics ; toxicity ; Dose-Response Relationship, Drug ; Female ; Hazardous Substances ; toxicity ; Lethal Dose 50 ; Rats ; Rats, Sprague-Dawley ; Toxicity Tests, Acute ; methods
9.Biodistribution and Postmortem Redistribution of Emamectin Benzoate in Intoxicated Mice.
Wei-wei TANG ; Yu-cai LIN ; Yan-xu LU
Journal of Forensic Medicine 2016;32(1):26-30
OBJECTIVE:
To investigate the lethal blood level, the target organs and tissues, the toxicant storage depots and the postmortem redistribution in mice died of emamectin benzoate poisoning.
METHODS:
The mice model of emamectin benzoate poisoning was established via intragastric injection. The main poisoning symptoms and the clinical death times of mice were observed and recorded dynamically in the acute poisoning group as well as the sub-acute poisoning death group. The pathological and histomorphological changes of organs and tissues were observed after poisoning death. The biodistribution and postmortem redistribution of emamectin benzoate in the organs and tissues of mice were assayed by the enzyme-linked immunosorbent assay (ELISA) at 0h, 24h, 48h and 72h after death. The lethal blood concentrations and the concentrations of emamectin benzoate were detected by high performance liquid chromatography (HPLC) at different time points after death.
RESULTS:
The symptoms of nervous and respiratory system were observed within 15-30 min after intragastric injection. The average time of death was (45.8 ± 7.9) min in the acute poisoning group and (8.0 ± 1.4) d in the sub-acute poisoning group, respectively. The range of acute lethal blood level was 447.164 0-524.463 5 mg/L. The pathological changes of the organs and tissues were observed via light microscope and immunofluorescence microscope. The changes of emamectin benzoate content in the blood, heart, liver, spleen, lung, kidney and brain of poisoning mice showed regularity within 72 h after death (P < 0.05).
CONCLUSION
The target organs of emamectin benzoate poisoning include heart, liver, kidney, lung, brain and contact position (stomach). The toxicant storage depots are kidney and liver. There is emamectin benzoate postmortem redistribution in mice.
Animals
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Autopsy
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Chromatography, High Pressure Liquid
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Ivermectin/toxicity*
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Lethal Dose 50
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Mice
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Postmortem Changes
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Tissue Distribution
10.Toxicity of Methylcyclohexane and Its Effect on the Reproductive System in SD Rats.
Hyeon Yeong KIM ; Min Gu KANG ; Tae Gyun KIM ; Chung Won KANG
Safety and Health at Work 2011;2(3):290-300
OBJECTIVES: There is limited data regarding the toxicity of methylcyclohexane, despite its wide use in rubber adhesives, paint diluents, and cleansing agents. This study aimed to verify the toxicity and influence on the reproductive system of methylcyclohexane after its repeated injection in Sprague Dawley (SD) rats. METHODS: Methylcyclohexane was injected subcutaneously into male and female SD rats once a day, five times a week, for 13 weeks at different doses (0, 10, 100, and 1,000 mg/kg/day) for each group. The toxicity of testing material was verified by observing the change in body and organ weight, hematological change, pathological findings, and effect on the reproductive system at each different concentration. RESULTS: In the 1,000 mg/kg/day group, there were cases of animal deaths. In animals that survived, hematological changes, including a decrease in the red blood cell count, were observed. A considerable weight gain or loss and pathological abnormalities in the liver, kidney, and other organs were found. However, the 10 and 100 mg/kg/day groups did not cause deaths or other specific abnormalities. In terms of reproductive toxicity, there were changes in hormone levels, including a significant decrease in hormones such as estradiol and progesterone (p < 0.001) in male animals. Menstrual cycle change for female animals did not show concentration dependency. CONCLUSION: When injected repeatedly for 13 weeks, methylcyclohexane proved to be toxic for the liver, heart, and kidney at a high dose. The absolute toxic dose was 1,000 mg/kg/day, while the no observed adverse effect level was less than 100 mg/kg/day. The substance exerted little influence on the reproductive system.
Adhesives
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Animals
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Cyclohexanes
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Detergents
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Erythrocyte Count
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Estradiol
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Female
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Heart
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Humans
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Kidney
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Lethal Dose 50
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Liver
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Male
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Menstrual Cycle
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No-Observed-Adverse-Effect Level
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Organ Size
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Paint
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Progesterone
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Rats
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Rubber
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Weight Gain