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Sample records for repeated-dose oral toxicity

  1. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... strains of young healthy adult animals should be employed. The females should be nulliparous and...

  2. Investigation of repeated dose (90 day oral toxicity, reproductive/developmental toxicity and mutagenic potential of ‘Calebin A’

    Directory of Open Access Journals (Sweden)

    Muhammed Majeed

    2015-01-01

    Full Text Available The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as “No Observed Adverse Effect Level (NOAEL” under the test conditions.

  3. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

    Science.gov (United States)

    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida

    2014-05-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.

  4. Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda

    2013-06-01

    Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

  5. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    Science.gov (United States)

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  6. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats.

    Science.gov (United States)

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

    2009-02-01

    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while testing of cosmetic ingredients.

  7. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

    Science.gov (United States)

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

    2012-04-10

    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  8. Evaluation of 90-day Repeated Dose Oral Toxicity, Glycometabolism, Learning and Memory Ability, and Related Enzyme of Chromium Malate Supplementation in Sprague-Dawley Rats.

    Science.gov (United States)

    Feng, Weiwei; Wu, Huiyu; Li, Qian; Zhou, Zhaoxiang; Chen, Yao; Zhao, Ting; Feng, Yun; Mao, Guanghua; Li, Fang; Yang, Liuqing; Wu, Xiangyang

    2015-11-01

    Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the 90-day oral toxicity of chromium malate in Sprague-Dawley rats. The present study inspected the effect of chromium malate on glycometabolism, glycometabolism-related enzymes, lipid metabolism, and learning and memory ability in metabolically healthy Sprague-Dawley rats. The results showed that all rats survived and pathological, toxic, feces, and urine changes were not observed. Chromium malate did not cause measurable damage on liver, brain, and kidney. The fasting blood glucose, serum insulin, insulin resistance index, C-peptide, hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels of normal rats in chromium malate groups had no significant change when compared with control group and chromium picolinate group under physiologically relevant conditions. The serum and organ content of Cr in chromium malate groups had no significant change compared with control group. No significant changes were found in morris water maze test and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and true choline esterase (TChE) activity. The results indicated that supplementation with chromium malate did not cause measurable toxicity and has no obvious effect on glycometabolism and related enzymes, learning and memory ability, and related enzymes and lipid metabolism of female and male rats. The results of this study suggest that chromium malate is safe for human consumption.

  9. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto

    2008-02-01

    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  10. Acute and repeated dose toxicity studies of different β-cyclodextrin-based nanosponge formulations.

    Science.gov (United States)

    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

  11. [Twenty-eight days repeated dose toxicity test of N-(fluorodichloromethylthio)phthalimide in rats].

    Science.gov (United States)

    Matsushima, Y; Tsuda, M; Naito, K; Saitoh, M; Isama, K; Ikarashi, Y; Kawasaki, Y; Momma, J; Kitajima, S; Kaniwa, M

    1995-01-01

    N-(Fluorodichloromethylthio)phthalimide (Fluor-folpet) has been widely used as an anti-mold and anti-bacterial agent. In this study, 28 days repeated-dose oral toxicity study of fluor-folpet was carried out in Slc:Wistar rats. An oral toxicity study for fluor-folpet, the twenty-eight days test, repeated-dose, oral administration, was performed as follows: Five week-old rats, male and female, 10 rats, each/group, were treated with intragastric administration of fluor-folpet with a dose of 0 (1% Sodium CMC, control), 20, 80 and 320 mg/kg, body weight. Recovery test, for 14 days after the last treatment, was examined for the control and the 320 mg/kg groups. The 320 mg/kg groups, both males and females, showed significantly reduced their body-weight gain compared with the control group. In the 320 mg/kg group, five out of 20 male rats and four out of 20 female rats died from dyspnea during the treatment period. In the female rats in the 320 mg/kg group, serum ChE level was decreased to 50% of control level and gamma-GT was increased in a dose-dependent manner, but these serum levels recovered after 14 days non-treatment period. No histopathological change, relating to the treatment, in liver was observed. Increased weight of the kidney and vacuolation in renal tubules were found in both sexes of 320 mg/kg group. Hyperkeratosis and hyperplasia of the stomach epithelium were observed at the dose more than 80 mg/kg in male, and more than 20 mg/kg in female. A supplemental study, repeated-dose, oral administration in rats carried out to examine the dyspnea revealed that severe acute toxic damages in epithelium of nasal cavity and meatus nasopharyngeus were induced by intragastric administration of fluor-folpet. Fluor-folpet is shown to be cytotoxic. In conclusion, the no-observed-effect level (NOEL) for fluor-folpet was not found under the experimental conditions employed in this repeated-dose toxicity study.

  12. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

    Science.gov (United States)

    Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A

    2009-01-01

    The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

  13. Comparison of the repeated dose toxicity of isomers of dinitrotoluene.

    Science.gov (United States)

    Lent, Emily May; Crouse, Lee C B; Quinn, Michael J; Wallace, Shannon M

    2012-03-01

    Dinitrotoluene (DNT) is a nitroaromatic explosive used in propellant mixtures and in the production of plastics. Isomers of DNT were administered daily via oral gavage to male Sprague-Dawley rats for 14 days to determine the subacute toxicity of individual isomers of DNT. The 3,5-DNT isomer was the most toxic isomer, inducing weight loss and mortality within 3 days. Cyanosis and anemia were observed for all isomers. Exposure to 2,4-, 2,6-, and 3,5-DNT resulted in decreased testes mass and degenerative histopathological changes. Increased splenic mass was observed for 2,4-, 2,6-, and 2,5-DNT. Extramedullary hematopoiesis of the spleen was noted for all isomers, while lymphoid hyperplasia of the spleen was noted for all isomers except 2,5-DNT. Increased liver mass was observed for 2,3-DNT and 3,4-DNT. Hepatocellular lesions were observed for 2,6-DNT and 2,4-DNT. Neurotoxic effects were noted for 3,4-DNT, 2,4-DNT, and 3,5-DNT.

  14. Investigation of the toxicity of some organophosphorus pesticides in a repeated dose study in rats.

    Science.gov (United States)

    Baconi, Daniela Luiza; Bârcă, Maria; Manda, Gina; Ciobanu, Anne Marie; Bălălău, C

    2013-01-01

    The study aimed to the investigation of the toxicity of organophosphorus pesticides malathion (MLT) and diazinon (DZN) in Wistar rats in a repeated dose study for 35 days. MLT and DZN in corn oil vehicle were oral administered. Body and organs weights, plasma and brain cholinesterase activities, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathological changes in liver and kidney, and some parameters of the immune function, such as leukocyte formula, spleen weight and cellularity, spleen lymphocytes proliferation in response to concanavalin A (Con A) were investigated; the potential oxidative stress (malondialdehyde in plasma and brain, and blood catalase activity) was also evaluated. No clinical toxicity signs attributed to pesticides were noted; no significant changes in the organ weights have been found. Body weight tends slightly to increase, predominantly in DZN treated rats. The results suggest that plasma cholinesterase is more susceptible than brain cholinesterase to the inhibitory effect of DZN and MLT. Other serum biochemical parameters showed no significant difference. DZN produced a marked increase of the number of spleen lymphocytes without a significant gain of the relative spleen weight. The both pesticides produced an increase of the number of mononuclear cells÷weight spleen. The splenic lymphocyte proliferation has not been influenced by MLT or DZN treatment. Histopathological observations identified some changes (vasodilatation, microvacuoles, and granular dystrophy) in the liver, with MLT, inducing macrovacuolar steatosis. The study indicates that repeated exposure, at subclinical doses, to organophosphorus MLT and DZN causes some biochemical, histopathological and immune alterations in rats.

  15. Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae in Swiss Mice

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    Germana Freire Rocha Caldas

    2013-01-01

    Full Text Available Hyptis martiusii Benth. (Lamiaceae is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM. Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice.

  16. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

    Science.gov (United States)

    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  17. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Scala, R.A.; Bevan, C.; Beyer, B.K. (Exxon Biomedical Sciences, Inc., East Millstone, NJ (United States))

    1992-08-01

    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  18. Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients.

    Science.gov (United States)

    Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera

    2012-03-01

    Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

  19. Study of four week repeated dose toxic test of Sweet Bee Venom in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Jae-Seuk Park

    2010-12-01

    Full Text Available Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56㎎/㎏ body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7

  20. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

    NARCIS (Netherlands)

    Tluczkiewicz, I.; Batke, M.; Kroese, D.; Buist, H.; Aldenberg, T.; Pauné, E.; Grimm, H.; Kühne, R.; Schüürmann, G.; Mangelsdorf, I.; Escher, S.E.

    2013-01-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evalua

  1. 啮齿类动物28天重复剂量经口毒性改良试验简介与进展%Introduction and progress on the enhancement of repeated dose 28-day oral toxicity study in rodents

    Institute of Scientific and Technical Information of China (English)

    王恒娟; 刘兆平

    2012-01-01

    Repeated dose 28-day oral toxicity study in rodents ( OECD Test Guidelines 407) is widely used to evaluate the general toxicity of chemicals. In 1998, the Organization for Economic Co-operation and Development (OECD) enhanced existing TG 407 to develop new Test Guidelines for screening and testing potential endocrine disruptors. This procedure has been verified by an extensive international validation program. To provide reference for developing endocrine disruptor evaluation system in China, the enhanced TG 407, its progress and its advantages and disadvantages were summarized in this paper.%经济合作与发展组织(Organization for Economic Co-operation and Development,OECD)推荐的啮齿类动物28天重复剂量经口毒性试验( OECD TG 407)是一种广泛用于评价化学物一般毒性的毒理学试验方案.OECD在1998年对其进行改良后,建立TG 407改良试验并经世界多国实验室验证,用于检测化学物的内分泌干扰作用.本文简要介绍了OECD TG 407改良试验指南,并对其进展情况以及优缺点进行综述,以期为我国的内分泌干扰物的评价体系提供参考.

  2. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

    Science.gov (United States)

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  3. Collaborative work on evaluation of ovarian toxicity. 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats.

    Science.gov (United States)

    Tamura, Toru; Yokoi, Ryohei; Okuhara, Yuji; Harada, Chiho; Terashima, Yukari; Hayashi, Morimichi; Nagasawa, Tatsuya; Onozato, Tomoya; Kobayashi, Kazuo; Kuroda, Junji; Kusama, Hiroshi

    2009-01-01

    In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal cornification was also observed at 20 mg/kg and the precoital interval was significantly shortened. All of the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implantation losses. These results suggested that a 2-week administration period would be sufficient to detect the ovarian toxicity of mifepristone in repeated dose toxicity study and the pathological findings in the ovaries would reflect the alterations in female reproductive endpoints in the female fertility study.

  4. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

    Science.gov (United States)

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  5. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

    Science.gov (United States)

    Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

    2013-01-01

    The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS).

    Science.gov (United States)

    Tluczkiewicz, Inga; Batke, Monika; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia E

    2013-11-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.

  7. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya

    2007-11-01

    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

  8. Zinc oxide nanoparticles: a 90-day repeated-dose dermal toxicity study in rats

    Directory of Open Access Journals (Sweden)

    Ryu HJ

    2014-12-01

    was dose-dependent irritation at the site of application, there were no abnormal findings related to ZnO NPs in other organs. Increased concentrations of ZnO in the liver, small intestine, large intestine, and feces were thought to result from oral ingestion of ZnO NPs via licking. Penetration of ZnO NPs through the skin seemed to be limited via the dermal route. This study demonstrates that there was no observed adverse effect of ZnO NPs up to 1,000 mg/kg body weight when they are applied dermally. Keywords: zinc oxide, nanoparticles, subchronic toxicity, dermal exposure

  9. Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.

    Science.gov (United States)

    Ishii, Shun-ichiro; Ube, Masayuki; Okada, Miyoko; Adachi, Tamiko; Sugimoto, Jiro; Inoue, Yoshimi; Uno, Yoshifumi; Mutai, Mamoru

    2009-01-01

    To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

  10. Toxicological assessment of heavy straight run naphtha in a repeated dose/reproductive toxicity screening test.

    Science.gov (United States)

    McKee, Richard H; Steup, David; Schreiner, Ceinwen; Podhasky, Paula; Malley, Linda A; Roberts, Linda

    2014-01-01

    Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

  11. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

    Science.gov (United States)

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N

    2000-10-01

    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  12. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

    Science.gov (United States)

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C

    2014-01-01

    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general.

  13. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    Science.gov (United States)

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  14. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.

    Science.gov (United States)

    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi

    2015-03-01

    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.

  15. (1)H NMR-based metabolomics study on repeat dose toxicity of fine particulate matter in rats after intratracheal instillation.

    Science.gov (United States)

    Zhang, Yannan; Hu, Hejing; Shi, Yanfeng; Yang, Xiaozhe; Cao, Lige; Wu, Jing; Asweto, Collins Otieno; Feng, Lin; Duan, Junchao; Sun, Zhiwei

    2017-07-01

    Systemic metabolic effects and toxicity mechanisms of ambient fine particulate matter (PM2.5) remain uncertain. In order to investigate the mechanisms in PM2.5 toxicity, we explored the endogenous metabolic changes and possible influenced metabolic pathways in rats after intratracheal instillation of PM2.5 by using a (1)H nuclear magnetic resonance (NMR)-based metabolomics approach. Liver and kidney histopathology examinations were also performed. Chemical characterization demonstrated that PM2.5 was a complex mixture of elements. Histopathology showed cellular edema in liver and glomerulus atrophy of the PM2.5 treated rats. We systematically analyzed the metabolites changes of serum and urine in rats using (1)H NMR techniques in combination with multivariate statistical analysis. Significantly reduced levels of lactate, alanine, dimethylglycine, creatine, glycine and histidine in serum, together with increased levels of citrate, arginine, hippurate, allantoin and decreased levels of allthreonine, lactate, alanine, acetate, succinate, trimethylamine, formate in urine were observed of PM2.5 treated rats. The mainly affected metabolic pathways by PM2.5 were glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, citrate cycle (TCA cycle), nitrogen metabolism and methane metabolism. Our study provided important information on assessing the toxicity of PM2.5 and demonstrated that metabolomics approach can be employed as a tool to understand the toxicity mechanism of complicated environmental pollutants. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Construction of the Database of Rat Repeated-dose Toxicity Tests of Pesticides for the Toxicological Characterization of Hepatocyte Hypertrophy.

    Science.gov (United States)

    Masuda, Akane; Masuda, Miyabi; Kawano, Takuya; Kitsunai, Yoko; Nakayama, Haruka; Nakajima, Hiroyuki; Kojima, Hiroyuki; Kitamura, Shigeyuki; Uramaru, Naoto; Hosaka, Takuomi; Sasaki, Takamitsu; Yoshinari, Kouichi

    2017-01-01

     Liver and hepatocyte hypertrophy can be induced by exposure to chemical compounds, but the mechanisms and toxicological characteristics of these phenomena have not yet been investigated extensively. In particular, it remains unclear whether the hepatocyte hypertrophy induced by chemical compounds should be judged as an adaptive response or an adverse effect. Thus, understanding of the toxicological characteristics of hepatocyte hypertrophy is of great importance to the safety evaluation of pesticides and other chemical compounds. To this end, we have constructed a database of potentially toxic pesticides. Using risk assessment reports of pesticides that are publicly available from the Food Safety Commission of Japan, we extracted all observations/findings that were based on 90-day subacute toxicity tests and 2-year chronic toxicity and carcinogenicity tests in rats. Analysis of the database revealed that hepatocyte hypertrophy was observed for 37-47% of the pesticides investigated (varying depending on sex and testing period), and that centrilobular hepatocyte hypertrophy was the most frequent among the various types of hepatocyte hypertrophy in both the 90-day and 2-year studies. The database constructed in this study enables us to investigate the relationships between hepatocyte hypertrophy and other toxicological observations/findings, and thus will be useful for characterizing hepatocyte hypertrophy.

  17. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya

    2008-01-01

    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  18. Prediction of the carcinogenic potential of human pharmaceuticals using repeated dose toxicity data and their pharmacological properties

    Directory of Open Access Journals (Sweden)

    Jan Willem Van Der Laan

    2016-10-01

    Full Text Available In an exercise designed to reduce animal use, we analysed the results of rat sub-chronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumour outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred and forty-three of the 239 compounds not inducing putative preneoplastic lesions in the sub-chronic study did not induce tumours in the carcinogenicity study (True Negatives - TN, whereas 96 compounds were categorised as False Negatives (FN, because tumours were observed in the carcinogenicity study. For the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumours in the carcinogenicity study (True positives - TP, and 19 only showed preneoplastic lesions in subchronic studies but no tumours in the carcinogenicity study (False positives - FP. In addition, we then re-assessed the prediction of the tumour outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN. For 67 compounds the presence of cellular hyperplasia as evidence for proliferative action could be found (TP. Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92 % and the ability to detect carcinogens at 98 %. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorised as FN. 1 as FP, thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological

  19. Prospective evaluation of potential toxicity of repeated doses of Thymus vulgaris L. extracts in rats by means of clinical chemistry, histopathology and NMR-based metabonomic approach.

    Science.gov (United States)

    Benourad, Fouzia; Kahvecioglu, Zehra; Youcef-Benkada, Mokhtar; Colet, Jean-Marie

    2014-10-01

    In the field of natural extracts, research generally focuses on the study of their biological activities for food, cosmetic, or pharmacological purposes. The evaluation of their adverse effects is often overlooked. In this study, the extracts of Thymus vulgaris L. were obtained by two different extraction methods. Intraperitoneal injections of both extracts were given daily for four days to male Wistar Han rats, at two different doses for each extract. The evaluation of the potential toxic effects included histopathological examination of liver, kidney, and lung tissues, as well as serum biochemistry of liver and kidney parameters, and (1)H-NMR-based metabonomic profiles of urine. The results showed that no histopathological changes were observed in the liver and kidney in rats treated with both extracts of thyme. Serum biochemical investigations revealed significant increases in blood urea nitrogen, creatinine, and uric acid in animals treated with polyphenolic extract at both doses. In these latter groups, metabonomic analysis revealed alterations in a number of urine metabolites involved in the energy metabolism in liver mitochondria. Indeed, the results showed alterations of glycolysis, Krebs cycle, and β-oxidative pathways as evidenced by increases in lactate and ketone bodies, and decreases in citrate, α-ketoglutarate, creatinine, hippurate, dimethylglycine, and dimethyalanine. In conclusion, this work showed that i.p. injection of repeated doses of thyme extracts causes some disturbances of intermediary metabolism in rats. The metabonomic study revealed interesting data which could be further used to determine the cellular pathways affected by such treatments.

  20. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif

    2014-01-01

    Full Text Available Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD concepts: (i PPARγ activation in hepatocytes and (ii PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

  1. Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats.

    Science.gov (United States)

    Kobayashi, Katsumi; Sakuratani, Yuki; Abe, Takemaru; Yamazaki, Kazuko; Nishikawa, Satoshi; Yamada, Jun; Hirose, Akihiko; Kamata, Eiichi; Hayashi, Makoto

    2011-01-01

    In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.74% for sodium. CV of electrolytes was comparatively small, whereas enzymes had large CV. Large differences in CV were observed for major parameters among 7-8 test facilities. The changes in CV were grossly classified into 11. Our study revealed that a statistical significant difference is usually detected if there is a difference of 7% in mean values between the groups and the groups have a CV of about 7%. A parameter with a CV as high as 30% may be significantly different, if the difference of the mean between the groups is 30%. It would be ideal to use median value to assess the treatment-related effect, rather than mean, when the CV is very high. We recommend using CV of the body weight as a standard to judge the adverse effect level.

  2. 氟氯氰菊酯亚急性吸入毒性实验研究%Inhalation toxicity of cyfluthrin for 28-day repeated dose in rats

    Institute of Scientific and Technical Information of China (English)

    秦珩; 乔善磊; 顾军; 钟义红; 杨洪宝; 王玉邦; 施爱民

    2012-01-01

    Objective To determine the inhalation toxicity and find the non -observed adverse effect level (NOAEL) of cyfluthrin for a 28-day repeated dose in rats. Methods Clean-grade SD rats were randomly divided into 5 groups with 5 females and 5 males in each. The animals inhaled DMSO or cyfluthrin at the concentration of 0, 7. 81 , 9. 05 and 18. 98 mg/m for 4 weeks (6 h/d, 5 d/w). At the end of inhalation , all the animals were kindly sacrificed. Their organs were collected for histopathological examination . Blood samples were collected for analysis of complete blood count , biochemistry and coagulation. Results The animals in 18. 98 mg/m3 group were found scratching repeatedly around the mouth, listless, fidgeting, trembling, discharging blood around the mouth and nose . However, symptoms in females were less serious than in males. Furthermore , the body mass , feed efficiency , weight of kidney of animals in this dose male group were found decreased compared with the control group . Biochemistry detection revealed that serum AST was elevated markedly in both genders of 18. 98 mg/m3 group and in males of 9. 05 mg/m3 group. No obvious abnormity was found in 7.81 mg/m3 group or control group. Conclusion Based on the results above, the non-observed adverse effect level (NOAEL) of cyfluthrin in SD rats is 7. 81 mg/m3 for 28 d repeated inhalation in this study.%目的 观察氟氯氰菊酯染毒大鼠亚急性吸入毒性.方法 7周龄清洁级SD大鼠随机分成5组,每组雌雄各5只,分别吸入氟氯氰菊酯0,7.81,9.05,18.98 mg/m3及溶剂二甲亚砜,每天6 h,每周5 d,共28 d.实验结束时取血液做常规生化指标、血细胞指标、血凝学指标检测.取心、肝、脾等8种主要脏器称重并做病理组织学检查.结果 18.98 mg/m3组动物在染毒中呈现反复抓挠口周、烦躁不安、鼻有血性分泌物、颤抖,染毒结束后呈现萎靡、蜂腰、四肢无力的体征.雌性动物的毒性表现较雄性低.与溶剂对照组相

  3. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen.

    Science.gov (United States)

    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki

    2015-03-01

    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study.

  4. Preclinical toxicity profile of oral bilastine.

    Science.gov (United States)

    Lucero, María Luisa; Arteche, Joseba K; Sommer, E W; Casadesus, Agustín

    2012-06-01

    As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage.

  5. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster

    DEFF Research Database (Denmark)

    Langkilde, Søren; Mandimika, T.; Schrøder, Malene

    2009-01-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine...... to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity...... of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios...

  6. Statistical tools for analysing the data obtained from repeated dose toxicity studies with rodents: a comparison of the statistical tools used in Japan with that of used in other countries.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Guhatakurta, Soma; Cherian, K M; Ohnishi, Mariko

    2011-01-01

    In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé's multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene's test, since the commonly used Bartlett's test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett's test, and for those show heterogeneity of variance, we recommend Steel's test.

  7. A 28-day repeat dose toxicity study of steroidal glycoalkaloids a-solanine and a-chaconine in the Syrian Golden Hamster

    NARCIS (Netherlands)

    Langkilde, S.; Mandimika, T.; Schroder, M.; Meyer, O.; Slob, W.; Peijnenburg, A.A.C.M.; Poulsen, M.

    2009-01-01

    Glycoalkaloids ¿-solanine and ¿-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of ¿-solanine to ¿-chaconine m

  8. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

    Science.gov (United States)

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  9. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    Science.gov (United States)

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  10. Oral toxicity of elephant foot yam (Amorphophallus paeoniifolius tuber in mice

    Directory of Open Access Journals (Sweden)

    Yadu Nandan Dey

    2017-02-01

    Full Text Available Context: Amorphophallus paeoniifolius tuber is an important constituent of Ayurvedic system of medicine. The tuber of this plant has high medicinal value and is consumed as a food. It is associated with acridity (itchy sensation in mouth and throat upon oral consumption and presence of high oxalates raphides. Aims: To evaluate the acute and subacute oral toxicity studies of methanolic (APME and aqueous (APAE extracts of Amorphophallus paeoniifolius tuber in Swiss albino mice according to OECD guidelines. Methods: In acute oral toxicity study, the mice were orally administered a single dose of APME or APAE (2000 mg/kg and clinical signs and mortality were observed for 14 days. In subacute (repeated dose oral toxicity study, the mice were administered once daily, orally with APME or APAE (1000 mg/kg up to 28 days. The parameters assessed were behavior, clinical signs, body weight, feed and water consumption, urinary, biochemical, hematological and major organ weights and histology. Results: In acute toxicity study, there was no treatment related mortality and morbidity in any of the group. In subacute toxicity study, there were no significant changes in behavior, body weight, feed and water consumption, urinary, biochemical, hematological and organ weight and histological parameters compared to vehicle treated group. There was no treatment related mortality or morbidity. Conclusions: Administration of methanolic and aqueous extracts of Amorphophallus paeoniifolius tuber, individually in acute and 28 days repeated dose in mice, did not exhibit any toxicity or adverse effect at the doses used.

  11. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

    Science.gov (United States)

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

  12. A k-NN algorithm for predicting the oral sub-chronic toxicity in the rat.

    Science.gov (United States)

    Gadaleta, Domenico; Pizzo, Fabiola; Lombardo, Anna; Carotti, Angelo; Escher, Sylvia E; Nicolotti, Orazio; Benfenati, Emilio

    2014-01-01

    Repeated dose toxicity is of the utmost importance to characterize the toxicological profile of a chemical after repeated administration. Its evaluation refers to the Lowest-Observed-(Adverse)-Effect-Level (LO(A)EL) explicitly requested in several regulatory contexts, such as REACH and EC Regulation 1223/2009 on cosmetic products. So far in vivo tests have been the sole viable option to assess repeated dose toxicity. We report a customized k-Nearest Neighbors approach for predicting sub-chronic oral toxicity in rats. A training set of 254 chemicals was used to derive models whose robustness was challenged through leave-one-out cross-validation. Their predictive power was evaluated on an external dataset comprising 179 chemicals. Despite the intrinsically heterogeneous nature of the data, our models give promising results, with q²≥0.632 and external r²≥0.543. The confidence in prediction was ensured by implementing restrictive user-adjustable rules excluding suspicious chemicals irrespective of the goodness in their prediction. Comparison with the very few LO(A)EL predictive models in the literature indicates that the results of the present analysis can be valuable in prioritizing the safety assessment of chemicals and thus making safe decisions and justifying waiving animal tests according to current regulations concerning chemical safety.

  13. Repeated-dose liver micronucleus test of 4,4'-methylenedianiline using young adult rats.

    Science.gov (United States)

    Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    Liver micronucleus (MN) tests using partial hepatectomized rats or juvenile rats have been shown to be useful for the detection of hepatic carcinogens. Moreover, Narumi et al. established the repeated-dose liver MN test using young adult rats for integration into general toxicity. In the present study, in order to examine the usefulness of the repeated-dose liver MN test, we investigated MN induction with a 14 or 28 day treatment protocol using young adult rats treated with 4,4′-methylenedianiline (MDA), a known hepatic carcinogen. MDA dose-dependently induced micronuclei in hepatocytes in 14- and 28-day repeated-dose tests. However, although statistically significant increases in micronuclei were observed in bone marrow cells at two dose levels in the 14-day study, there was no dose response and no increases in micronuclei in the 28-day study. These results indicate that the evaluation of genotoxic effects using hepatocytes is effective in cases where chromosomal aberrations are not clearly detectable in bone marrow cells. Moreover, the repeated-dose liver MN test allows evaluation at a dose below the maximum tolerable dose, which is required for the conventional MN test because micronucleated hepatocytes accumulate. The repeated-dose liver MN test employed in the present study can be integrated into the spectrum of general toxicity tests without further procedural modifications.

  14. Repeated dose 28-day oral toxicity study in Wistar rats with a mixture of five pesticides often found as residues in food: alphacypermethrin, bromopropylate, carbendazim, chlorpyrifos and mancozeb

    DEFF Research Database (Denmark)

    Jacobsen, H.; Østergaard, G.; Lam, Henrik Rye;

    2004-01-01

    , haematocrite and haemoglobin concentration was significantly reduced in both male and female rats of groups 5 and 6. Relative liver weight was significantly increased in groups 3-6 male and female rats. Absolute thyroid gland weight was significantly increased in groups 3, 5 and 6 male rats and of groups 3......-6 female rats, and relative thyroid gland weight was significantly increased in groups 2-6 male rats and of groups 3-6 female rats. Absolute thymus weight of groups 3-6 male and female rats and relative thymus weight of groups 3-6 male rats and groups 3 and 4 female rats was significantly decreased. A mild...... degree of centrilobular cell hypertrophy of the liver was seen in all male rats and of three female rats of group 6. In the thyroid gland follicular cell hypertrophy was present in one female in the control group and in six females and seven males of group 6. It was concluded that inhibition...

  15. Repeated dose pharmacokinetics of pancopride in human volunteers.

    Science.gov (United States)

    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A

    1994-11-01

    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze-dried Powder of Tenebrio molitor Larvae (Yellow Mealworm).

    Science.gov (United States)

    Han, So-Ri; Yun, Eun-Young; Kim, Ji-Young; Hwang, Jae Sam; Jeong, Eun Ju; Moon, Kyoung-Sik

    2014-06-01

    The larval form of Tenebrio molitor (T. molitor) has been eaten in many countries and provides benefits as a new food source of protein for humans. However, no information exists regarding its safety for humans. The objective of the present study was to evaluate the genotoxicity and repeated dose oral toxicity of the freeze-dried powder of T. molitor larvae. The genotoxic potential was evaluated by a standard battery testing: bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo micronucleus test. To assess the repeated dose toxicity, the powder was administered once daily by oral gavage to Sprague-Dawley (SD) rats at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 28 days. The parameters which were applied to the study were mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. The freezedried powder of T. molitor larvae was not mutagenic or clastogenic based on results of in vitro and in vivo genotoxicity assays. Furthermore, no treatment-related changes or findings were observed in any parameters in rats after 28 days oral administration. In conclusion, the freeze-dried powder of T. molitor larvae was considered to be non-genotoxic and the NOAEL (No Observed Adverse Effect Level) was determined to be 3000 mg/kg/day in both sexes of SD rats under our experimental conditions.

  17. 注射用右旋雷贝拉唑钠大鼠13周重复给药毒性研究%Study on Repeated Dose Toxicity of Dexrabeprazole Sodium Injection in Rats for 13 Weeks

    Institute of Scientific and Technical Information of China (English)

    戴晓莉; 戴学栋; 郭峰; 胡建庭; 马玉奎

    2016-01-01

    目的:研究SD大鼠连续静脉给予注射用右旋雷贝拉唑钠13周的毒性作用。方法选取SD大鼠190只,雌性各半,分为溶媒对照组、注射用雷贝拉唑钠市售对照80 mg·kg-1组、注射用右旋雷贝拉唑钠80、20、5 mg·kg-1组及注射用雷贝拉唑钠、注射用右旋雷贝拉唑钠各剂量毒代卫星组,每天给药1次,连续给药13周,停药恢复4周。试验期间,全部动物每周称量体重和摄食量,给药13周及停药恢复4周时腹主动脉取血进行血液相关指标检测,剖检摘取脏器进行组织病理学检查;卫星组动物分别于首次和末次给药后颈静脉采血进行毒代动力学检测。结果注射用右旋雷贝拉唑钠80、20 mg·kg-1剂量下可导致大鼠出现呼吸急促、步态不稳、俯卧不动等症状,血液中RBC、HGB、HCT含量降低、甲状腺出现小滤泡形成增多,停药4周后血液学异常指标均恢复正常,但甲状腺病理学改变未能完全恢复。结论重复静脉注射给予注射用右旋雷贝拉唑钠80、20 mg·kg-1剂量下可导致SD大鼠红细胞相关指标可逆性改变、甲状腺病理改变。%Objective To observe the toxicity damage of dexrabeprazole sodium injection in rats for 13 Weeks.Methods One hundred and ninety rats(female half)were randomly divided into vehicle control group, rabeprazole sodium injection control group, three dexrabeprazole sodium injection groups with different dosages (80, 20 and 5 mg·kg-1), in addition, rabeprazole sodium injection and dexrabeprazole sodium injection satellite group. Then the group should be given the injection once a day for 13 weeks, after that, stopped to recovery for 4 weeks. During the test, all the animals should weigh weight and food intake. When stopped injection and ifnishing recovery, blood taken from abdominal aorta, organ coefifcient and histopathology were measured for the overall toxicity assessment. Respectively, Satellite animals were

  18. Subacute oral toxicity study of ethanolic leaves extracts of Strobilanthes crispus in rats

    Institute of Scientific and Technical Information of China (English)

    Kean Tatt Lim; Vuanghao Lim; Jin Han Chin

    2012-01-01

    Objective:To examine the oral toxicity of repeated dosing of Strobilanthes crispus (S. crispus) ethanol leaves extract on the liver and kidney functions in Sprague Dawley rats. Methods:Young female rats aged between 8 and 12 week-old were randomly assigned into four groups with five animals each group (n=5). The first group served as control, while the second, third and fourth groups were orally treated with a single dose daily with 150 mg/kg, 300 mg/kg, and 600 mg/kg of S. crispus ethanol leaves extract for 14 d consecutively. Cage-side observation was conducted for first 4 h after each dosing. The body weight changes, food consumptions and water intake were also recorded. Serum biochemical parameters, i.e., aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine and urea were determined at Day 15. All results were expressed as mean±SD and analysed using Dunnett's test. Results: It was obtained that 14-day oral administration of S. crispus ethanol leaves extract did not cause any adverse effects or lethality to the female Sprague Dawley rats. No significant changes in serum biochemical parameters, relative organs weights, body weights, food intake and water consumptions were observed between the treatment groups and control. Conclusions:In conclusion, 14-day oral administration of S. crispus ethanol leaves extract was safe to be consumed in female rats without affecting the liver and kidney functions.

  19. Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles.

    Science.gov (United States)

    Warheit, D B; Brown, S C; Donner, E M

    2015-10-01

    Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of

  20. Oral toxicity of bacterial toxins against thrips species

    NARCIS (Netherlands)

    Gerritsen, L.J.M.; Visser, J.H.; Jongsma, M.A.

    2004-01-01

    The oral toxicity of excretion products of several Photorhabdus and Xenorhabdus strains was tested on two thrips species: Frankliniella occidentalis and Thrips tabaci. Out of 46 Photorhabdus isolates and 6 Xenorhabdus isolates only 6 North American P. temperata isolates were toxic to the thrips spec

  1. Oral toxicity of bacterial toxins against thrips species

    NARCIS (Netherlands)

    Gerritsen, L.J.M.; Visser, J.H.; Jongsma, M.A.

    2004-01-01

    The oral toxicity of excretion products of several Photorhabdus and Xenorhabdus strains was tested on two thrips species: Frankliniella occidentalis and Thrips tabaci. Out of 46 Photorhabdus isolates and 6 Xenorhabdus isolates only 6 North American P. temperata isolates were toxic to the thrips

  2. 40 CFR 799.9110 - TSCA acute oral toxicity.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA acute oral toxicity. 799.9110 Section 799.9110 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES... Part 792—Good Laboratory Practice Standards. (3) Test procedures—(i) Preparations. Healthy young...

  3. Subchronic oral toxicity studies with y-cyclodextrin in rats

    NARCIS (Netherlands)

    Lina, B.A.R.; Bär, A.

    1998-01-01

    The toxicity of γ-cyclodextrin (γ-CD), a cyclic polymer of eight α-1,4-linked glucopyranosyl units with potential applications as a food ingredient, was examined in a 2-week pilot study followed by a 13-week oral toxicity study in Wistar rats. In the 2-week study, the test substance was administered

  4. Comparative toxicity and biodistribution assessments in rats following subchronic oral exposure to copper nanoparticles and microparticles.

    Science.gov (United States)

    Lee, In-Chul; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Shin, In-Sik; Moon, Changjong; Kim, Je-Hein; Kim, Hyoung-Chin; Kim, Jong-Choon

    2016-10-28

    Copper nanoparticles (Cu NPs) have great potential in electronics and biomedical fields because of their efficient thermodynamic and anti-microbial properties. However, their potential toxic effects and kinetic data following repeated exposure are still unclear. We evaluated the physicochemical properties of Cu NPs (25 nm) and copper microparticles (Cu MPs, 14-25 μm). Comparative in vivo toxicity of Cu NPs and Cu MPs was evaluated by conducting a 28-day repeated oral dose study at equivalent dose levels of 0, 100, 200, and 400 mg/kg/day (vehicle, 1 % hydroxypropyl methylcellulose). We determined Cu levels in the blood, tissues, urine, and feces by using inductively coupled plasma mass spectrometry. The solubility of Cu NPs and Cu MPs was 84.5 and 17.2 %, respectively, in an acidic milieu; however, they scarcely dissolved in vehicle or intestinal milieus. The specific surface area of Cu NPs and Cu MPs was determined to be 14.7 and 0.16 m(2)/g, respectively. Cu NPs exhibited a dose-dependent increase of Cu content in the blood and tested organs, with particularly high levels of Cu in the liver, kidney, and spleen. Only for liver and kidney increased Cu levels were found in Cu MPs-treated rats. Cu NPs caused a dose-related increase in Cu levels in urine, whereas Cu MPs did not affect the urine Cu levels. Extremely high levels of Cu were detected in the feces of Cu MPs-treated rats, whereas much lower levels were detected in the feces of Cu NPs-treated rats. A comparative in vivo toxicity study showed that Cu NPs caused damages to red blood cells, thymus, spleen, liver, and kidney at ≥200 mg/kg/days, but Cu MPs did not cause any adverse effects even at the highest dose. Overall, the in vivo repeated dose toxicity study of Cu NPs and Cu MPs demonstrated that large surface area and high solubility in physiological milieus could directly influence the toxicological responses and biodistribution of Cu particles when administered orally. Under these experimental

  5. 40 CFR 798.2650 - Oral toxicity.

    Science.gov (United States)

    2010-07-01

    ... an adequate toxicological evaluation include: Analyses of lipids, hormones, acid/base balance....2650 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT... considered appropriate to all studies: Electrolyte balance, carbohydrate metabolism, and liver and kidney...

  6. Pharmacology of ayahuasca administered in two repeated doses.

    Science.gov (United States)

    Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi

    2012-02-01

    Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

  7. Acute and 28-day repeated oral toxicological evaluation of Kuruthi Azhal Chooranam – a Siddha preparation on rodents

    OpenAIRE

    Marimuthu Kannadasana; Ganesan Sumathy; Palanivel Thirusangu Sangeetha; Chidambaram Saravanababu; Kathirvelu Baskar

    2016-01-01

    Objective: To determine the effect of phytochemicals in acute and repeated dose of 28-day oral toxicity of Kuruthi Azhal Chooranam (KAC) in Sprague Dawley rats of both sexes. Methods: Acute oral toxicity was conducted with 2000 mg/kg body weight of KAC orally and the treated animals were observed for signs of toxicity at 30 min, 1, 2, 4 and 24 h and for up to 14 days. In repeated 28-day oral toxicity study, the KAC formulation was administered orally with 600, 900 and 1200 mg/k...

  8. Experimental oral lead toxicity in young dogs

    Energy Technology Data Exchange (ETDEWEB)

    Stowe, H.D.; Goyer, R.A.; Krigman, M.M.; Wilson, M.; Cates, M.

    1973-02-01

    Litter-mate male pups were fed a calcium-and-phosphorus-low purified diet with and without 100 ppm of lead as lead acetate from age 6 to 18 weeks. Lead-toxic dogs exhibited cyclic but terminally severe anorexia and cachexia, significant anemia, normoblastocytosis and leukopenia within six weeks, hypoproteinemia, decreased serum albumin, ..cap alpha../sub 1/-globulin, ..beta../sub 2/-globulin, alkaline phosphatase and lactic dehydrogenase 1, elevated serum glutamic oxaloacetic and pyruvic transaminases, delayed closure of the thoracic vertebral epiphyses, lead lines in the distal radii and thoracic spinous processes, enlargement of liver, kidney, and brain, hepatic fatty metamorphosis, focal proximal renal tubular necrosis, hydropic degeneration of spermatognia, and lead inclusion body formation. Approximately 97% of the tissue lead was estimated to be skeletal; the greatest concentration of lead in the brain was found in the occipital gray matter.

  9. Subacute (90 Days) Oral Toxicity Studies of Kombucha Tea

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Kombucha tea (KT) is a popular health beverage and is used as an alternative therapy. KT is prepared by placing the kombucha culture in solution of tea and sugar and allowing to ferment. The inoculum is a fungus consisting of symbiotic colony of yeast and bacteria. KT is consumed in several countries and is believed to have prophylactic and therapeutic benefits in a wide variety of ailments, viz., intestinal disorders, arthritis, ageing and stimulation of immunological system. Though KT is used in several parts of the world its beneficial effects and adverse effects have not been scientifically evaluated. Since there are no animal toxicological data on KT, subacute oral toxicity study was carried out. Five groups of rats were maintained: (a) control group given tap water orally, (b) KT given 2 ml/kg orally, (c) plain tea (PT) given 2 ml/kg orally, (d) KT given in drinking water, 1% (v/v) and (e) PT given in drinking water, 1% (v/v). The rats were given this treatment daily for a period of 90 days. Weekly records of weight, feed intake, water intake and general behaviour were monitored. There was no significant difference in the growth of the animals as evidenced by the progressive body weight change. The organ to body weight ratio and histological evaluation did not show any toxic signs. The haematological and biochemical variables were within the clinical limits. The study indicates that rats fed KT for 90 days showed no toxic effects.

  10. Antioxidant Capacity, Cytotoxicity, and Acute Oral Toxicity of Gynura bicolor

    Directory of Open Access Journals (Sweden)

    Wuen Yew Teoh

    2013-01-01

    Full Text Available Gynura bicolor (Compositae which is widely used by the locals as natural remedies in folk medicine has limited scientific studies to ensure its efficacy and nontoxicity. The current study reports the total phenolic content, antioxidant capacity, cytotoxicity, and acute oral toxicity of crude methanol and its fractionated extracts (hexane, ethyl acetate, and water of G. bicolor leaves. Five human colon cancer cell lines (HT-29, HCT-15, SW480, Caco-2, and HCT 116, one human breast adenocarcinoma cell line (MCF7, and one human normal colon cell line (CCD-18Co were used to evaluate the cytotoxicity of G. bicolor. The present findings had clearly demonstrated that ethyl acetate extract of G. bicolor with the highest total phenolic content among the extracts showed the strongest antioxidant activity (DPPH radical scavenging assay and metal chelating assay, possessed cytotoxicity, and induced apoptotic and necrotic cell death, especially towards the HCT 116 and HCT-15 colon cancer cells. The acute oral toxicity study indicated that methanol extract of G. bicolor has negligible level of toxicity when administered orally and has been regarded as safe in experimental rats. The findings of the current study clearly established the chemoprevention potential of G. bicolor and thus provide scientific validation on the therapeutic claims of G. bicolor.

  11. Acute Oral Toxicity and Kinetic Behaviors of Inorganic Layered Nanoparticles

    Directory of Open Access Journals (Sweden)

    Jin Yu

    2013-01-01

    Full Text Available Layered double hydroxide (LDH nanoparticles, also known as anionic clays, have attracted a great deal of interest for their potential as delivery carriers. Recent studies showed that LDH nanoparticles can efficiently deliver drugs or bioactive molecules into cells, which are highly related to their endocytic pathway. However, the efficient cell permeation capacity of LDH may also raise concern about their toxicity potential. In this study, the acute oral toxicity of LDH nanoparticles was assessed, and their kinetic behaviors, such as plasma concentration-time curve, tissue distribution, and excretion, were also evaluated in mice. No significant effects of oral LDH nanoparticles on behaviors, body weight gain, survival rate, and organosomatic index were observed up to the dose of 2000 mg/kg for 14 days. Serum biochemical parameters did not significantly increase, indicating that LDH nanoparticles did not cause acute liver or kidney injury. Plasma concentration of LDH nanoparticles rapidly decreased within 30 min depending on exposure doses, but they did not accumulate in any specific organ. Their excretion via urine and feces was observed within 24 h. These findings suggest that LDH nanoparticles do not exhibit acute oral toxicity and favorable kinetic behaviors in mice and, therefore, will be promising candidates for biological and pharmaceutical applications.

  12. Evaluation of the sub-acute oral toxic effect of methanol extract of Clinacanthus nutans leaves in rats

    Institute of Scientific and Technical Information of China (English)

    Xiu Wen P’ng; Gabriel Akyrem Akowuah; Jin Han Chin

    2013-01-01

    Objective: To examine the possible sub-acute toxic effect after 14 d oral administration with 0.3 g/kg, 0.6 g/kg and 0.9 g/kg of methanol leaves extract of Clinacanthus nutans (C. nutans) on liver and kidney functions in young male Sprague Dawley (SD) rats. Methods: This study was carried out according to OECD 407 guideline. A total of 24 young healthy male SD rats aged between 8-12 weeks old were used throughout the experiments. Each group consisted of six rats (n=6). All animals were observed twice daily until day-14. Body weight, food consumption and water intake were measured on day-3, 7 and day-14. Blood samples were collected and used to analyse the serum levels of AST, ALT, ALP, bilirubins, urea and creatinine in rats. Relative organ weights for liver, kidney, heart, spleen and lung were calculated. Results: From the results obtained, all the serum biochemical parameters, food and water intake, relative organs weight showed no significant changes when compared to the control group. No lethality and abnormal behavioural changes were seen in both control and treatment groups during experiment.Conclusions: For conclusion, repeatedly dosing of C. nutans extract at 0.3g/kg, 0.6g/kg and 0.9 g/kg up to 14 d was proven safe in male SD rats without causing any adverse effects and organ damages in male SD rats.

  13. Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma.

    Science.gov (United States)

    Vail, D M; Husbands, B D; Kamerling, S G; Simpson, H; Kurzman, I D; McDonnell, A

    2012-01-01

    Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. Client-owned dogs with measurable lymphoma. Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials. Copyright © 2012 by the American College of Veterinary Internal Medicine.

  14. Acute oral and percutaneous toxicity of pesticides to mallards: Correlations with mammalian toxicity data

    Science.gov (United States)

    Hudson, R.H.; Haegele, M.A.; Tucker, R.K.

    1979-01-01

    Acute oral (po) and 24-hr percutaneous (perc) LD50 values for 21 common pesticides (19 anticholinesterases, of which 18 were organophosphates, and one was a carbamate; one was an organochlorine central nervous system stimulant; and one was an organonitrogen pneumotoxicant) were determined in mallards (Anas platyrhynchos). Three of the pesticides tested were more toxic percutaneously than orally. An index to the percutaneous hazard of a pesticide, the dermal toxicity index (DTI = po LD50/perc LD50 ? 100), was also calculated for each pesticide. These toxicity values in mallards were compared with toxicity data for rats from the literature. Significant positive correlations were found between log po and log percutaneous LD50 values in mallards (r = 0.65, p 0.10). Variations in percutaneous methodologies are discussed with reference to interspecies variation in toxicity values. It is recommended that a mammalian DTI value approaching 30 be used as a guideline for the initiation of percutaneous toxicity studies in birds, when the po LD50 and/or projected percutaneous LD50 are less than expected field exposure levels.

  15. A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

    Science.gov (United States)

    Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

    2014-01-01

    A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

  16. Subacute(90Days) Oral Toxicity Studies of Kombucha Tea

    Institute of Scientific and Technical Information of China (English)

    R.VIJAYARAGHAVAN; MANINDERSINGH; 等

    2000-01-01

    Kombucha tes(KT) is a popular health beverage and is used as an alternative therapy,KT is prepared by placing the kombucha culture in solution of tea and sugar and allowing to ferment,The inoculum is a fungus consisting of symbiotic colony of yeast and bacteria.KT is consumed in several coutries and is believed to have prophylactic and therapeutic benefits in a wide variety of ailments,viz.,intestinal disorders,arthritis,ageing and stiumulation of immunological system.Though KT is used in several parts of the world its eneficial effects and adverse effects have not been scientifically evaluated.Since there are no animal toxicological data on KT,subacute oral toxicity study was carried out.Five goups of rats were maintained:(a) control group given tap water orally,(b) KT given 2ml/kg orally,(c)plain tea(PT) given 2ml/kg orally,(d)KT given in drinking water,1%(v/v)and (e)PT given indrinking water,1%(v/v).The rats were given this treatment daily for a period of 90 days,Weekly records of weight,feed intake,water intake and general behaviour were monitored.There was no significant difference in the growth of the animals as evidenced by the progrssive body weight change.The organ to body weight ration and histologuical evaluation did not show any toxic signs.The haematological and biochemical variables,were within the clinical limits.The study indicates that rats fed KT for 90 day showed no toxic effects.

  17. Acute oral toxicities of wildland fire control chemicals to birds

    Science.gov (United States)

    Vyas, N.B.; Spann, J.W.; Hill, E.F.

    2009-01-01

    Wildland fire control chemicals are released into the environment by aerial and ground applications to manage rangeland, grassland, and forest fires. Acute oral 24 h median lethal dosages (LD50) for three fire retardants (Fire-Trol GTS-R?, Phos-Chek D-75F?, and Fire-Trol LCG-R?) and two Class A fire suppressant foams (Silv-Ex? and Phos-Chek WD881?) were estimated for northern bobwhites, Colinus virginianus, American kestrels, Falco sparverius, and red-winged blackbirds, Agelaius phoeniceus. The LD50s of all chemicals for the bobwhites and red-winged blackbirds and for kestrels dosed with Phos-Chek WD881? and Silv-Ex? were above the predetermined 2000 mg chemical/kg body mass regulatory limit criteria for acute oral toxicity. The LD50s were not quantifiable for kestrels dosed with Fire-Trol GTS-R?, Phos-Chek D-75F?, and Fire-Trol LCG-R? because of the number of birds which regurgitated the dosage. These chemicals appear to be of comparatively low order of acute oral toxicity to the avian species tested.

  18. Acute and subacute oral toxicity of periodate salts in rats.

    Science.gov (United States)

    Lent, Emily May; Crouse, Lee C B; Eck, William S

    2017-02-01

    Periodate salts are being developed as potential replacements for perchlorate due to potential health hazards associated with exposure to perchlorate. The aim of this study was to investigate acute and subacute effects of periodate salts in rats. Acute oral toxicity of potassium and sodium periodate was determined using the Sequential Stage-Wise Probit method. The LD50 for potassium periodate was 732 (95% CI = 539-838, slope = 13.4) and 685 mg/kg (95% CI = 580-809, slope = 10.6) for females and males, respectively. The LD50 for sodium periodate was 318 (95% CI = 292-347, slope = 24.3) and 741 mg/kg (95% CI = 704-779, slope = 31.2) for females and males, respectively. In the subacute study, rats were administered sodium periodate at five doses (1/16 LD50 up to LD50) or distilled water for 14-days via oral gavage. Female rats in the 318 mg/kg-day group and male rats in the 185, 370, and 741 mg/kg-day groups exhibited moribundity, kidney toxicity, uremia, and a stress response. BMDL10s of 17.2 and 33.7 mg/kg-day were derived for females and males, respectively. Comparison with the NOAEL for perchlorate-induced thyroid toxicity in rats (0.009 mg/kg-day) suggests sodium periodate is less toxic than perchlorate on a subacute basis. Copyright © 2016. Published by Elsevier Inc.

  19. Toxicity of colloidal silica nanoparticles administered orally for 90 days in rats

    Directory of Open Access Journals (Sweden)

    Kim YR

    2014-12-01

    Full Text Available Yu-Ri Kim,1,* Seung-Young Lee,3,* Eun Jeong Lee,1 Sung Ha Park,4 Nak-won Seong,3 Heung-Sik Seo,3 Sung-Sup Shin,3 Seon-Ju Kim,3 Eun-Ho Meang,3 Myeong-Kyu Park,3 Min-Seok Kim,3 Cheol-Su Kim,5 Soo-Ki Kim,5 Sang Wook Son,2 Young Rok Seo,6 Boo Hyon Kang,7 Beom Seok Han,8 Seong Soo A An,9 Beom-Jun Lee,10 Meyoung-Kon Kim1 1Department of Biochemistry and Molecular Biology, 2Department of Dermatology, Korea University Medical School and College, 3General Toxicology Team, Korea Testing and Research Institute, Seoul, Republic of Korea; 4Department of Biochemistry, University of Bath, Bath, UK; 5Department of Microbiology, Wonju College of Medicine, Yonsei University, Gangwon, 6Department of Life Science, Institute of Environmental Medicine for Green Chemistry, Dongguk University, Seoul, 7Nonclinical Research Institute, Chemon Inc, Gyeonggi, 8Toxicological Research Center, Hoseo University, Chungnam, 9Department of Bionanotechnology, Gachon University, Gyeonggi, 10College of Veterinary Medicine, Chungbuk National University, Chungbuk, Republic of Korea *These authors contributed equally to this work Abstract: This study was undertaken to investigate the potential toxicity and establish the no observed adverse effect level (NOAEL and target organ(s of negatively charged colloidal silica particles of different sizes, ie, SiO2EN,20(- (20 nm or SiO2EN,100(- (100 nm, administered by gavage in Sprague-Dawley rats. After verification of the physicochemical properties of the SiO2 particles to be tested, a preliminary dose range-finding study and 90-day repeated dose study were conducted according to the Organisation for Economic Cooperation and Development test guideline. Based on the results of the 14-day dose range-finding study, a high dose was determined to be 2,000 mg/kg, and middle and low doses were set at 1,000 and 500 mg/kg, respectively. In the 90-day toxicity study, there were no animal deaths in relation to administration of SiO2 particles of

  20. ACUTE ORAL TOXICITY STUDY OF CLINACANTHUS NUTANS IN MICE

    Directory of Open Access Journals (Sweden)

    Xiu Wen P'ng, Gabriel Akyirem Akowuah and Jin Han Chin*

    2012-11-01

    Full Text Available Clinacanthus nutans Lindau (Family: Acanthaceae has attracted public interest recently due to its high medicinal values for the treatment of cancer, inflammation and various skin problems. This study was aimed to determine the oral LD50 value of the methanol leaves extract of C. nutans and identify the targeted organs in mice. This acute oral toxicity study was conducted in accordance to OECD 423 guidelines by using male Swiss albino mice weighing 25-35 g. First group was served as control group which received distilled water (vehicle while second and third group were orally treated with single daily dose of 0.9 g/kg and 1.8 g/kg of methanol leaves extract of C. nutans, respectively. All the animals were closely observed for 14 days. Body weight for each mouse was recorded at day-0, day-3, day-7 and day-14. Relative organ weights for liver, kidney, spleen, lung and heart were also determined. All the results were presented as mean ± standard deviation and analyzed using Dunnett’s Test after ANOVA test. From the results obtained, no mortality was observed in both treatment groups either post 24 hours or 14 days of oral administration of C. nutans. Body weight for each mouse and relative organ weight showed insignificant difference when compared to the control group. In conclusion, acute exposure of 1.8 g/kg of C. nutans was safe in male mice without causing any adverse effects or mortality. The oral LD50 of methanol leaves extract of C. nutans was suggested to be greater than 1.8 g/kg bw in male mice.

  1. Oral Toxicity of 2,4-Dinitroanisole in Rats.

    Science.gov (United States)

    Lent, Emily May; Crouse, Lee C B; Wallace, Shannon M

    2016-11-01

    Subacute and subchronic studies were conducted to assess the toxicity of 2,4-dinitroanisole (DNAN) and to provide information important for protecting the health of military and civilian personnel. In the subchronic study, male and female Sprague-Dawley rats were dosed with DNAN via oral gavage at 0, 1.25, 5, 20, and 80 mg/kg/d. Likely owing to its conversion to 2,4-dinitrophenol, an inhibitor of energy homeostasis, DNAN caused an apparent increase in metabolism, leading to reduced feed efficiency ratios and body mass gains in males. Anemia, splenic enlargement, hemosiderosis, and extramedullary hematopoiesis indicated blood as a target organ, with females more sensitive than males. The DNAN was a testicular toxicant, causing decreased mass of testes and epididymides, as well as degeneration and atrophy of testicular seminiferous tubules and epididymal aspermia. Stereotypical behavior in males, gait irregularities, and cerebellar lesions indicated that DNAN is neurotoxic. Splenic enlargement, anemia, testicular toxicity, and neurotoxicity occurred only at or near lethal doses in the subchronic study. © The Author(s) 2016.

  2. In vitro examination of oral tissue conditioners potential toxicity

    Directory of Open Access Journals (Sweden)

    Krunić Nebojša

    2011-01-01

    Full Text Available The oral tissue conditioners are applied temporarily to the gingival surface of a denture for the purpose of reconditioning the abused denture supporting tissues, allowing them to return to a normal, healthy state. According to chemical composition they can be classified into methacrylic and silicon conditioners. The objective of this research was to examine the potential toxicity of one, seven and thirty day extracts of different concentrations. Different effective concentrations (5, 12.5, 25 and 50% of two silicone and four methacrylic conditioners extracts were used after extraction period of one, seven and thirty days. Amount of toxic substances and dynamics of their release were monitored by high-pressure liquid chromatography (HPLC. HPLC analysis could not be applied to the silicone conditioners because they consist of polymeric and inorganic 19 substances. Evaluation of cell proliferation, as cytotoxic parameters, was done by Mosmann’s MTT assay based on reduction of yellow tetrazole (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide - MTT to purple formazan by mitochondrial succinate dehydrogenase of metabolic active cells. With increasing of extraction period, the amount of released potential toxic substances increased. The cytotoxicity of tested materials significantly increased with extract concentration increase and duration of extraction period. To improve the biological characteristics of mobile dentures relined by soft materials, soaking in water the day before insertion into patient’s mouth was recommended. Silicone conditioners showed less cytotoxicity compared to the methacrylic conditioners, so they are more appropriate for daily dental practice.

  3. Repeated dose toxicity and relative potency of 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for induction of CYP1A1, CYP1A2 and thymic atrophy in female Harlan Sprague-Dawley rats.

    Science.gov (United States)

    Hooth, Michelle J; Nyska, Abraham; Fomby, Laurene M; Vasconcelos, Daphne Y; Vallant, Molly; DeVito, Michael J; Walker, Nigel J

    2012-11-15

    In this study we assessed the relative toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague-Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50,000 and 500,000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015-0.0072, for PCN 66 and 0.00029-0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO toxic equivalency factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity.

  4. The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data - A case study with caffeine.

    Science.gov (United States)

    Bessems, Jos G M; Paini, Alicia; Gajewska, Monika; Worth, Andrew

    2017-03-10

    Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (Cmax), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  5. Strain differences in toxicity of oral cadmium intake in rats.

    Science.gov (United States)

    Ninkov, Marina; Popov Aleksandrov, Aleksandra; Mirkov, Ivana; Demenesku, Jelena; Mileusnic, Dina; Jovanovic Stojanov, Sofija; Golic, Natasa; Tolinacki, Maja; Zolotarevski, Lidija; Kataranovski, Dragan; Brceski, Ilija; Kataranovski, Milena

    2016-10-01

    Influence of genetic background on toxicity of oral cadmium (Cd) administration (30 days, in drinking water; 5 ppm and 50 ppm of cadmium) was examined in Albino Oxford (AO) and Dark Agouti (DA) rats. Similar cadmium deposition was noted in gut and draining mesenteric lymph nodes (MLN) of both strains but intensity and/or the pattern of responses to cadmium in these tissues differ. Less intense intestinal damage and leukocyte infiltration was observed in gut of cadmium-exposed AO rats. While gut-associated lymph node cells of DA rats responded to cadmium with an increase of cell proliferation, oxidative activity, IFN-γ, IL-17 production and expression, no changes of these activities of MLN cells of cadmium-treated AO rats were observed. Spleen, which accumulated cadmium comparable to MLN, responded to metal by drop in cell viability and by reduced responsiveness of proliferation and cytokine production to stimulation in DA rats solely, which suggest tissue dependence of cadmium effects. More pronounced cadmium effects on MLN and spleen cells of DA rats (which accumulated similar cadmium doses as AO rats), showed greater susceptibility of this strain to cadmium. The results presented, for the first time, depict the influence of genetic background to effects of oral cadmium administration. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Toxicity and biodistribution of orally administered casein nanoparticles.

    Science.gov (United States)

    Gil, Ana Gloria; Irache, Juan Manuel; Peñuelas, Iván; González Navarro, Carlos Javier; López de Cerain, Adela

    2017-08-01

    In the last years, casein nanoparticles have been proposed as carriers for the oral delivery of biologically active compounds. However, till now, no information about their possible specific hazards in vivo was available. The aim of this work was to assess the safety of casein nanoparticles when administered orally to animals through a 90 days dose-repeated toxicity study (OECD guideline 408), that was performed in Wistar rats under GLP conditions. After 90 days, no evidences of significant alterations in animals treated daily with 50, 150 or 500 mg/kg bw of nanoparticles were found. This safety agrees well with the fact that nanoparticles were not absorbed and remained within the gut as observed by radiolabelling in the biodistribution study. After 28 days, there was a generalized hyperchloremia in males and females treated with the highest dose of 500 mg/kg bw, that was coupled with hypernatremia in the females. These effects were related to the presence of mannitol which was used as excipient in the formulation of casein nanoparticles. According to these results, the No Observed Adverse Effect Level (NOAEL) could be established in 150 mg/kg bw/day and the Lowest Observed Effect Level (LOEL) could be established in 500 mg/kg bw/day. Copyright © 2017. Published by Elsevier Ltd.

  7. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

    NARCIS (Netherlands)

    aan het Rot, Marije; Collins, Katherine A.; Murrough, James W.; Perez, Andrew M.; Reich, David L.; Charney, Dennis S.; Mathew, Sanjay J.

    2010-01-01

    Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days)

  8. Neutral red uptake cytotoxicity tests for estimating starting doses for acute oral toxicity tests.

    Science.gov (United States)

    Stokes, William S; Casati, Silvia; Strickland, Judy; Paris, Michael

    2008-05-01

    In vitro cytotoxicity assays can be used as alternative toxicity tests to reduce the total number of animals needed for acute oral toxicity tests. This unit describes two methods for determining the in vitro cytotoxicity of test substances using neutral red uptake (NRU) and using the in vitro data to determine starting doses for in vivo acute oral systemic toxicity tests, e.g., the up-and-down procedure or the acute toxic class method. The use of the NRU methods to determine starting doses for acute oral toxicity tests may reduce the number of animals required, and for relatively toxic substances, this approach may also reduce the number of animals that die or require humane euthanasia due to severe toxicity. An interlaboratory validation study has demonstrated that the methods are useful and reproducible for these purposes. Two standardized protocols provide details for performing NRU tests with rodent and human cells.

  9. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies.

    Science.gov (United States)

    McFadden, Lisa G; Bartels, Michael J; Rick, David L; Price, Paul S; Fontaine, Donald D; Saghir, Shakil A

    2012-07-01

    Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (αmodel was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the α level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets.

  10. Pharmacokinetics of metadoxine for injection after repeated doses in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    L(U) Yuan; KANG Zi-sheng; LIU Yan; LI Tian-yun; XIAO Yong-hong

    2007-01-01

    @@ Alcohol-induced liver disease is one of the main epidemic problems nowadays. Metadoxine is a pyridoxine-pyrrolidone carboxylate with significant scavenging property. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, help restore the functional structure of the liver and relieve neuro-psychological disorders associated with alcohol intoxication.1-3 The purpose of the study was to assay the pharmacokinetics of domestic metadoxine after repeated doses.

  11. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2017-05-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm(2), interquartile range: 693-963 cm(2); placebo: 822 cm(2), interquartile range: 710-1020 cm(2); geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  12. Can TiC nanoparticles produce toxicity in oral administration to rats?

    Directory of Open Access Journals (Sweden)

    Julie Laloy

    2014-01-01

    Conclusion: No sign of toxicity was found after oral administration. TiC was excreted mostly in feces producing mineral absorption alterations. Low traces were retrieved in urine, indicating that TiC can cross the intestinal barrier.

  13. Modelling acute oral mammalian toxicity. 1. Definition of a quantifiable baseline effect.

    Science.gov (United States)

    Koleva, Yana K; Cronin, Mark T D; Madden, Judith C; Schwöbel, Johannes A H

    2011-10-01

    Quantitative structure-activity relationships (QSARs) provide a useful tool to define a relationship between chemical structure and toxicity and allow for the prediction of the toxicity of untested chemicals. QSAR models based upon an anaesthetic or narcosis mechanism represent a baseline, or minimum, toxicity, i.e. unless a chemical acts by another, more specific, mechanism, its toxicity will be predicted by such models. The aim of this investigation was to develop baseline models for the acute toxicity of chemicals to mammals (rat and mouse) following the oral route of administration. The availability of such baseline toxicity models for mammalian species can provide a probe for testing new chemicals with respect to their molecular mechanism of toxicity. Multiple-regression type structure-toxicity relationships were derived . (i.e., from oral log LD(50)(-1) data for mammalian species (rat and mouse) and the 1-octanol/water partition coefficient (log P) of classic non-polar narcotics). Subsequently, these models were used to distinguish between reactive chemicals of different mechanistic domains and baseline toxic chemicals. Comparison of measured toxicity data for oral rat and mouse LD(50) with predictions from baseline QSAR provides a means of identifying mechanistic categories and for categorising more specific acute mechanisms. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Relationship between lethal toxicity in oral administration and injection to mice: effect of exposure routes.

    Science.gov (United States)

    Wang, Yu; Ning, Zhong H; Tai, Hong W; Long, Shuang; Qin, Wei C; Su, Li M; Zhao, Yuan H

    2015-03-01

    The lethal toxicity (LD₅₀) in oral administration, intravenous, intraperitoneal, intramuscular and subcutaneous injections were used to investigate relationships of log 1/LD₅₀ from different exposure routes. Regression analysis showed that log 1/LD₅₀ in oral route was related to the toxicity in injection route. This relationship in lethality between the two routes is apparently due to the same mechanisms of the compounds to the same species. However, the scatter in the correlation curve indicates that exposure route is an important factor that influences the relationship. Some compounds with low intestinal absorption exhibit much less toxicity in oral administration than that in the injection route. A systemic bias of log 1/LD₅₀ between oral and injection routes indicates that tissue distribution of compounds between blood and target site is a very rapid process, leading to log 1/LD₅₀ in injection greater than those in oral administration. Although compounds can be metabolized in the body both from oral and injection routes, first-pass metabolism occurs in oral route but not in injection route. This will result in decrease of toxicity in oral route for most compounds as compared with injection route. In addition, experimental uncertainty, differences in gender, and species can also affect relationships of log1/LD₅₀ between exposure routes.

  15. Oral and Topical Toxicity of Fipronil to Melon Fly and Oriental Fruit Fly (Diptera: Tephritidae)

    Science.gov (United States)

    BACKGROUND: The objective of this study was to develop basic oral and topical toxicity data for Fipronil in Solulys protein bait to wild melon fly, Bactrocera cucurbitae (Coquillett) and the oriental fruit fly, Bactrocera dorsalis (Hendel). RESULTS: For the oral study, both females and males were ...

  16. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-02-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

  17. Effect of repeated doses of mercuric chloride on the kinetics of iron in rats

    Energy Technology Data Exchange (ETDEWEB)

    Grosicki, A.; Kossakowski, S. [National Veterinary Research Institute, Pulawy (Poland)

    1994-12-31

    The effect of repeated doses of 0.5 and 1.0 mg HgCl{sub 2}/kg b.w. given intragastrically for 30 days on the absorption and distribution of intragastrically trace dose of {sup 59}FeCl{sub 3} was studied in male Wistar rats. Both doses of mercury distributed the absorption of Fe-59 from the gastrointestinal track. Furthermore, the results revealed a dose-dependent influence of mercury on the content of Fe-59 in the organs and the AUC values. (author). 14 refs, 2 figs, 1 tab.

  18. Repeated doses of melatonin protects against focal cerebral ischemia in the rat

    OpenAIRE

    Pei, Z; Pang, SF; Cheung, RTF

    2000-01-01

    We studied the time window of neuroprotection against focal ischemia by a single dose or repeated doses of melatonin (MT) at 5 mg/kg. Adult male Sprague-Dawley rats (280 to 360 g) were anesthetized with sodium pentobarbital (60 mg/kg, I.P.) to undergo reversible right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hours. Arterial blood pressure, heart rate and cerebral blood flow were monitored, and rectal temperature was kept between 36.5 and 37.5 ºC throughout anesthesia. ...

  19. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates.

    Science.gov (United States)

    Johnston, C C; Stremler, R; Horton, L; Friedman, A

    1999-03-01

    The purpose of this randomized clinical trial was to test the efficacy of repeated versus single dose sucrose to decrease pain from routine heel stick procedures in preterm neonates. Infants (n = 48) in the first week of life with a mean gestational age of 31 weeks received 0.05 ml of 24% sucrose solution or sterile water by mouth (1) 2 min prior to actual lancing of the heel; (2) just prior to lancing, and (3) 2 min after lancing. The single-dose group received sucrose for the first dose and water for the second and third dose; the repeated-dose group received sucrose three times, and the placebo group received only water. The Premature Infant Pain Profile (PIPP) scores were obtained for five 30-second blocks from lancing. Both sucrose groups had lower PIPP scores (single sucrose pain scores, 6.8-8.2, p = 0.07; repeated sucrose pain scores, 5.3-6. 2, p < 0.01) than water (pain scores 7.9-9.1), and in the last block, the repeated dose had lower scores than the single dose (6.2 vs. 8. 2, p < 0.05).

  20. Comparative toxicity study on classical and modified version of Jawarish Jalinoos (a traditional Unani formulation in rats

    Directory of Open Access Journals (Sweden)

    Gulam Mohammed Husain

    2017-03-01

    Conclusion: The 90-day repeated dose oral toxicity study demonstrates that the no observed adverse effect level of SFJJ and JJ is greater than 2024 mg/kg bw/d and 2000 mg/kg bw/d (p.o. in rats, respectively. Both formulations were found to be safe up to the tested dose levels and experimental conditions, and therefore safe for clinical use as specified in the literature.

  1. Acute oral toxicity of chemicals in terrestrial life stages of amphibians: Comparisons to birds and mammals.

    Science.gov (United States)

    Crane, Mark; Finnegan, Meaghean; Weltje, Lennart; Kosmala-Grzechnik, Sylwia; Gross, Melanie; Wheeler, James R

    2016-10-01

    Amphibians are currently the most threatened and rapidly declining group of vertebrates and this has raised concerns about their potential sensitivity and exposure to plant protection products and other chemicals. Current environmental risk assessment procedures rely on surrogate species (e.g. fish and birds) to cover the risk to aquatic and terrestrial life stages of amphibians, respectively. Whilst a recent meta-analysis has shown that in most cases amphibian aquatic life stages are less sensitive to chemicals than fish, little research has been conducted on the comparative sensitivity of terrestrial amphibian life stages. Therefore, in this paper we address the questions "What is the relative sensitivity of terrestrial amphibian life stages to acute chemical oral exposure when compared with mammals and birds?" and "Are there correlations between oral toxicity data for amphibians and data for mammals or birds?" Identifying a relationship between these data may help to avoid additional vertebrate testing. Acute oral amphibian toxicity data collected from the scientific literature and ecotoxicological databases were compared with toxicity data for mammals and birds. Toxicity data for terrestrial amphibian life stages are generally sparse, as noted in previous reviews. Single-dose oral toxicity data for terrestrial amphibian life stages were available for 26 chemicals and these were positively correlated with LD50 values for mammals, while no correlation was found for birds. Further, the data suggest that oral toxicity to terrestrial amphibian life stages is similar to or lower than that for mammals and birds, with a few exceptions. Thus, mammals or birds are considered adequate toxicity surrogates for use in the assessment of the oral exposure route in amphibians. However, there is a need for further data on a wider range of chemicals to explore the wider applicability of the current analyses and recommendations.

  2. Four-week oral toxicity study with erythritol in rats

    NARCIS (Netherlands)

    Til, H.P.; Modderman, J.

    1996-01-01

    Erythritol was orally administered to Wistar rats at dietary levels of 0, 5, and 10% for 4 weeks. Soft stools and diarrhea were observed in male and female animals of the 10% group and in female animals of the 5% group. These symptoms disappeared during the course of the study. Mean body weights of

  3. Four-week oral toxicity study with erythritol in rats

    NARCIS (Netherlands)

    Til, H.P.; Modderman, J.

    1996-01-01

    Erythritol was orally administered to Wistar rats at dietary levels of 0, 5, and 10% for 4 weeks. Soft stools and diarrhea were observed in male and female animals of the 10% group and in female animals of the 5% group. These symptoms disappeared during the course of the study. Mean body weights of

  4. Acute oral toxicity of Pereskia bleo and Pereskia grandifolia in mice

    OpenAIRE

    Sim, K. S.; A M Sri Nurestri; Sinniah, S. K.; Kim, K. H.; Norhanom, A. W.

    2010-01-01

    Pereskia bleo and Pereskia grandifolia, belonging to the botanical family Cactaceae, have been traditionally used by the locals in Malaysia for treatment of various ailments. The current study reports the outcome of acute oral toxicity investigation of Pereskia bleo and Pereskia grandifolia, on ICR mice. No mortalities or evidence of adverse effects have been observed in ICR mice following acute oral administration at the highest dose of 2500 mg/ kg crude extracts of Pereskia bleo and Pereski...

  5. ACUTE AND SUB-CHORONIC ORAL TOXICITY OF ASIATICOSIDE TO MICE

    Directory of Open Access Journals (Sweden)

    Uvarajan Sampath

    2012-09-01

    Full Text Available The components in Centellaasiatica (gotukala, vallarai was reported to possess different biological activities in various in vitro and in vivo test models including gastric ulcer healing, wound healing, memory enhancing, immunomodulating effects along with cytotoxic, neuroprotective, antioxidant potential. Asiaticoside is one of the major triterpenoid saponin isolated from Centellaasiatica. Currently, there is no evidence for safety details of asiaticoside in experimental mice. The purpose of this study is to explore the acute and sub-chronic oral toxicities of asiaticoside. Acute oral toxicity study was conducted by giving 300-5000 mgkg-1 bodyweight of asiaticoside and the animals were observed after 1 h administration of the drug and also examined after 14 days of administration for mortality and morbidity.The lethal dose (LD50 was found to greater than 2000 mgkg⁻¹ bodyweight. In sub-chronic oral toxicity studies, the selected oral doses were 200, 500, 1000 mgkg⁻¹and the evaluation was carried out after 90 days of oral administration of asiaticoside. Biochemical, histopathological and hematological changes along with body and relative organ weights of the mice were analysed and significant changes were observed in the mice treated with 1000 mgkg-1 of asiaticoside.. The observed results were statistically analyzed using one way ANOVA which suggested that Asiaticoside does not possess any toxic effect up to 500mg/kg bodyweight and it is best suited for any kind of future application related to its efficacy.

  6. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Science.gov (United States)

    2010-07-01

    ... performance such as gonadal function, mating behavior, conception, development of the conceptus, and... not be limited to, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and... recommended 1 . Investigations of plasma or serum must include sodium, potassium, glucose, total cholesterol...

  7. Inhalation exposure system used for acute and repeated-dose methyl isocyanate exposures of laboratory animals.

    Science.gov (United States)

    Adkins, B; O'Connor, R W; Dement, J M

    1987-06-01

    Laboratory animals were exposed by inhalation for 2 hr/day (acute) or 6 hr/day (four consecutive days, repeated dose) to methyl isocyanate (MIC). Exposures were conducted in stainless steel and glass inhalation exposure chambers placed in stainless steel, wire mesh cages. MIC was delivered with nitrogen via stainless steel and Teflon supply lines. Chamber concentrations ranged from 0 to 60 ppm and were monitored continuously with infrared spectrophotometers to 1 ppm and at 2-hr intervals to 20 ppb with a high performance liquid chromatograph equipped with a fluorescence detector. Other operational parameters monitored on a continuous basis included chamber temperature (20-27 degrees C), relative humidity (31-64%), static (transmural) pressure (-0.3 in.), and flow (300-500 L/min). The computer-assistance system interfaced with the inhalation exposure laboratory is described in detail, including the analytical instrumentation calibration system used throughout this investigation.

  8. Toxicidad aguda oral de la o-vainillina Acute oral toxicity of o-vanillin

    Directory of Open Access Journals (Sweden)

    Yamisleydi Alonso Moreno

    2008-04-01

    Full Text Available El 2-hidroxi-3-metoxibenzaldehído (o-vainillina posee una probada actividad anti sickling y una baja actividad hemolítica sobre hematíes SS y normales, por lo que puede ser eficaz en el tratamiento de la anemia drepanocítica, enfermedad genética de alta prevalencia a nivel global. En este sentido se desarrolló un estudio de toxicidad aguda oral, con el objetivo de determinar sus efectos adversos. Se administró una dosis de 2 000 mg/kg de peso corporal a un grupo de ratas (3 hembras y 3 machos y el vehículo a otro grupo utilizado como control. Los animales se mantuvieron en observación durante 14 días, se determinaron las variaciones de peso, la presencia o no de síntomas y signos clínicos, y la necropsia al finalizar el estudio. Como resultado no se observó disminución del peso corporal en ninguno de los grupos experimentales, presentaron síntomas como: piloerección, respiración acelerada, actividad disminuida, acicalamiento, aislamiento a la esquina de la caja y la muerte de un animal. El análisis macroscópico de los órganos no detectó variación alguna. La DL50 de la o-vainillina se encuentra por encima de 2 000 mg/kg de peso corporal, según el sistema global armonizado2-hydroxy-3-methoxybenzaldehyde (o-vanillin has a proven anitsickling activity and a low haemolytic activity on SS and normal red corpuscles, so it may be efficient in the treatment of drepanocytic anemia, a genetic disease of high prevalence at the world level. In this sense, an acute oral toxicity study was conducted aimed at determining its adverse effects. A dose of 2 000 mg/kg of body weight was administered to a group of rats (3 females and 3 males, where the vehicle was given to the control group. The animals were observed for 14 days. The variations of weight, the presence or not of symptoms and clinical signs, and the necropsy at the end of the study were determined. Body weight reduction was not observed in any of the experimental groups. They

  9. The Acute Oral Toxicity of Commonly Used Pesticides in Iran, to Honeybees (Apis Mellifera Meda

    Directory of Open Access Journals (Sweden)

    Rasuli Farhang

    2015-06-01

    Full Text Available The honey bee is credited with approximately 85% of the pollinating activity necessary to supply about one-third of the world’s food supply. Well over 50 major crops depend on these insects for pollination. The crops produce more abundantly when honey bees are plentiful. Worker bees are the ones primarily affected by pesticides. Poisoning symptoms can vary depending on the developmental stage of the individual bee, and the kind of chemical employed. The oral toxicity of these insecticides: (phosalone and pirimicarb, acaricide (propargite, insecticide and acaricide (fenpropathrin, fungicides, and bactericides (copper oxychloride and the Bordeaux mixture, were evaluated for the purposes of this research. The results showed that fenpropathrin had high acute oral toxicity (LC50-24h and LC50-48 were 0.54 and 0.3 ppm, respectively. Propargite had 7785 ppm (active ingredient for LC50-24h and 6736 ppm (active ingredient for LC50-48h in honeybees and is therefore, non-toxic to Apis mellifera. On the other hand, copper oxychloride had minimum acute oral toxicity to honeybees (LC50-24h and LC50-48 were 4591.5 and 5407.9 ppm, respectively and was therefore considered non-toxic. Also, the Bordeaux mixture was safe to use around honeybees. Phosalone and primicarb were considered highly and moderately toxic to honeybees, respectively.

  10. Aqueous extract of Senecio candicans DC induce liver and kidney damage in a sub-chronic oral toxicity study in Wistar rats.

    Science.gov (United States)

    Lakshmanan, Hariprasath; Raman, Jegadeesh; Pandian, Arjun; Kuppamuthu, Kumaresan; Nanjian, Raaman; Sabaratam, Vikineswary; Naidu, Murali

    2016-08-01

    Senecio candicans DC. (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris, district, Tamil Nadu. The present investigation was carried out to evaluate the sub-chronic toxicity of an aqueous extract of Senecio candicans (AESC) plant in Wistar albino rats. The study was conducted in consideration of the OECD 408 study design (Repeated Dose 90-Day Oral Toxicity Study in Rodents) and the extract was administered via gavage at doses of 250, 500 or 750 mg/kg body weight per day for 90-days. Hematological, biochemical parameters were determined on days 0, 30, 60 and 90 of administration. Animals were euthanized after 90 d treatment and its liver and kidney sections were taken for histological study. The results of sub-chronic study showed significant increase (P < 0.05) in serum uric acid, creatinine, aspartate transaminase (AST) and alanine transaminase (ALP) levels. Histological examination of liver showed mild mononuclear infiltration in the portal trait, enlarged nucleus around the central vein and mild loss of hepatocyte architecture in rats treated with 750 mg/kg of AESC. Histological examination of kidney showed focal interstitial fibrosis, crowding of glomeruli and mild hydropic change with hypercellular glomeruli in rats treated with 750 mg/kg of AESC. However, no remarkable histoarchitectural change in hepatocytes and glomeruli were observed in rats treated with lower concentrations (250 and 500 mg/kg b.w.) of AESC compared to control group animals. The no-observed adverse effect level (NOAEL) of AESC in the present study was 500 mg/kg b.w. Signs of toxic effects are evident from the current study. Although AESC contains low concentrations of PA, findings from this study suggest that regular consumers of herbal remedies derived from this plant may develop kidney and liver toxicity. Further studies on the isolation and characterization of PAs are necessary to determine the safe dose level of the extract for therapeutic use

  11. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    Science.gov (United States)

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  12. Subacute (28-day) toxicity of furfural in Fischer 344 rats: A comparison of the oral and inhalation route

    NARCIS (Netherlands)

    Arts, J.H.E.; Muijser, H.; Appel, M.J.; Kuper, C.F.; Bessems, J.G.M.; Woutersen, R.A.

    2004-01-01

    The subacute oral and inhalation toxicity of furfural vapour was studied in Fischer 344 rats to investigate whether route-to-route extrapolation could be employed to derive the limit value for inhalation exposure from oral toxicity data. Groups of 5 rats per sex were treated by gavage daily for 28 d

  13. Acute Oral Toxicity Potential of 4-Nitrophenyl Methkyl Phenyl Phosphinate.

    Science.gov (United States)

    1982-09-01

    methyl phenyl phosphinate Chemical Abstract Service Registry No.: None Molecular structure: C Ii NO P 13 12 4 .0 0~ NO., CH3 o o...C 56.33 56.17 H 4.36 4.28 N 5.05 5.14 P 11.17 11.25 2. Chemical Name: Polysorbate 80 (Tween 80) Chemical Abstract Service Registry No.: 9005-65-6...administration particularly in chronic toxicity studies in experimental data. 3. Chemical Name: Citric Acid, monohydrate Chemical Abstract Service

  14. Subacute oral toxicity investigation of nanoparticulate and ionic silver in rats

    DEFF Research Database (Denmark)

    Hadrup, Niels; Löschner, Katrin; Bergström, Anders

    2012-01-01

    Subacute toxicity of 14 nm nanoparticulate silver (Ag-NP) stabilised with polyvinylpyrrolidone and ionic silver in the form of silver acetate (Ag-acetate) was investigated in four-week-old Wistar rats. Animals received orally by gavage the following: vehicle control (10 $, 6 #); Ag-NP at doses: 2...

  15. Six Month Oral Toxicity Study of WR238605 Succinate in Rats. Volume 1

    Science.gov (United States)

    1996-02-02

    collection and fixation of the following tissues/organs in 10% neutral buffered formalin (NBF). The subcutaneously implanted microchip was also...10 10 10 10 10 10 10 10 10 ivf r.\\< •-Significant Difference from Control P < .05 Page 58 Table 8.2 SIX MONTH ORAL TOXICITY STUDY OF WR23

  16. Subchronic (13-week) oral toxicity study of α-cyclodextrin in dogs

    NARCIS (Netherlands)

    Lina, B.A.R.; Bär, A.

    2004-01-01

    The oral toxicity of α-cyclodextrin (α-CD) was examined in a 13-week feeding study in which groups of Beagle dogs received α-CD in the diet at concentrations of 0 (control), 5, 10, or 20% (4dogs/sex/group). No treatment-related changes were noted in behavior or appearance of the dogs and no mortalit

  17. Subchronic (13-week) oral toxicity study of y-cyclodextrin in dogs

    NARCIS (Netherlands)

    Til, H.P.; Bär, A.

    1998-01-01

    The oral toxicity of γ-cyclodextrin (γ- CD) was examined in a 13-week feeding study in which four groups of four male and four female Beagle dogs received γ-CD in the diet at concentrations of 0 (control), 5, 10, or 20%. No treatment-related changes were noted in behavior or appearance of the dogs a

  18. Chronic oral DDT toxicity in juvenile coho and chinook salmon

    Science.gov (United States)

    Buhler, Donald R.; Rasmusson, Mary E.; Shanks, W.E.

    1969-01-01

    Technical and p,p′-DDT was incorporated into test diets and fed to juvenile chinook and coho salmon for periods as long as 95 days. Pure p,p′-DDT was slightly more toxic to young salmon than was the technical DDT mixture. Chinook salmon appeared to be 2–3 times more sensitive to a given concentration of DDT in the diet than were coho salmon. The size of the fish greatly influenced toxicity, smaller younger fish being more susceptible to a given diet than larger older fish. The dose of DDT accumulated within the median survival time ranged from 27–73 mg/kg for chinook salmon and from 56–72 mg/kg for coho salmon. The extrapolated 90-dose LD50 (Hayes, 1967) for young chinook and coho salmon were 0.0275 and 0.064 mg/kg/day, respectively. Liver size decreased on prolonged feeding with DDT, and carcass lipid content was increased. A severe surface ulceration of the nose region appeared in coho salmon fed DDT over long periods. In addition, an interesting localized degeneration of the distal convoluted tubule was observed in the kidney of coho salmon receiving DDT.

  19. Acute and sub-acute oral toxicity profile of Acorus calamus (Sweet flag) in rodents

    Institute of Scientific and Technical Information of China (English)

    Arunachalam Muthuraman; Nirmal Singh

    2012-01-01

    Objective: To determine the acute and sub-acute oral toxicity profile of the hydroalcoholic extract of Acorus calamus (HAE-AC) in mice and rats respectively. Methods: In acute toxicity study, mice were assessed to any alteration of general behavior and mortality rate within 24 h. Further, in sub-acute toxicity study, rats were used for assessment of mortality, body weight, hematological, biochemical and histopathological changes. Results: Single oral administrations of the HAE-AC 2500-10000 mg/kg induced increase in general behavioral abnormalities in mice. The mortality rate also increased with increasing dosage (median lethal dose; LD50 = 5 070.59 mg/kg). Daily single oral doses of HAE-AC 200, 500 and 1 000 mg/kg were observed to be well tolerated behaviorally after 28 days of dosing and induced no significant changes in body and organs weights of rats. Further, a mild rise in the levels of alanine transaminase (ALT), aspartate transaminase (AST) and histopatholological changes in liver tissue was noted at 1000 mg/kg dose of HAE-AC. Conclusions: Overall, the findings of this study indicate that, HAE-AC is non-toxic and has at high dose, a mild but acceptable toxicity potential.

  20. Acute oral toxicity of Pereskia bleo and Pereskia grandifolia in mice

    Directory of Open Access Journals (Sweden)

    K S Sim

    2010-01-01

    Full Text Available Pereskia bleo and Pereskia grandifolia, belonging to the botanical family Cactaceae, have been traditionally used by the locals in Malaysia for treatment of various ailments. The current study reports the outcome of acute oral toxicity investigation of Pereskia bleo and Pereskia grandifolia, on ICR mice. No mortalities or evidence of adverse effects have been observed in ICR mice following acute oral administration at the highest dose of 2500 mg/ kg crude extracts of Pereskia bleo and Pereskia grandifolia. This is the first report on the acute oral toxicity of Pereskia bleo and Pereskia grandifolia and the findings of this study are in agreement with those of in vitro experiments and thus provide scientific validation on the use of the leaves of Pereskia bleo and Pereskia grandifolia.

  1. Critique on the use of the standardized avian acute oral toxicity test for first generation anticoagulant rodenticides

    Science.gov (United States)

    Vyas, Nimish B.; Rattner, Barnett A.

    2012-01-01

    Avian risk assessments for rodenticides are often driven by the results of standardized acute oral toxicity tests without regards to a toxicant's mode of action and time course of adverse effects. First generation anticoagulant rodenticides (FGARs) generally require multiple feedings over several days to achieve a threshold concentration in tissue and cause adverse effects. This exposure regimen is much different than that used in the standardized acute oral toxicity test methodology. Median lethal dose values derived from standardized acute oral toxicity tests underestimate the environmental hazard and risk of FGARs. Caution is warranted when FGAR toxicity, physiological effects, and pharmacokinetics derived from standardized acute oral toxicity testing are used for forensic confirmation of the cause of death in avian mortality incidents and when characterizing FGARs' risks to free-ranging birds.

  2. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

    Science.gov (United States)

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria

    2015-09-01

    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  3. Acute oral toxicity of the herbicide BUREX EKO in pheasants.

    Science.gov (United States)

    Legáth, J; Mlynarcíková, H; Svický, E; Lenhardt, L; Kacmár, P; Benová, K; Kovác, G

    1996-12-01

    The aim of this study was to determine the acute LD50, clinical symptoms and pathological changes of acute BUREX EKO intoxication in pheasants according to OECD No 205. Medium lethal dose (LD50) of BUREX EKO in pheasant is 3.84 ml/kg body weight with the upper level of reliability 4.50 ml and lower level of reliability 3.27 ml/kg body weight. As far as the calculation to the effective substance is concerned it is 1077 mg of chloridazone per kg body weight with the interval of reliability from 919 to 1263 mg/kg body weight. Calculated the effective substance of chloridazone (3.84 ml is LD50 of BUREX EKO which contains 1077 mg of chloridazone) BUREX EKO can be classified as the moderately toxic substance to pheasants. There were following clinical symptoms of the BUREX EKO intoxication in pheasants: apathy, drowsiness, incapability to move, ruffled feathers, slight diarrhoea, strenuous respiration, tonico-clonical cramps before death, decease with the head expressively bent rearwards. There was a relatively fast beginning of rigor mortis in dead pheasants. Pathologico-anatomical dissection of the pheasants obtained under conditions of acute intoxication did not reveal any changes on the organs of both experimental and control pheasants which would be immediately connected with the effect of the administered substance. Hyperaemia was recorded by histologico-pathological investigation of the liver and kidneys. No changes on the brain and intestine wall were recorded.

  4. Subchronic (13-week) oral toxicity of neohesperidin dihydrochalcone in rats.

    Science.gov (United States)

    Lina, B A; Dreef-van der Meulen, H C; Leegwater, D C

    1990-07-01

    Neohesperidin dihydrochalcone was administered to groups of 20 male and 20 female Wistar rats at dietary levels of 0, 0.2, 1.0 and 5.0% for 91 days. No treatment-related ophthalmoscopical, haematological or histopathological effects were observed. In the high-dose group, a marked caecal enlargement occurred in both sexes, accompanied by soft stools in the early stages of the study, somewhat lower plasma urea concentrations and increased plasma alkaline phosphatase activity and a decreased urinary pH. This group also showed slight growth depression accompanied by transient reduction in food intake; in males the body weights remained relatively low throughout the experimental period. Furthermore, bilirubin level was increased in females and total protein level was decreased in males of the high-dose group. The above changes were considered adaptive responses or chance effects rather than manifestations of clear toxicity. The low-and intermediate- dose groups did not show any compound-related untoward effect. It was concluded that the intermediate dose, providing an overall intake of about 750 mg neohesperidin dihydrochalcone per kg body weight per day, was the no-effect level.

  5. Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters

    2016-10-01

    Full Text Available Rhabdomyosarcoma (RMS, a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV, are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS and alveolar rhabdomyosarcoma (ARMS cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

  6. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide.

    Science.gov (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan

    2009-06-01

    Repeated cyclophosphamide (CP) chemotherapy increases the risk of developing bladder cancer, which could be due to the extremely rapid proliferation of urothelial cells observed in hyperplastic urothelium induced by CP treatment. We investigated the effect of melatonin on the development of urothelial hyperplasia induced by repeated CP treatment. Male ICR mice were injected with CP (150 mg/kg) or melatonin (10 mg/kg) with CP once a week for 3, 4 and 5 weeks. Transmission and scanning electron microscopy, immunohistochemistry and Western blot analysis were used to study the ultrastructure, apoptosis, proliferation and differentiation of urothelial cells. Repeated doses of CP caused the development of hyperplastic urothelium with up to ten cell layers and increased proliferation and apoptotic indices regarding Ki-67 and active caspase-3 immunohistochemistry, respectively. Scanning electron microscopy observations, cytokeratin and asymmetrical unit membrane immunohistochemistry and Western blot analysis showed a lower differentiation state of superficial urothelial cells. Melatonin co-treatment prevented the development of hyperplastic urothelium, statistically significantly decreased proliferation and apoptotic indices after four and five doses of CP and caused higher differentiation state of superficial urothelial cells.

  7. PRELIMINARY PHYTOCHEMICAL ANALYSIS AND ACUTE ORAL TOXICITY STUDY OF CLITORIA TERNATEA LINN. ROOTS IN ALBINO MICE

    Directory of Open Access Journals (Sweden)

    Deka Manalisha

    2011-12-01

    Full Text Available Clitoria ternatea has been using since the ancient times for its medicinal values. Almost all the parts of the plant have medicinal property. The root of the plant is reported to have anti diarrheal, Anti histamic, cholinergic activity etc. Traditionally the root has been using for the treatment of many diseases like leucorrhoea, diarrhea, urinary problems, diuretic, impotency, stomach trouble etc. The present study was designed to investigate the preliminary phytochemical analysis and acute oral toxicity of the root of the plant. The shed dried materials were grinded and used in the study. The preliminary phytochemical analysis was done by following standard protocols. For acute oral toxicity study, methanolic extract of the root was used. The extract was prepared by standard protocol. The preliminary phytochemical analysis showed the presence of proteins, carbohydrates, glycosides, resins, saponin, flavonoid, alkaloids, steroids and phenol. The acute oral toxicity study showed no mortality up to a dose of 3000 mg per kg body weight. The presence of plant chemicals revealed the medicinal values and the non toxic property of the plant indicated the value of the plant as medicine. Thus we can conclude that, the root of the plant can be used as a safe drug against many diseases.

  8. Acute oral toxicity and biodistribution study of zinc-aluminium-levodopa nanocomposite

    Science.gov (United States)

    Kura, Aminu Umar; Saifullah, Bullo; Cheah, Pike-See; Hussein, Mohd Zobir; Azmi, Norazrina; Fakurazi, Sharida

    2015-03-01

    Layered double hydroxide (LDH) is an inorganic-organic nano-layered material that harbours drug between its two-layered sheets, forming a sandwich-like structure. It is attracting a great deal of attention as an alternative drug delivery (nanodelivery) system in the field of pharmacology due to their relative low toxic potential. The production of these nanodelivery systems, aimed at improving human health through decrease toxicity, targeted delivery of the active compound to areas of interest with sustained release ability. In this study, we administered zinc-aluminium-LDH-levodopa nanocomposite (ZAL) and zinc-aluminium nanocomposite (ZA) to Sprague Dawley rats to evaluate for acute oral toxicity following OECD guidelines. The oral administration of ZAL and ZA at a limit dose of 2,000 mg/kg produced neither mortality nor acute toxic signs throughout 14 days of the observation. The percentage of body weight gain of the animals showed no significant difference between control and treatment groups. Animal from the two treated groups gained weight continuously over the study period, which was shown to be significantly higher than the weight at the beginning of the study ( P models for short periods of time. It also highlighted the potential distribution ability of Tween-80 coated nanocomposite after oral administration.

  9. PRELIMINARY PHYTOCHEMICAL ANALYSIS AND ACUTE ORAL TOXICITY STUDY OF MUCUNA PRURIENS LINN. IN ALBINO MICE

    Directory of Open Access Journals (Sweden)

    Deka Manalisha

    2012-02-01

    Full Text Available Mucuna Pruriens Linn. is an annual, climbing shrub which has an important place among aphrodisiac herbs in India since the ancient times. The plant has been using traditionally for many medicinal purposes such as Infertility, Parkinson’s disease, Loss of libido, Antioxidant, Anti venom, Anti microbial etc. The present study was carried out to investigate the preliminary phytochemical analysis and acute oral toxicity of the seeds of M.pruriens on albino mice. Matured seeds of M.pruriens were dried in shed and grinded in a mechanical grinder. The preliminary phytochemical analysis was done by following standard protocols. For acute oral toxicity study, methanolic extract of the seeds were used. The extract was prepared in a Soxlet apparatus. The preliminary phytochemical analysis showed the presence of protein, carbohydrates, glycosides, alkaloids, steroids, flavonoids, phenols and tannins. The acute oral toxicity study showed no mortality up to a dose of 4000 mg per kg body weight. The presence of plant chemicals revealed the medicinal values and the non toxic property of the plant indicated the value of the plant as medicine. Thus, we can conclude that, the seed of the plant can be used as a safe drug against many diseases.

  10. Oral Toxicity and Intestinal Transport Mechanism of Colloidal Gold Nanoparticle-Treated Red Ginseng

    Science.gov (United States)

    Bae, Song-Hwa; Yu, Jin; Go, Mi-Ran; Kim, Hyun-Jin; Hwang, Yun-Gu; Choi, Soo-Jin

    2016-01-01

    (1) Background: Application of nanotechnology or nanomaterials in agricultural food crops has attracted increasing attention with regard to improving crop production, quality, and nutrient utilization. Gold nanoparticles (Au-NPs) have been reported to enhance seed yield, germination rate, and anti-oxidant potential in food crops, raising concerns about their toxicity potential. In this study, we evaluated the oral toxicity of red ginseng exposed to colloidal Au-NPs during cultivation (G-red ginseng) in rats and their intestinal transport mechanism. (2) Methods: 14-day repeated oral administration of G-red ginseng extract to rats was performed, and body weight, hematological, serum biochemical, and histopathological values were analyzed. An in vitro model of human intestinal follicle-associated epithelium (FAE) and an intestinal epithelial monolayer system were used for intestinal transport mechanistic study. (3) Results: No remarkable oral toxicity of G-red ginseng extract in rats was found, and Au-NPs did not accumulate in any organ, although Au-NP transfer to G-red ginseng and some increased saponin levels were confirmed. Au-NPs were transcytozed by microfold (M) cells, but not by a paracellular pathway in the intestinal epithelium. (4) Conclusion: These findings suggest great potential of Au-NPs for agricultural food crops at safe levels. Further study is required to elucidate the functional effects of Au-NPs on ginseng and long-term toxicity. PMID:28335336

  11. Reduced Glutathione Mediates Resistance to H2S Toxicity in Oral Streptococci.

    Science.gov (United States)

    Ooi, Xi Jia; Tan, Kai Soo

    2016-01-22

    Periodontal disease is associated with changes in the composition of the oral microflora, where health-associated oral streptococci decrease while Gram-negative anaerobes predominate in disease. A key feature of periodontal disease-associated anaerobes is their ability to produce hydrogen sulfide (H2S) abundantly as a by-product of anaerobic metabolism. So far, H2S has been reported to be either cytoprotective or cytotoxic by modulating bacterial antioxidant defense systems. Although oral anaerobes produce large amounts of H2S, the potential effects of H2S on oral streptococci are currently unknown. The aim of this study was to determine the effects of H2S on the survival and biofilm formation of oral streptococci. The growth and biofilm formation of Streptococcus mitis and Streptococcus oralis were inhibited by H2S. However, H2S did not significantly affect the growth of Streptococcus gordonii or Streptococcus sanguinis. The differential susceptibility of oral streptococci to H2S was attributed to differences in the intracellular concentrations of reduced glutathione (GSH). In the absence of GSH, H2S elicited its toxicity through an iron-dependent mechanism. Collectively, our results showed that H2S exerts antimicrobial effects on certain oral streptococci, potentially contributing to the decrease in health-associated plaque microflora. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  12. Oral bioaccessibility of toxic metals in contaminated oysters and relationships with metal internal sequestration.

    Science.gov (United States)

    Gao, Shi; Wang, Wen-Xiong

    2014-12-01

    The Hong Kong oysters Crassostrea hongkongensis are widely farmed in the estuarine waters of Southern China, but they accumulate Cu and Zn to alarmingly high concentrations in the soft tissues. Health risks of seafood consumption are related to contaminants such as toxic metals which are bioaccessible to humans. In the present study, we investigated the oral bioaccessibility of five toxic metals (Ag, Pb, Cd, Cu and Zn) in contaminated oysters collected from different locations of a large estuary in southern China. In all oysters, total Zn concentration was the highest whereas total Pb concentration was the lowest. Among the five metals, Ag had the lowest oral bioaccessibility (38.9-60.8%), whereas Cu and Zn had the highest bioaccessibility (72.3-93.1%). Significant negative correlation was observed between metal bioaccessibility and metal concentration in the oysters for Ag, Cd, and Cu. We found that the oral bioaccessibility of the five metals was positively correlated with their trophically available metal fraction (TAM) in the oyster tissues, and negatively correlated with metal distribution in the cellular debris. Thus, metal partitioning in the TAM and cellular debris controlled the oral bioaccessibility to humans. Given the dependence of oral bioaccessibility on tissue metal contamination, bioaccessibility needs to be incorporated in the risk assessments of contaminated shellfish. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice.

    Science.gov (United States)

    Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy; Al-Meteri, Mokhlid Hamed

    2011-04-01

    Normal adult inbred SWR/J mice were used to investigate the teratogenic and other possible toxic effects of various dose levels of sildenafil citrate (Viagra) on fetuses. Multiple dose levels of 6.5, 13.0, 19.5, 26.0, 32.5 or 40.0 mg of sildenafil citrate/kg body weight (which correspond to the multiples of 1, 2, 3, 4, 5 or 6 of human 50 mg Viagra, respectively) were orally administered into pregnant mice on days 7-9, 10-12 or 13-15 of gestation. On day 17 of pregnancy, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) and for external, internal and skeletal malformations. A total of 285 pregnant mice were used in the present study. None of the dams treated with sildenafil citrate at any of the oral dose levels used in the present study died during the experimental period and all dams treated with the drug failed to reveal overt signs of maternal toxicity. Moreover, the results of the present study clearly demonstrate that none of the multiple oral dose levels of the drug at any time interval used has induced any external, internal or skeletal malformations in the fetuses obtained from treated females. However, the dose level of 40 mg/kg body weight of sildenafil citrate has a growth suppressing effect on alive fetuses when it was administered at all the time intervals used in the present study. Furthermore, the dose levels 26.0, 32.5 and 40 mg/kg of the drug have embryo-fetal toxicity when the drug is applied on days 13-15 of gestation. The possible mechanisms involved in the embryo-fetal toxicity and fetal growth suppressing effects of sildenafil citrate were discussed. The results of this study have important implications for the widespread use of this drug.

  14. Acute and Chronic Oral Toxicity of a Partially Purified Plaunotol Extract from Croton stellatopilosus Ohba

    Directory of Open Access Journals (Sweden)

    Chatchai Chaotham

    2013-01-01

    Full Text Available Plaunotol, an acyclic diterpenoid with highly effective antigastric ulcer properties, has been commercially isolated from leaves of Croton stellatopilosus Ohba. This Thai medicinal plant was traditionally used in the form of crude extracts, suggesting that it is possible to administer these plaunotol-containing extracts without toxicity. To confirm its safety, the oral toxicity of a partially purified plaunotol extract (PPE was evaluated in vivo. The PPE was simply prepared by 95% ethanol reflux extraction followed by hexane partition. The obtained extract was analyzed and found to contain 43% w/w of plaunotol and another compound, likely a fatty acid-plaunotol conjugate that is considered a major impurity. Oral administration of PPE to ICR mice and Wistar rats was conducted to evaluate acute and chronic toxicity of the plaunotol extract, respectively. The acute toxicity study demonstrated that PPE was practically nontoxic based on its high median lethal dose value (LD50=10.25 g/kg. The chronic toxicity studies also showed the absence of mortality and clinical symptoms in all rats treated with 11–1,100 mg/kg/day of PPE during a 6-month period. Histopathological and hematological analyses revealed that altered liver and kidney function and increased blood platelet number, but only at the high doses (550–1,100 mg/kg/day. These results suggest that PPE is potentially safe for further development as a therapeutic agent in humans.

  15. Acute and sub-acute oral toxicity of Brazilian red propolis in rats.

    Science.gov (United States)

    da Silva, Rafaela Oliveira; Andrade, Valléria Matos; Bullé Rêgo, Ester Seixas; Azevedo Dória, Grace Anne; Santos Lima, Bruno Dos; da Silva, Francilene Amaral; de Souza Araújo, Adriano Antunes; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Cordeiro Cardoso, Juliana; Zanardo Gomes, Margarete

    2015-07-21

    Propolis is a bee product widely used in folk medicine due to its numerous pharmacological properties. However, samples from different regions can differ in chemical composition, effectiveness, and side effects. Despite the widespread use of Brazilian red propolis, which is an isoflavone-rich variety, its toxicity has not been carefully studied. To assess the acute and sub-acute toxicity of the hydroethanolic extract of red propolis (HERP) administered orally to rats. HERP for the acute (300mg/kg) and sub-acute (10, 100 and 200mg/kg) toxicity studies was administered orally to rats according to OECD Guidelines 420 and 407, respectively. Clinical signs were identified, and hematological and biochemical analyses were performed. Water and food uptake as well as body and organ weights of animals were recorded. The acute study revealed no lethal effects at 300mg/kg of HERP, but toxic signs were observed, as HERP had an LD50 of more than 300mg/kg, indicating a warning. The most toxic signals in sub-acute studies were observed in males at a dose of 200mg/kg HERP. These results suggest estrogen-like activity, possibly from the isoflavones in HERP. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Oral and intramuscular toxicity of inorganic and organic mercury chloride to growing quail

    Science.gov (United States)

    Hill, E.F.; Soares, J.H.

    1987-01-01

    The lethal toxicity of inorganic (HgCl2) and organic (CH3HgCl) mercury chloride was compared for Coturnix (Japanese quail, Coturnix japonica) of different ages from hatch through adulthood by single-dose acute oral and intramuscular injections and by a 5-d dietary trial. Sublethal mercury toxicity was studied by evaluation of plasma and brain cholinesterase activity. CH3HgCl was more toxic than HgCl2 in all tests at each age tested. LD50s consistently increased over the first 4 wk for both acute methods and both mercurials and then stabilized. The striking difference between single-dose acute and 5-d dietary tests was that CH3HgCl averaged about twice as toxic as HgCl2 by both acute methods, compared to 100 times as toxic by the dietary method. For example, at 2 wk of age, the oral LD50s for CH3HgCl and HgCl2 were 18 and 42 mg/kg and the dietary LC50s were 47 and 5086 ppm. When birds were fed HgCl2 and developed clinical signs of intoxication, they could recover once treatment was withdrawn; however, on CH3HgCl, clinical signs often commenced after treatment was withdrawn, and then actually intensified for several days and culminated in death.

  17. Safety Evaluation of Oral Toxicity of Carica papaya Linn. Leaves: A Subchronic Toxicity Study in Sprague Dawley Rats

    Directory of Open Access Journals (Sweden)

    Zakiah Ismail

    2014-01-01

    Full Text Available The subchronic toxicity effect of the leaf extract of Carica papaya Linn. in Sprague Dawley (SD rats was investigated in this study. The extract was prepared by dissolving the freeze dried extract of the leaves in distilled water and was administered orally to SD rats (consisted of 10 rats/sex/group at 0 (control, 0.01, 0.14, and 2 g/kg body weight (BW for 13 weeks. General observation, mortality, and food and water intake were monitored throughout the experimental period. Hematological and biochemical parameters, relative organ weights, and histopathological changes were evaluated. The study showed that leaf extract when administered for 13 weeks did not cause any mortality and abnormalities of behavior or changes in body weight as well as food and water intake. There were no significant differences observed in hematology parameters between treatment and control groups; however significant differences were seen in biochemistry values, for example, LDH, creatinine, total protein, and albumin. However, these changes were not associated with histopathological changes. In conclusion, the results suggested that daily oral administration of rats with C. papaya leaf extract for 13 weeks at a dose up to fourteen times the levels employed in traditional medicine practice did not cause any significant toxic effect.

  18. Should oral gavage be abandoned in toxicity testing of endocrine disruptors?

    OpenAIRE

    Vandenberg, Laura N; Welshons, Wade V.; Frederick S vom Saal; Toutain, Pierre-Louis

    2014-01-01

    For decades, hazard assessments for environmental chemicals have used intra-gastric gavage to assess the effects of ‘oral’ exposures. It is now widely used – and in some cases required – by US federal agencies to assess potential toxicity of endocrine disrupting chemicals (EDCs). In this review we enumerate several reasons why gavage is not appropriate for the assessment of EDCs using bisphenol A (BPA) as a main example. First, whereas human dietary exposures interact with the oral mucosa, ga...

  19. Safety Evaluation of Turmeric Polysaccharide Extract: Assessment of Mutagenicity and Acute Oral Toxicity

    OpenAIRE

    Chandrasekaran Chinampudur Velusami; Srinivasa Rao Boddapati; Srikanth Hongasandra Srinivasa; Edwin Jothie Richard; Joshua Allan Joseph; Murali Balasubramanian; Amit Agarwal

    2013-01-01

    Curcuma longa Linn. (Zingiberaceae) commonly known as turmeric has long been used for centuries as a spice and household remedy. The present study was carried out to assess the possible mutagenic potential and acute oral toxicity of polysaccharide extract of turmeric rhizome (NR-INF-02) using standard tests. The standard battery of in vitro genotoxicity tests, bacterial reverse mutation test (BRMT), chromosome aberration (CA), and micronucleus (MN) tests were employed to assess the possible m...

  20. Influence of Two Depuration Periods on the Activity and Transcription of Antioxidant Enzymes in Tilapia Exposed to Repeated Doses of Cylindrospermopsin under Laboratory Conditions

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    Victoria Ríos

    2014-03-01

    Full Text Available The cyanobacterial toxin Cylindrospermopsin (CYN, a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and gene expression of some glutathione related enzymes in tilapias (Oreochromis niloticus exposed to a single dose of CYN has been reported. However, little is known about the effects induced by repeated doses of this toxin in tilapias exposed by immersion and the potential reversion of these biochemical alterations after two different depuration periods (3 or 7 days. In the present study, tilapias were exposed by immersion to repeated doses of a CYN-containing culture of Aphanizomenon ovalisporum during 14 days, and then were subjected to depuration periods (3 or 7 days in clean water in order to examine the potential reversion of the effects observed. The activity and relative mRNA expression by real-time polymerase chain reaction (PCR of the antioxidant enzymes glutathione peroxidase (GPx and soluble glutathione-S-transferases (sGST, and also the sGST protein abundance by Western blot analysis were evaluated in liver and kidney of fish. Results showed significant alterations in most of the parameters evaluated and their recovery after 3 days (GPx activity, sGST relative abundance or 7 days (GPx gene expression, sGST activity. These findings not only confirm the oxidative stress effects produced in fish by cyanobacterial cells containing CYN, but also show the effectiveness of depuration processes in mitigating the CYN-containing culture toxic effects.

  1. Acute toxicity assessment of choline by inhalation, intraperitoneal and oral routes in Balb/c mice.

    Science.gov (United States)

    Mehta, Amit Kumar; Arora, Naveen; Gaur, Shailendra Nath; Singh, Bhanu Pratap

    2009-08-01

    Studies suggest that choline has potential to be used as a dietary supplement and a drug for immune inflammatory diseases like asthma and rhinitis. But there are apprehensions regarding adverse effects of choline when given orally in high doses. To address this knowledge gap, toxicity assessment of choline chloride was carried out by intranasal (i.n.), oral and intraperitoneal (i.p.) routes in Balb/c mice for 28days. Body weight, food and water consumption of mice were recorded daily. Hematology and clinical chemistry were assessed to check hepatocellular functions and morphological alterations of the cells. Splenocyte counts were analysed for evaluating cellular immunity. Liver function test was performed by assaying different enzyme systems in serum such as, urea, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Body weight, food and water consumption did not differ between mice treated with choline and the saline control group. Hematologic and biochemical variables were not affected with any increase in serum toxicity marker enzymes indicating normal liver functioning. Choline administration did not affect total cholesterol and high density lipoprotein levels as compared to their respective controls. Urea and blood urea nitrogen levels in choline treated mice were not different than controls. Creatinine level was, however, higher than control in i.p. treatment group, but other parameters were normal. In conclusion, the repeated consumption of choline chloride via i.n. and oral or i.p. routes did not cause toxicity in mice in the toxicological endpoints examined.

  2. Acute Oral Toxicity of Methanolic Seed Extract of Cassia fistula in Mice

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    Sreenivasan Sasidharan

    2011-06-01

    Full Text Available Background and objective: Cassia fistula is widely used in traditional medicine to treat various types of ailments. The evaluation of toxic properties of C. fistula is crucial when considering public health protection because exposure to plant extracts can result in undesirable effects on consumers. Hence, in this study the acute oral toxicity of C. fistula seeds extract was investigated in mice. Results: Oral administration of crude extract at the highest dose of 5000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that C. fistula in nontoxic. Throughout 14 days of the treatment no changes in behavioural pattern, clinical sign and body weight of mice in both control and treatment groups. Also there were no any significant elevations observed in the biochemical analysis of the blood serum. Further, histopathological examination revealed normal architecture and no significant adverse effects observed on the kidney, heart, liver, lung and spleen. Conclusions: Overall, the results suggest that, the oral administration of C. fistula methanolic seeds extract did not produce any significant toxic effect in mice. Hence, the extract can be utilized for pharmaceutical formulations.

  3. Acute oral toxicity and histopathological study of combination of endosulfan and cypermethrin in wistar rats.

    Science.gov (United States)

    Raj, Jaya; Mohineesh; Ray, Ruma; Dogra, T D; Raina, Anupuma

    2013-01-01

    Endosulfan, a neurotoxic organochlorine insecticide and cypermethrin, a synthetic pyrethroid insecticide used to control pests in domestic, industrial, and agricultural situations. The present study was carried out to investigate the acute oral toxicity, behavioral and histopathological changes of combination of endosulfan and cypermethrin in albino rats. According to Miller and Tainter analysis method, at 48 h, LD50 value of combination of endosulfan and cypermethrin (ratio 1:1) in rats was found to be 691.83 mg/kg bw by oral gavage. When combination of both these pesticides was administered orally at concentration of 103.72 mg/kg bw, 172.95 mg/kg bw and 207.50 mg/kg bw, respectively, as a single dose, no significant changes in behavior of rats was observed, neither in dosed nor in control group of rats. Combination of endosulfan- and cypermethrin-treated rats showed mild histopathological changes in liver and kidney in group IV (207.50 mg/kg BW) as compared to the control. However, no significant changes were observed in brain and small intestine at either dose of combination of endosulfan and cypermethrin with respect to control. Thus, the present study, first of its kind in India, demonstrated the oral toxicity, behavioral, and histo-architectual alterations after induction of combination of endosulfan and cypermethrin at acute doses in Wistar rats.

  4. Cytotoxicity and Oral Acute Toxicity Studies of Lantana camara Leaf Extract

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    Badakhshan Mahdi Pour

    2011-05-01

    Full Text Available Background: The objective of this study was to investigate the toxicity of Lantana camara methanol extract. Methods: In order to evaluate the toxicity of Lantana camara, the acute toxicity of the methanolic extract on adult mice and cytotoxicity test on Vero cell line were investigated. A fixed large dose of 2 g/kg body weight of L. camara leaf extract was administrated by a single oral gavage according to the OECD procedure. Results: In 2 weeks, L. camara leaf extract showed no obvious acute toxicity. While female mice lost body weight after being treated with single dose of leaf extract in acute toxicity test, male ones lost organ mass, particularly for heart and kidney. The biochemical liver function tests showed significantly elevated TBIL and ALT in the L. camara leaf extract treated female mice group compared with the control group. Cytotoxicity effect of leaf extract of L. camara was estimated through a MTT assay. Cytotoxicity tests on Vero cell line disclosed that leaf extract at concentrations up to 500 µg/mL inhibited the growth of cells 2.5 times less than did Triton 100× 1%. More interestingly, the cytotoxicity initiated to decline at elevated concentrations of this extract. Conclusions: The results of both tests confirm that L. camara shows a pro toxic effect.

  5. Acute and subchronic oral toxicities of Calendula officinalis extract in Wistar rats.

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    Lagarto, Alicia; Bueno, Viviana; Guerra, Isbel; Valdés, Odalys; Vega, Yamile; Torres, Leonid

    2011-05-01

    We have studied the acute and subchronic oral toxicities of Calendula officinalis extract in male and female Wistar rats. A single acute C. officinalis extract dose of 2000 mg/kg dissolved in distilled water was administered by oral gavage for acute toxicity. Subchronic doses of 50, 250 and 1000 mg/kg/day were administered in drinking water. The major toxicological endpoints examined included animal body weight, water and food intake, selected tissue weights, and histopathological examinations. In addition, we examined blood elements: hematocrit, hemoglobin concentration, erythrocyte count, total and differential leukocyte count and blood clotting time and blood chemistry: glucose, total cholesterol, urea, total proteins, alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In the acute study, there were no mortality and signs of toxicity. In the subchronic study, several of the blood elements were significantly affected in males and females after 90 days; hemoglobin, erythrocytes, leukocytes and blood clotting time. For blood chemistry parameters, ALT, AST and alkaline phosphatase were affected. Histopathological examination of tissues showed slight abnormalities in hepatic parenchyma that were consistent with biochemical variations observed. These studies indicate that the acute and subchronic toxicities of C. officinalis extract are low.

  6. Acute Oral Toxicity and Brine Shrimp Lethality of Elaeis guineensis Jacq., (Oil Palm Leaf Methanol Extract

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    Yeng Chen

    2010-11-01

    Full Text Available Elaeis guineensis (Arecaceae is widely used in West African traditional medicine for treating various ailments. An evaluation on the toxicity of extracts of this plant is crucial to support the therapeutic claims. The acute oral toxicity and brine shrimp lethality of a methanolic extract of this plant was tested. Oral administration of crude extract at the highest dose of 5,000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that E. guineensis is nontoxic. Normal behavioral pattern, clinical signs and histology of vital organs confirm this evidence. The E. guineensis extracts screened for toxicity against brine shrimp had 50% lethal concentration (LC50 values of more than 1.0 mg/mL (9.00 and 3.87 mg/mL, at 6 and 24 h, respectively, confirming that the extract was not toxic. Maximum mortalities occurred at 100 mg/mL concentration while the least mortalities happened to be at 0.195 mg/mL concentration. The results of both tests confirm that E. guineensis is nontoxic and hence safe for commercial utilization.

  7. Acute oral toxicity and brine shrimp lethality of Elaeis guineensis Jacq., (oil palm leaf) methanol extract.

    Science.gov (United States)

    Syahmi, Abdul Rani Muhamad; Vijayarathna, Soundararajan; Sasidharan, Sreenivasan; Latha, Lachimanan Yoga; Kwan, Yuet Ping; Lau, Yee Ling; Shin, Lai Ngit; Chen, Yeng

    2010-11-10

    Elaeis guineensis (Arecaceae) is widely used in West African traditional medicine for treating various ailments. An evaluation on the toxicity of extracts of this plant is crucial to support the therapeutic claims. The acute oral toxicity and brine shrimp lethality of a methanolic extract of this plant was tested. Oral administration of crude extract at the highest dose of 5,000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that E. guineensis is nontoxic. Normal behavioral pattern, clinical signs and histology of vital organs confirm this evidence. The E. guineensis extracts screened for toxicity against brine shrimp had 50% lethal concentration (LC₅₀) values of more than 1.0 mg/mL (9.00 and 3.87 mg/mL, at 6 and 24 h, respectively), confirming that the extract was not toxic. Maximum mortalities occurred at 100 mg/mL concentration while the least mortalities happened to be at 0.195 mg/mL concentration. The results of both tests confirm that E. guineensis is nontoxic and hence safe for commercial utilization.

  8. In vivo toxicity of orally administrated silicon dioxide nanoparticles in healthy adult mice.

    Science.gov (United States)

    Hassankhani, Ramin; Esmaeillou, Mohammad; Tehrani, Ali Asghar; Nasirzadeh, Keyvan; Khadir, Fatemeh; Maadi, Hamid

    2015-01-01

    The increasing use of silica nanoparticles (SiNPs) in various applications including industrial, agriculture, and medicine has raised concerns about their potential risks to human health. Various nanotoxicity researches have been done on the assessment of SiNPs' toxic effects; however, a few in vivo investigations exist. In this investigation, an in vivo study was done in order to evaluate the oral toxicity of SiNPs. The biochemical levels of 19 different serum parameters were assessed. Moreover, the histopathological changes have been examined as well. We showed that SiNPs with diameters of 10-15 nm in size can cause significant changes in albumin, cholesterol, triglyceride, total protein, urea, HDL, and LDL as well as in alkaline phosphatase and aspartate aminotransferase activity. In addition, histopathological examinations demonstrated that SiNPs have toxic effects on various tissues including liver, kidney, lung, and testis.

  9. Oral LD50 toxicity modeling and prediction of per- and polyfluorinated chemicals on rat and mouse.

    Science.gov (United States)

    Bhhatarai, Barun; Gramatica, Paola

    2011-05-01

    Quantitative structure-activity relationship (QSAR) analyses were performed using the LD(50) oral toxicity data of per- and polyfluorinated chemicals (PFCs) on rodents: rat and mouse. PFCs are studied under the EU project CADASTER which uses the available experimental data for prediction and prioritization of toxic chemicals for risk assessment by using the in silico tools. The methodology presented here applies chemometrical analysis on the existing experimental data and predicts the toxicity of new compounds. QSAR analyses were performed on the available 58 mouse and 50 rat LD(50) oral data using multiple linear regression (MLR) based on theoretical molecular descriptors selected by genetic algorithm (GA). Training and prediction sets were prepared a priori from available experimental datasets in terms of structure and response. These sets were used to derive statistically robust and predictive (both internally and externally) models. The structural applicability domain (AD) of the models were verified on 376 per- and polyfluorinated chemicals including those in REACH preregistration list. The rat and mouse endpoints were predicted by each model for the studied compounds, and finally 30 compounds, all perfluorinated, were prioritized as most important for experimental toxicity analysis under the project. In addition, cumulative study on compounds within the AD of all four models, including two earlier published models on LC(50) rodent analysis was studied and the cumulative toxicity trend was observed using principal component analysis (PCA). The similarities and the differences observed in terms of descriptors and chemical/mechanistic meaning encoded by descriptors to prioritize the most toxic compounds are highlighted.

  10. Subchronic oral toxicity study of Vegeta in Sprague-Dawley rats

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    Hedi R. Dewoto

    2006-12-01

    Full Text Available The objective of this study was to determine the safety and toxic effect of Vegeta giving orally for a period of 90 days in rats. Eighty rats of Sprague-Dawley strain were randomly devided into 4 groups. Each group consists of 20 rats, 10 male and 10 female rats. Each group received 0.25 g/ kgBW; 0.50 g / kgBW; 1.00 g / kgBW Vegeta (in aquadest solution respectively, and the control group received 5 mL /kgBW aquadest , given orally by gastric tube for 90 days. The rat’s body weight and behavior were daily evaluated. On the 90th day, the rats were decapitated and the blood samples were withdrawn for evaluation of Hemoglobin, leucocyte, SGPT, SGOT, creatinine, and ureum concentration. Visceral organs were also removed, being weighted and were examined microscopically. The results showed that Vegeta with dose of 0.25 g / kgBW; 0.50 g / kgBW, and 1.00 g / kgBW did not affect body weight, liver and renal function compared to control group. There was no significant difference for hemoglobin value compared to control group, but the number of leucocyte increased in 1.00 g / kgBW Vegeta dose group, which was possibly caused by infection. In Vegeta group, there was different spleen and brain weight in male rats, and different lung and heart weight in female rats compared to the control group. However, since it was not dose-related and there was no specific abnormality in microscopic examination compared to the control group, it was not indicated as Vegeta toxic effect. The No observed effect level (NOEL value of Vegeta for 90 day oral administration in male and female rats of Sprague-Dawley strain was 1.00 g / kgBW. (Med J Indones 2006; 15:223-8Keywords: Vegeta, subchronic toxicity, oral, rats

  11. Oral treatment with herbal formula B401 alleviates penile toxicity in aging mice with manganism.

    Science.gov (United States)

    Hsu, Chih-Hsiang; Lin, Ching-Lung; Wang, Sheue-Er; Sheu, Shuenn-Jyi; Chien, Chiang-Ting; Wu, Chung-Hsin

    2015-01-01

    The present study aims to elucidate the roles of nitric oxide synthase activity, oxidative stress, inflammation, and apoptosis in penile toxicity of aging mice associated with excess manganese (Mn) treatment and to investigate the effect of oral treatment with the herbal formula B401 in this respect. ICR strain mice were divided into two groups: the vehicle (sham group) and the B401 (50 mg/kg) group. The mice were orally treated for 5 days; then a high single dose of MnCl2 (100 mg/kg) was given by intraperitoneal injection to the mice. One day after MnCl2 treatment, corpora cavernosal tissues of both Mn-treated mice and their controls were simultaneously sampled to examine their immunohistochemical staining and Western blot analysis. Nitric oxide (NO) production, levels of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), expression levels of factors governing angiogenesis (vascular endothelial growth factor), oxidative stress (catalase, superoxide dismutase 2,4-hydroxynonenal), inflammation (tumor necrosis factor alpha), apoptosis (B-cell lymphoma 2 [Bcl-2], Bcl-2-associated X protein [Bax], cleaved poly(adenosine diphosphate-ribose) polymerase [c-PARP], cytochrome C, caspase-12, and caspase-3) were evaluated in penile corpus cavernosum of the mice. We found that penile toxicity in the mice was enhanced under excess Mn treatment through reduction of NOS activity and increase in oxidative stress, inflammation, and apoptosis in the penile cavernous tissue. Furthermore, the penile toxicity in mice with manganism was alleviated by oral B401 treatment through enhancement of both nitric oxide synthesis and angiogenesis, with simultaneous reduction of oxidative stress, inflammation, and apoptosis in penile corpus cavernosum. We suggest that the herbal formula B401 may serve as a potential dietotherapeutic supplement for penile toxicity or dysfunction in aging males.

  12. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

    Science.gov (United States)

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven

    2015-04-01

    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  13. Acute and 28-day repeated oral toxicological evaluation of Kuruthi Azhal Chooranam - a Siddha preparation on rodents

    Institute of Scientific and Technical Information of China (English)

    Marimuthu Kannadasana; Ganesan Sumathy; Palanivel Thirusangu Sangeetha; Chidambaram Saravanababu; Kathirvelu Baskar

    2016-01-01

    Objective:To determine the effect of phytochemicals in acute and repeated dose of 28-day oral toxicity of Kuruthi Azhal Chooranam (KAC) in Sprague Dawley rats of both sexes. Methods:Acute oral toxicity was conducted with 2 000 mg/kg body weight of KAC orally and the treated animals were observed for signs of toxicity at 30 min, 1, 2, 4 and 24 h and for up to 14 days. In repeated 28-day oral toxicity study, the KAC formulation was administered orally with 600, 900 and 1 200 mg/kg body weight/day to all the three groups of rats. The animals were observed for clinical signs of toxicity, mortality and morbidity throughout the study. Also body weight, feed consumption, haematological, plasma biochemistry and serum electrolytes, gross pathology, weights of the organ and histology were studied for no-observed-adverse-effect level. High dose of KAC formulation and control reversal groups were also included for delayed toxic effects determination. Results:In the acute toxicity study of KAC formulation, 2 000 mg/kg body weight dose exhibited no toxic signs and mortality during study. In sub-acute 28-day repeated dose toxicity study, there was no significant difference found between control and KAC treated groups (body weight, haematology, biochemistry and serum electrolytes). No abnormalities was found in gross pathology, organs weight and histological observation after KAC treatment. Conclusions:The current study suggests that LD50 of KAC was > 2 000 mg/kg and no-observed-adverse-effect level was>1 200 mg/kg/day in rats. KAC could be used as Siddha drug for various indications.

  14. Acute Oral Toxicity Study of GAL-57 (Bentazon + Dicamba Herbicide in Rats

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    Dragica Brkić

    2009-01-01

    Full Text Available An acute oral toxicity study of the herbicide GAL-57 (Avalon, a mixture of bentazon and dicamba as active ingredients, was conducted to assess its acute oral toxicity to rats, using a new method that has been used in the past several years (2001. Clinical observations were performed for all animals after different time intervals, and gross necropsy was performed at termination of examination. Clinical symptoms (decreased activity, prone position, abnormal limb position, decreased righting reflex, decreased grip and limb tone, decreased body and abdominal tone and dyspnoea from mild to marked degree were noted after administration of 2000 mg/kg. Animals were found dead 30 minutes to one hour after the treatment. GAL-57 did not cause any clinical sings at single 300 mg/kg bw dose. The physical condition and behaviour of animals were normal during the 14-day observation period. The acute oral LD-50 value of the GAL-57 proved to be between 300 and 2000 mg/kg body weight in rats and was ranked into Poison group III according to Serbian criteria, category 4 of the Global Harmonized Classification System and Category III of the EPA classification.

  15. Phytochemical Screening and Acute Oral Toxicity Study of Java Tea Leaf Extracts

    Science.gov (United States)

    Safinar Ismail, Intan; Azam, Amalina Ahmad; Abas, Faridah; Shaari, Khozirah; Sulaiman, Mohd Roslan

    2015-01-01

    The term Java tea refers to the decoction of Orthosiphon stamineus (OS) Benth (Lamiaceae) leaves, which are widely consumed by the people in Europe and South East Asian countries. The OS leaves are known for their use in traditional medicinal systems as a prophylactic and curative agent for urinary stone, diabetes, and hypertension and also as a diuretic agent. The present study was aimed at evaluating its possible toxicity. Herein, the major phytochemical constituents of microwave dried OS leaf, which is the common drying process for tea sachets in the market, were also identified. The acute oral toxicity test of aqueous, 50% aqueous ethanolic, and ethanolic extracts of OS was performed at a dose of 5000 mg/Kg body weight of Sprague-Dawley rats. During the 14-day study, the animals were observed for any mortality, behavioral, motor-neuronal abnormalities, body weight, and feed-water consumption pattern. The hematological and serum biochemical parameters to assess the kidney and liver functions were carried out, along with the histological analysis of these organs. It was found that all microwave dried OS leaf extracts did not cause any toxic effects or mortality at the administered dose. No abnormality was noticed in all selected parameters in rats of both sexes as compared with their respective control groups. Thus, the possible oral lethal dose for microwave dried Java tea leaves is more than 5000 mg/Kg body weight. PMID:26819955

  16. Acute oral toxicity studies of Swietenia macrophylla seeds in Sprague Dawley rats

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    Madhu Katyayani Balijepalli

    2015-01-01

    Full Text Available Background: Swietenia macrophylla King. (Meliaceae seeds (SMS; commonly known as sky fruit and locally known in Malaysia as Tunjuk Langit; have been used in traditional Malay medicine for the treatment of diabetes and hypertension. The people eat only a tiny amount of raw seed, weighing not more than 5 mg. Aim: To evaluate the safety of Swietenia macrophylla seeds (SMS at a single-dose oral administration of 2 g/kg body weight (bw in sprague dawley (SD rats. Materials and Methods: Eight-week old male and female SD rats were administered a single-oral dose of 2g/kg bw. The rats′ general behavior, and toxic signs were observed throughout the 14-day study period. The food and water intake by rats and their body weight were monitored during the study period. At the end of the study period, the relative weights of the organs (lung, liver, spleen, heart, kidney, testis, stomach; the hematological and biochemical parameters were measured; the architecture and histology of the organs (liver, kidney and lungs were observed. Results: Oral administration of SMS to rats did not affect, either food or water intake; relative organ weight of vital organs; the hematological and biochemical parameters; did not show significant changes in the architecture and histology of vital organs. Overall, there were neither signs of toxicity nor deaths recorded during the study period. Conclusion: The rat dose of 2 g/kg bw is equivalent to the human dose of 325 mg/kg bw, which is well below the usual amount consumed by people, did not show any signs of toxicity in rats.

  17. Oral toxicity of silver ions, silver nanoparticles and colloidal silver--a review.

    Science.gov (United States)

    Hadrup, Niels; Lam, Henrik R

    2014-02-01

    Orally administered silver has been described to be absorbed in a range of 0.4-18% in mammals with a human value of 18%. Based on findings in animals, silver seems to be distributed to all of the organs investigated, with the highest levels being observed in the intestine and stomach. In the skin, silver induces a blue-grey discoloration termed argyria. Excretion occurs via the bile and urine. The following dose-dependent animal toxicity findings have been reported: death, weight loss, hypoactivity, altered neurotransmitter levels, altered liver enzymes, altered blood values, enlarged hearts and immunological effects. Substantial evidence exists suggesting that the effects induced by particulate silver are mediated via silver ions that are released from the particle surface. With the current data regarding toxicity and average human dietary exposure, a Margin of Safety calculation indicates at least a factor of five before a level of concern to the general population is reached.

  18. Antidiarrheal activity and acute oral toxicity of Mentha longifolia L. essential oil

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    Ghader Jalilzadeh-Amin

    2015-02-01

    Full Text Available Objectives: Mentha longifolia L. (Lamiaceae is an annual herb that is used in the Iranian traditional medicine for treating stomach and intestinal disorders. The purpose of this study was to determine the protective effect of M. longifolia on experimental diarrhea in a rat model. Materials and Methods: The antidiarrheal activity of essential oil of M. longifolia (20-80 mg/kg was investigated against castor oil-induced diarrhea in rats using loperamide as the standard reference drug. In acute toxicity evaluation, rats were orally administrated with single dose of EOML at doses ranging from 10 to 1000 mg/kg. Results: EOML caused a significant (p

  19. Oral treatment with herbal formula B401 alleviates penile toxicity in aging mice with manganism

    OpenAIRE

    Hsu CH; Lin CL; Wang SE; Sheu SJ; Chien CT; Wu CH

    2015-01-01

    Chih-Hsiang Hsu,1 Ching-Lung Lin,1 Sheue-Er Wang,1 Shuenn-Jyi Sheu,2 Chiang-Ting Chien,1 Chung-Hsin Wu1 1Department of Life Science, National Taiwan Normal University, 2Brion Research Institute of Taiwan, Taipei, Taiwan Abstract: The present study aims to elucidate the roles of nitric oxide synthase activity, oxidative stress, inflammation, and apoptosis in penile toxicity of aging mice associated with excess manganese (Mn) treatment and to investigate the effect of oral treatment with the ...

  20. Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats.

    Science.gov (United States)

    Sengupta, Pinaki; Nandi, Utpal; Pal, Tapan Kumar

    2012-02-01

    Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.

  1. Beryllium metal I. experimental results on acute oral toxicity, local skin and eye effects, and genotoxicity.

    Science.gov (United States)

    Strupp, Christian

    2011-01-01

    The toxicity of soluble metal compounds is often different from that of the parent metal. Since no reliable data on acute toxicity, local effects, and mutagenicity of beryllium metal have ever been generated, beryllium metal powder was tested according to the respective Organisation for Economical Co-Operation and Development (OECD) guidelines. Acute oral toxicity of beryllium metal was investigated in rats and local effects on skin and eye in rabbits. Skin-sensitizing properties were investigated in guinea pigs (maximization method). Basic knowledge about systemic bioavailability is important for the design of genotoxicity tests on poorly soluble substances. Therefore, it was necessary to experimentally compare the capacities of beryllium chloride and beryllium metal to form ions under simulated human lung conditions. Solubility of beryllium metal in artificial lung fluid was low, while solubility in artificial lysosomal fluid was moderate. Beryllium chloride dissolution kinetics were largely different, and thus, metal extracts were used in the in vitro genotoxicity tests. Genotoxicity was investigated in vitro in a bacterial reverse mutagenicity assay, a mammalian cell gene mutation assay, a mammalian cell chromosome aberration assay, and an unscheduled DNA synthesis (UDS) assay. In addition, cell transformation was tested in a Syrian hamster embryo cell assay, and potential inhibition of DNA repair was tested by modification of the UDS assay. Beryllium metal was found not to be mutagenic or clastogenic based on the experimental in vitro results. Furthermore, treatment with beryllium metal extracts did not induce DNA repair synthesis, indicative of no DNA-damaging potential of beryllium metal. A cell-transforming potential and a tendency to inhibit DNA repair when the cell is severely damaged by an external stimulus were observed. Beryllium metal was also found not to be a skin or eye irritant, not to be a skin sensitizer, and not to have relevant acute oral

  2. Evaluación de la toxicidad aguda oral e irritación sobre mucosa bucal de la solución CM-95 tratada magnéticamente Oral acute toxicity and irritation on buccal mucosa evaluation of the CM-95 solution magnetically treated

    Directory of Open Access Journals (Sweden)

    Jorge Díaz Bestard

    2008-12-01

    -10. In Acute Toxicity Class method was used the Limit Test, in Sprague Dawley females rats, where the dose was related to the magnetic induction level, in this case 0.16 T, applied to CM-95 Solution; and the administration volume of aqueous solution was calculated on base 2 ml per 100 g body weight. Determination of oral mucosa irritation was carried out in female golden Syrian hamsters by means of a repeated doses test during 7 days of treatment in right gular bag, with a cotton pellet impregnated with 0.5 ml of CM-95 Solution magnetically treated with the same induction. Neither mortality nor evidences of toxic signs were observed for the test of acute toxicity, and an irritation index of 0 was obtained on oral mucosa irritation test, reason why the studied substance was framed as "not classified" and "non irritating" according to the applied methodology. These results will complement other toxicological studies to guarantee the safety of this Solution for its future use as a drug by oral route.

  3. Acute and chronic oral toxicity of standardized water extract from the fruit of Phyllanthus emblica Linn.

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    K Jaijoy

    2010-03-01

    Full Text Available Summary: Phyllanthus emblica Linn. (Euphorbiaceae is an herbal plant commonly used in Asian traditional medicine systems for treatment of many disorders. In the present study, we investigated for the first time acute and chronic toxicity of the standardized water extract of P. emblica fruit. The water extract of P. emblica was prepared according to the Thai Herbal Pharmacopoeia and standardized to 20% gallic acid. For studying acute toxicity study, single oral dose of 5000 mg water extract /kg body weight was administered to Sprague Dawley rats (five females, five males. The results showed no toxicity in terms of general behavior change, mortality, or change in gross appearance of internal organs (LD50 > 5,000 mg/kg. Chronic toxicity was studied by daily oral dose (ten females, ten males of 300, 600 and 1,200 mg/kg for 270 days. The results showed slightly significant differences in the body and organ weights between the control and treatment groups. In addition, the rats were analyzed for final body and organ weights, necropsy, and hematological, blood chemical and histopathological parameters. Hematological analysis and clinical blood chemistry revealed slightly changes, but were within the normal limits. No gross or histopathology findings were observed in the treatment groups. Altogether, the standardized water extract from the fruit of P. emblica did not produce acute and chronic toxicity in its traditional uses. Industrial relevance: Traditional medicine is still stronghold of more than 50% of the world population, especially in developing countries. Nowadays, a number of medicinal plants (such as Phyllanthus emblica Linn. are commercially available on local markets as a tonic, food and/or dietary supplement product commonly used for clinical management of several conditions. Despite the widespread use of this plant, there is still little literature on the scientific evaluation of their toxicity. Results of the current study provide

  4. Sub-acute oral toxicity study of methanol leaves extract of Catharanthus roseus in rats

    Institute of Scientific and Technical Information of China (English)

    LYW Kevin; AH Hussin; I Zhari; JH Chin

    2012-01-01

    Objective: To examine the sub-acute (14 d) oral toxic effects of methanol leaves extract ofCatharanthus roseus (C. roseus) (Family: Apocynaceae) on liver and kidney functions in Sprague Dawley (SD) rats. Methods: Twenty four female SD rats were used throughout the experiment. The first group was orally treated with distilled water and served as control, whereas the remaining three groups were orally treated with single dose daily of 0.1 g/kg, 0.5 g/kg, 1 g/kg of C. roseus extract, respectively for 14 d. Cage-side observations were done daily. Any animal died during the experiment was dissected for gross organ examination. Body weight changed, food consumption and water intake were recorded weekly. Blood was collected via cardiac puncture on day-15 and used for determination of serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine and urea. The relative organ weights were also measured. All results were expressed as mean ± S.E.M and analysed using Dunnett’s test. The level of significance was set at P<0.05 when compared to the control group. Results: Repeated oral administration of 0.5 g/kg and 1 g/kg of methanol leaves extract of C. roseus caused mortality and diarrhoea in rats after few days of treatment. There were no significant changes observed in serum biochemical markers, body weight changed, water and food intake and relative organ weight in rats treated with a single dose daily of 0.1 g/kg of C. roseus extract treatment for 14 d when compared to control group. Conclusionds: Fourteen days repeated oral administration of 0.1 g/kg of methanol leaves extract of C. roseus was safe in female SD rats without causing any significant damages to liver and kidney.

  5. Acute Toxicity Prediction in Multiple Species by Leveraging Mechanistic ToxCast Mitochondrial Inhibition Data and Simulation of Oral Bioavailability.

    Science.gov (United States)

    Bhhatarai, Barun; Wilson, Daniel M; Bartels, Michael J; Chaudhuri, Shubhra; Price, Paul S; Carney, Edward W

    2015-10-01

    There is great interest in assessing the in vivo toxicity of chemicals using nonanimal alternatives. However, acute mammalian toxicity is not adequately predicted by current in silico or in vitro approaches. Mechanisms of acute toxicity are likely conserved across invertebrate, aquatic, and mammalian species, suggesting that dose-response concordance would be high and in vitro mechanistic data could predict responses in multiple species under conditions of similar bioavailability. We tested this hypothesis by comparing acute toxicity between rat, daphnia, and fish and by comparing their respective acute data to inhibition of mitochondria membrane potential (MMP) using U.S. Environmental Protection Agency ToxCast in vitro high-throughput screening data. Logarithmic scatter plots of acute toxicity data showed a clear relationship between fish, daphnia, and intravenous rat but not oral rat data. Similar plots versus MMP showed a well-delineated upper boundary for fish, daphnia, and intravenous data but were scattered without an upper boundary for rat oral data. Adjustments of acute oral rat toxicity values by simulating fractional absorption and CYP-based metabolism as well as removing compounds with hydrolyzable linkages or flagged as substrates for glucuronidation delineated an upper boundary for rat oral toxicity versus MMP. Mitochondrial inhibition at low concentrations predicted highly acutely toxic chemicals for fish and daphnia but not the rat where toxicity was often attenuated. This use of a single high-throughput screening assay to predict acute toxicity in multiple species represents a milestone and highlights the promise of such approaches but also the need for refined tools to address systemic bioavailability and the impact of limited absorption and first pass metabolism.

  6. Preliminary phytochemical, acute oral toxicity and antihepatotoxic study of roots of Paeonia officinalis Linn

    Institute of Scientific and Technical Information of China (English)

    Feroz Ahmad; Nahida Tabassum

    2013-01-01

    Objective: To carry out a preliminary phytochemical, acute oral toxicity and antihepatotoxic study of the roots of Paeonia officinalis (P. officinalis) L. Methods: Preliminary phytochemical investigation was done as per standard procedures. Acute oral toxicity study was conducted as per OECD 425 guidelines. The antihepatotoxic activity of aqueous extract of root of P. officinalis was evaluated against carbon tetrachloride (CCl4) induced hepatic damage in rats. Aqueous extract of P. officinalis at the dose levels of 100 and 200 mg/kg body weight was administered daily for 14 d in experimental animals. Liver injury was induced chemically, by CCl4 administration (1 mL/kg i.p.). The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum alkaline phosphatase (SALP), total bilirubin and total protein (TP) along with histopathological studies. Result: Phytochemical screening revealed that the roots ofP. officinalis contain alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids and proteins. The aqueous extract did not cause any mortality up to 2000 mg/kg. In rats that had received the root extract at the dose of 100 and 200 mg/kg, the substantially elevated AST, ALT, SALP, total bilirubin levels were significantly lowered, respectively, in a dose dependent manner, along with CCl4 while TP levels were elevated in these groups. Histopathology revealed regeneration of the livers in extract treated groups while Silymarin treated rats were almost normal. Conclusions: The aqueous extract of P. officinalis is safe and possesses antihepatotoxic potential.

  7. Experimental Basis for the High Oral Toxicity of Dinophysistoxin 1: A Comparative Study of DSP

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    Diego A. Fernández

    2014-01-01

    Full Text Available Okadaic acid (OA and its analogues, dinophysistoxin 1 (DTX1 and dinophysistoxin 2 (DTX2, are lipophilic and heat-stable marine toxins produced by dinoflagellates, which can accumulate in filter-feeding bivalves. These toxins cause diarrheic shellfish poisoning (DSP in humans shortly after the ingestion of contaminated seafood. Studies carried out in mice indicated that DSP poisonous are toxic towards experimental animals with a lethal oral dose 2–10 times higher than the intraperitoneal (i.p. lethal dose. The focus of this work was to study the absorption of OA, DTX1 and DTX2 through the human gut barrier using differentiated Caco-2 cells. Furthermore, we compared cytotoxicity parameters. Our data revealed that cellular viability was not compromised by toxin concentrations up to 1 μM for 72 h. Okadaic acid and DTX2 induced no significant damage; nevertheless, DTX1 was able to disrupt the integrity of Caco-2 monolayers at concentrations above 50 nM. In addition, confocal microscopy imaging confirmed that the tight-junction protein, occludin, was affected by DTX1. Permeability assays revealed that only DTX1 was able to significantly cross the intestinal epithelium at concentrations above 100 nM. These data suggest a higher oral toxicity of DTX1 compared to OA and DTX2.

  8. Experimental basis for the high oral toxicity of dinophysistoxin 1: a comparative study of DSP.

    Science.gov (United States)

    Fernández, Diego A; Louzao, M Carmen; Fraga, María; Vilariño, Natalia; Vieytes, Mercedes R; Botana, Luis M

    2014-01-03

    Okadaic acid (OA) and its analogues, dinophysistoxin 1 (DTX1) and dinophysistoxin 2 (DTX2), are lipophilic and heat-stable marine toxins produced by dinoflagellates, which can accumulate in filter-feeding bivalves. These toxins cause diarrheic shellfish poisoning (DSP) in humans shortly after the ingestion of contaminated seafood. Studies carried out in mice indicated that DSP poisonous are toxic towards experimental animals with a lethal oral dose 2-10 times higher than the intraperitoneal (i.p.) lethal dose. The focus of this work was to study the absorption of OA, DTX1 and DTX2 through the human gut barrier using differentiated Caco-2 cells. Furthermore, we compared cytotoxicity parameters. Our data revealed that cellular viability was not compromised by toxin concentrations up to 1 μM for 72 h. Okadaic acid and DTX2 induced no significant damage; nevertheless, DTX1 was able to disrupt the integrity of Caco-2 monolayers at concentrations above 50 nM. In addition, confocal microscopy imaging confirmed that the tight-junction protein, occludin, was affected by DTX1. Permeability assays revealed that only DTX1 was able to significantly cross the intestinal epithelium at concentrations above 100 nM. These data suggest a higher oral toxicity of DTX1 compared to OA and DTX2.

  9. Safety evaluation of turmeric polysaccharide extract: assessment of mutagenicity and acute oral toxicity.

    Science.gov (United States)

    Velusami, Chandrasekaran Chinampudur; Boddapati, Srinivasa Rao; Hongasandra Srinivasa, Srikanth; Richard, Edwin Jothie; Joseph, Joshua Allan; Balasubramanian, Murali; Agarwal, Amit

    2013-01-01

    Curcuma longa Linn. (Zingiberaceae) commonly known as turmeric has long been used for centuries as a spice and household remedy. The present study was carried out to assess the possible mutagenic potential and acute oral toxicity of polysaccharide extract of turmeric rhizome (NR-INF-02) using standard tests. The standard battery of in vitro genotoxicity tests, bacterial reverse mutation test (BRMT), chromosome aberration (CA), and micronucleus (MN) tests were employed to assess the possible mutagenic activity of NR-INF-02 (Turmacin). The results showed no mutagenic effect with NR-INF-02 up to a dose of 5000 µg/mL in BRMT. The results on CA and MN tests revealed the non clastogenic activity of NR-INF-02 in a dose range of 250.36 to 2500 µg/mL with and without metabolic activation (S9). In acute oral toxicity study, NR-INF-02 was found to be safe up to 5 g/kg body weight in Wistar rats. Overall, results indicated that polysaccharide extract of C. longa was found to be genotoxically safe and also exhibited maximum tolerable dose of more than 5 g/kg rat body weight.

  10. Safety Evaluation of Turmeric Polysaccharide Extract: Assessment of Mutagenicity and Acute Oral Toxicity

    Directory of Open Access Journals (Sweden)

    Chandrasekaran Chinampudur Velusami

    2013-01-01

    Full Text Available Curcuma longa Linn. (Zingiberaceae commonly known as turmeric has long been used for centuries as a spice and household remedy. The present study was carried out to assess the possible mutagenic potential and acute oral toxicity of polysaccharide extract of turmeric rhizome (NR-INF-02 using standard tests. The standard battery of in vitro genotoxicity tests, bacterial reverse mutation test (BRMT, chromosome aberration (CA, and micronucleus (MN tests were employed to assess the possible mutagenic activity of NR-INF-02 (Turmacin. The results showed no mutagenic effect with NR-INF-02 up to a dose of 5000 µg/mL in BRMT. The results on CA and MN tests revealed the non clastogenic activity of NR-INF-02 in a dose range of 250.36 to 2500 µg/mL with and without metabolic activation (S9. In acute oral toxicity study, NR-INF-02 was found to be safe up to 5 g/kg body weight in Wistar rats. Overall, results indicated that polysaccharide extract of C. longa was found to be genotoxically safe and also exhibited maximum tolerable dose of more than 5 g/kg rat body weight.

  11. Acute and subacute oral toxicity of Litsea elliptica Blume essential oil in rats

    Institute of Scientific and Technical Information of China (English)

    Siti Balkis BUDIN; Seri Masran SITINOR AIN; Baharuddin OMAR; Izatus Shima TAIB; Othman HIDAYATULFATHI

    2012-01-01

    Litsea elliptica Blume has been traditionally used to treat headache,fever,and stomach ulcer,and has also been used as an insect repellent.The acute and subacute toxicities of L.el/iptica essential oil were evaluated orally by gavage in female Sprague-Dawley rats.For the acute toxicity study,L.e//iptica essential oil was administered in doses from 500 to 4000 mg/kg (single dose),and in the subacute toxicity test,the following doses were used:125,250,and 500 mg/kg,for 28 consecutive days.In the acute toxicity study,L.elliptica essential oil caused dose-dependent adverse behaviours and mortality.The median lethal dose value was 3488.86 mg/kg and the acute non-observed-adversed-effect level value was found to be 500 mg/kg.The subacute toxicity study of L.elliptica essential oil did not reveal alterations in body weight,and food and water consumptions.The haematological and biochemical analyses did not show significant differences between control and treated groups in most of the parameters examined,except for the hemoglobin,mean cell hemoglobin concentration,mean cell volume,mean cell hemoglobin,serum albumin,and serum sodium.However,these differences were still within the normal range.No abnormalities or histopathological changes were observed in the liver,pancreatic islet of Langerhans,and renal glomerulous and tubular cells of all treated groups.In conclusion,L.el/iptica essential oil can be classified in the U group,which is defined as a group unlikely to present an acute hazard according to World Health Organization (WHO) classification.

  12. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats.

    Science.gov (United States)

    Sui, Hajime; Matsumoto, Hirotaka; Wako, Yumi; Kawasako, Kazufumi

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  13. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease.

    Science.gov (United States)

    Ferruzzi, Mario G; Lobo, Jessica K; Janle, Elsa M; Cooper, Bruce; Simon, James E; Wu, Qing-Li; Welch, Cara; Ho, Lap; Weaver, Connie; Pasinetti, Giulio M

    2009-01-01

    The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

  14. Oral treatment with herbal formula B401 alleviates penile toxicity in aging mice with manganism

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    Hsu CH

    2015-05-01

    Full Text Available Chih-Hsiang Hsu,1 Ching-Lung Lin,1 Sheue-Er Wang,1 Shuenn-Jyi Sheu,2 Chiang-Ting Chien,1 Chung-Hsin Wu1 1Department of Life Science, National Taiwan Normal University, 2Brion Research Institute of Taiwan, Taipei, Taiwan Abstract: The present study aims to elucidate the roles of nitric oxide synthase activity, oxidative stress, inflammation, and apoptosis in penile toxicity of aging mice associated with excess manganese (Mn treatment and to investigate the effect of oral treatment with the herbal formula B401 in this respect. ICR strain mice were divided into two groups: the vehicle (sham group and the B401 (50 mg/kg group. The mice were orally treated for 5 days; then a high single dose of MnCl2 (100 mg/kg was given by intraperitoneal injection to the mice. One day after MnCl2 treatment, corpora cavernosal tissues of both Mn-treated mice and their controls were simultaneously sampled to examine their immunohistochemical staining and Western blot analysis. Nitric oxide (NO production, levels of neuronal nitric oxide synthase (nNOS and endothelial nitric oxide synthase (eNOS, expression levels of factors governing angiogenesis (vascular endothelial growth factor, oxidative stress (catalase, superoxide dismutase 2,4-hydroxynonenal, inflammation (tumor necrosis factor alpha, apoptosis (B-cell lymphoma 2 [Bcl-2], Bcl-2-associated X protein [Bax], cleaved poly(adenosine diphosphate-ribose polymerase [c-PARP], cytochrome C, caspase-12, and caspase-3 were evaluated in penile corpus cavernosum of the mice. We found that penile toxicity in the mice was enhanced under excess Mn treatment through reduction of NOS activity and increase in oxidative stress, inflammation, and apoptosis in the penile cavernous tissue. Furthermore, the penile toxicity in mice with manganism was alleviated by oral B401 treatment through enhancement of both nitric oxide synthesis and angiogenesis, with simultaneous reduction of oxidative stress, inflammation, and apoptosis in

  15. Assessment of thirteen-week subchronic oral toxicity of cyadox in Beagle dogs.

    Science.gov (United States)

    Wang, Xu; Zhou, Wen; Ihsan, Awais; Chen, Dongmei; Cheng, Guyue; Hao, Haihong; Liu, Zhenli; Wang, Yulian; Yuan, Zonghui

    2015-11-01

    Cyadox (2-formylquinoxaline-N(1),N(4)-dioxide cyanocetylhydrazone) is a new antimicrobial agent and growth-promoter to be used in food-producing animals. Although its toxicity has been clearly documented in rodents, no study is available in non-rodent animals. Therefore, we studied the subchronic effects of cyadox in Beagle dogs to provide additional information with which to establish safety criteria for human exposure. For this purpose, 36 Beagle dogs, 18 males and 18 females, were divided into four groups and fed diets containing 0, 100, 450 and 2500 mg/kg of cyadox, respectively, for 13 weeks. It was found that there were no significant changes among the examined parameters, except for an increase in the level of serum potassium (K(+)) in 2500 mg/kg cyadox group in males at week 13 of the study. However, the K(+) level returned to normal during the recovery period. In conclusion, cyadox showed slight effects in Beagle dogs in the subchronic oral toxicity study. The no-observed-adverse-effect level of cyadox was considered to be 450 mg/kg diet, which equates to approximately 15.3-15.4 mg/kg b.w./day. The study provided subchronic effects of cyadox in Beagle dogs, suggesting that cyadox might present mild toxicity in non-rodents.

  16. Improving reptile ecological risk assessment: oral and dermal toxicity of pesticides to a common lizard species (Sceloporus occidentalis).

    Science.gov (United States)

    Weir, Scott M; Yu, Shuangying; Talent, Larry G; Maul, Jonathan D; Anderson, Todd A; Salice, Christopher J

    2015-08-01

    Reptiles have been understudied in ecotoxicology, which limits consideration in ecological risk assessments. The goals of the present study were 3-fold: to improve oral and dermal dosing methodologies for reptiles, to generate reptile toxicity data for pesticides, and to correlate reptile and avian toxicity. The authors first assessed the toxicity of different dosing vehicles: 100 μL of water, propylene glycol, and acetone were not toxic. The authors then assessed the oral and dermal toxicity of 4 pesticides following the up-and-down procedure. Neither brodifacoum nor chlorothalonil caused mortality at doses ≤ 1750 μg/g. Under the "neat pesticide" oral exposure, endosulfan (median lethal dose [LD50] = 9.8 μg/g) was more toxic than λ-cyhalothrin (LD50 = 916.5 μg/g). Neither chemical was toxic via dermal exposure. An acetone dosing vehicle increased λ-cyhalothrin toxicity (oral LD50 = 9.8 μg/g; dermal LD50 = 17.5 μg/g), but not endosulfan. Finally, changes in dosing method and husbandry significantly increased dermal λ-cyhalothrin LD50s, which highlights the importance of standardized methods. The authors combined data from the present study with other reptile LD50s to correlate with available avian data. When only definitive LD50s were used in the analysis, a strong correlation was found between avian and reptile toxicity. The results suggest it is possible to build predictive relationships between avian and reptile LD50s. More research is needed, however, to understand trends associated with chemical classes and modes of action.

  17. Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine.

    Science.gov (United States)

    Mancebo, A; Casacó, A; Sánchez, B; González, B; Gómez, D; León, A; Bada, A M; Arteaga, M E; González, Y; González, C; Pupo, M; Fuentes, Dasha

    2012-12-01

    Our goal was to assess the toxicity of two strengths (200 and 400 μg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10×), 28.6 and 57.1 μg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 μg, 57.1 μg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used.

  18. Acute and sub-acute oral toxicity assessment of the hydroalcoholic extract of Withania somnifera roots in Wistar rats.

    Science.gov (United States)

    Prabu, P C; Panchapakesan, S; Raj, C David

    2013-08-01

    Withania somnifera is a widely used medicinal plant for several disorders. Toxicity studies on Withania somnifera are not available. Acute and sub-acute oral toxicities of Withania somnifera root extract in Wistar rats were evaluated in the present study. In the acute toxicity study, WSR extract was administered to five rats at 2000 mg/kg, once orally and were observed for 14 days. No toxic signs/mortality were observed. In the sub-acute study, WSR extract was administered once daily for 28 days to rats at 500, 1000 and 2000 mg/kg, orally. No toxic signs/mortality were observed. There were no significant changes (P < 0.05) in the body weights, organ weights and haemato-biochemical parameters in any of the dose levels. No treatment related gross/histopathological lesions were observed. The present investigation demonstrated that the no observed adverse effect level was 2000 mg/kg body weight per day of hydroalcoholic extract of W. somnifera in rats and hence may be considered as non-toxic.

  19. Oral 4-week and 13-week toxicity studies of polyvinyl acetate vinyl laurate copolymer in rats.

    Science.gov (United States)

    Messinger, Horst; Bär, Albert

    2014-10-01

    Polyvinyl acetate vinyl laurate copolymer (PVAcVL) is a useful component of gum base for chewing gum production. The safety of PVAcVL was examined in a 4-week and a 13-week oral toxicity study in rats. Finely powdered PVAcVL was administered with the diet at levels of 1.25%, 2.0% and 5% in the 4-week study and 1.25%, 2.5% and 5% in the 13-week study. There were no treatment related effects on mortality, bodyweight gains feed efficiency, ophthalmoscopic findings, hematological and clinical chemical parameters, neurobehavioral observations as well as gross and histopathological changes of standard organs and tissues. The highest dose tested in the 13-week study (3783 and 4396mg/kgbw/d for males and females, respectively) proved to be a NOAEL.

  20. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

    Directory of Open Access Journals (Sweden)

    Balaji Ramachandran

    2016-01-01

    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  1. Experimental oral toxicity of domoic acid in cynomolgus monkeys (Macaca fascicularis) and rats. Preliminary investigations.

    Science.gov (United States)

    Tryphonas, L; Truelove, J; Todd, E; Nera, E; Iverson, F

    1990-10-01

    A recent outbreak of marine food poisoning in humans was attributed to the consumption of blue mussels (Mytilus edulis L.) contaminated with domoic acid (DA) that was produced by the diatom Nitzschia pungens. The clinical and morphological effects of single oral doses of extracts of mussels contaminated with DA or of DA isolated from toxic mussels were investigated in small groups (one to six) of cynomolgus monkeys (Macaca fascicularis; 0.5-10 mg DA/kg body weight) and of Sprague-Dawley rats (60 to 80 mg DA/kg body weight). Control animals were either given saline or were not treated. To test whether monosodium glutamate, present in the food consumed by some affected humans, and dimethylsulphoxide, suspected of being present in the plankton, enhanced the response, monosodium glutamate (at 0.25% of mussel extract bolus) or dimethylsulphoxide (at 1 g per bolus) were co-administered to two (one each) of the DA-treated monkeys. DA-treated monkeys developed transient excitation characterized by vomiting. DA-treated rats showed withdrawal followed by hyperexcitation and death (in one case). Mild to moderate central nervous system lesions consistent with neuroexcitation were present in both monkeys and rats. The addition of monosodium glutamate and dimethylsulphoxide had no significant effect on the appearance and severity of central nervous system clinical signs and lesions. The wide variations in the response of test animals to orally administered DA were attributed to the protective effect of vomiting, and to suspected incomplete or slow gastro-intestinal absorption of the toxic agent. The results reinforce the view that DA is an emetic and that under appropriate conditions may also inflict excitotoxic central nervous system damage.

  2. Preliminary phytochemical,acute oral toxicity and antihepatotoxic study of roots of Paeonia officinalis Linn.

    Institute of Scientific and Technical Information of China (English)

    Feroz; Ahmad; Nahida; Tabassum

    2013-01-01

    Objective:To carry out a preliminary phytochemical,acute oral toxicity and antihepatotoxic study of the roots of Paeonia officinalis(P.officinalis)L.Methods:Preliminary phytochemical investigation was done as per standard procedures.Acute oral toxicity study was conducted as per OECD 425 guidelines.The antihepatotoxic activity of aqueous extract of root of P.officinalis was evaluated against carbon tetrachloride(CCl4)induced hepatic damage in rats.Aqueous extract of P.officinalis at the dose levels of 100 and 200 mg/kg body weight was administered daily for 14 d in experimental animals.Liver injury was induced chemically,by CCl4 administration(1 mL/kg i.p.).The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase(AST),alanine aminotransferase(ALT),serum alkaline phosphatase(SALP),total bilirubin and total protein(TP)along with histopathological studies.Result:Phytochemical screening revealed that the roots of P.officinalis contain alkaloids,tannins,saponins,glycosides,carbohydrates,flavonoids,terpenes,steroids and proteins.The aqueous extract did not cause any mortality up to 2000 mg/kg.In rats that had received the root extract at the dose of 100 and 200 mg/kg,the substantially elevated AST,ALT,SALP,total bilirubin levels were significantly lowered,respectively,in a dose dependent manner,along with CCl4 while TP levels were elevated in these groups.Histopathology revealed regeneration of the livers in extract treated groups while Silymarin treated rats were almost normal.Conclusions:The aqueous extract of P.officinalis is safe and possesses antihepatotoxic potential.

  3. Should oral gavage be abandoned in toxicity testing of endocrine disruptors?

    Science.gov (United States)

    Vandenberg, Laura N; Welshons, Wade V; Vom Saal, Frederick S; Toutain, Pierre-Louis; Myers, John Peterson

    2014-06-25

    For decades, hazard assessments for environmental chemicals have used intra-gastric gavage to assess the effects of 'oral' exposures. It is now widely used--and in some cases required--by US federal agencies to assess potential toxicity of endocrine disrupting chemicals (EDCs). In this review we enumerate several reasons why gavage is not appropriate for the assessment of EDCs using bisphenol A (BPA) as a main example. First, whereas human dietary exposures interact with the oral mucosa, gavage exposures avoid these interactions, leading to dramatic differences in absorption, bioavailability and metabolism with implications for toxicokinetic assumptions and models. Additionally, there are well acknowledged complications associated with gavage, such as perforation of the esophagus that diminish its value in toxicological experiments. Finally, the gavage protocol itself can induce stress responses by the endocrine system and confound the assessment of EDCs. These serious flaws have not been taken into account in interpreting results of EDC research. We propose the exploration of alternatives to mimic human exposures when there are multiple exposure routes/sources and when exposures are chronic. We conclude that gavage may be preferred over other routes for some environmental chemicals in some circumstances, but it does not appropriately model human dietary exposures for many chemicals. Because it avoids exposure pathways, is stressful, and thus interferes with endocrine responses, gavage should be abandoned as the default route of administration for hazard assessments of EDCs.

  4. Stevens-Johnson Syndrome and toxic epidermal necrolysis overlap due to oral temozolomide and cranial radiotherapy.

    Science.gov (United States)

    Sarma, Nilendu

    2009-01-01

    A 46-year-old man developed Stevens-Johnson syndrome and toxic epidermal necrolysis overlap, with severe localized denudation of the skin on the head and neck, following radiotherapy and oral temozolomide therapy for cranial glioblastoma multiforme. He also had a primary malignant fibrous histiocytoma of the thigh that was amputated 5 years earlier. A rash developed after 7 days of radio- and chemotherapy. It was an extensive maculopapular rash that started over the temporal area of the head and rapidly spread, sparing only the distal limbs. Radiotherapy and temozolomide were stopped on the tenth day but the rash rapidly progressed for the next 4-6 days. Following this, the spread halted and complete recovery was observed within the next 2 weeks. The peculiarity of the presentation in this case was that the brunt of the disease with severe skin denudation was localized to the surrounding areas of cranial radiotherapy. The patient was also receiving oral phenytoin, diclofenac, and parenteral dexamethasone before chemotherapy was started. These medications were continued, even after development of the skin rash, until well after full recovery from the skin lesions. After critical evaluation of disease onset, progression, and recovery, and their relationship to the introduction and withdrawal of different medicines, it appeared that either temozolomide alone or in combination with radiotherapy most probably triggered the condition.

  5. Oral toxicity of Photorhabdus luminescens and Xenorhabdus nematophila (Enterobacteriaceae) against Aedes aegypti (Diptera: Culicidae).

    Science.gov (United States)

    da Silva, Onilda Santos; Prado, Geronimo Rodrigues; da Silva, João Luiz Rosa; Silva, Carlos Eugenio; da Costa, Marisa; Heermann, Ralf

    2013-08-01

    Dengue fever is an important vector-borne disease, mainly transmitted by Aedes aegypti. To date, there are no vaccines or effective drugs available against this arboviral disease. As mosquito control is practically the only method available to control dengue fever, alternative and cost-effective pest control strategies need to be explored. The gram-negative enteric bacteria Xenorhabdus and Photorhabdus are symbiotically associated with nematode parasites, which themselves are highly pathogenic for insect larvae. Here, we evaluate the oral toxicity of these entomopathogenic bacteria in A. aegypti larvae. The susceptibility of larvae (third late or fourth early instars) was assessed by exposing them to suspensions containing Photorhabdus luminescens or Xenorhabdus nematophila, respectively. Two diet treatments were tested with larvae fed on pet food and unfed larvae. After 24 h, larvae began to die when exposed to the bacteria. Exposure to P. luminescens killed 73% of the fed and 83% of the unfed larvae, respectively. In comparison, X. nematophila was less pathogenic, killing 52% of the larvae in the fed and 42% in the unfed treatment. Remarkably, cannibalism was observed in all bioassays after exposing larvae to either of the bacterial species. To our knowledge, this is the first report demonstrating the efficiency of these entomopathogenic bacteria for oral A. aegypti killing. Our results provide a promising basis for using these bacteria as bioinsecticides for mosquito control in the future.

  6. Photoprotective effect and acute oral systemic toxicity evaluation of the novel heterocyclic compound LQFM048.

    Science.gov (United States)

    Vinhal, Daniela C; de Ávila, Renato Ivan; Vieira, Marcelo S; Luzin, Rangel M; Quintino, Michelle P; Nunes, Liliane M; Ribeiro, Antonio Carlos Chaves; de Camargo, Henrique Santiago; Pinto, Angelo C; Dos Santos Júnior, Helvécio M; Chiari, Bruna G; Isaac, Vera; Valadares, Marize C; Martins, Tatiana Duque; Lião, Luciano M; de S Gil, Eric; Menegatti, Ricardo

    2016-08-01

    The new heterocyclic derivative LQFM048 (3) (2,4,6-tris ((E)-ethyl 2-cyano-3-(4-hydroxy-3-methoxyphenyl)acrylate)-1,3,5-triazine) was originally designed through the molecular hybridization strategy from Uvinul® T 150 (1) and (E)-ethyl 2-cyano-3-(4hydroxy-3-methoxyphenyl)acrylate (2) sunscreens, using green chemistry approach. This compound was obtained in global yields (80%) and showed an interesting redox potential. In addition, it is thermally stable up to temperatures around 250°C. It was observed that LQFM048 (3) showed a low degradation after 150min of sunlight exposure at 39°C, whereas the extreme radiation conditions induced a considerable photodegradation of the LQFM048 (3), especially when irradiated by VIS and VIS+UVA. During the determination of sun protection factor, LQFM048 (3) showed interesting results, specially as in association with other photoprotective compounds and commercial sunscreen. Additionally, the compound (3) did not promote cytotoxicity for 3T3 fibroblasts. Moreover, it was not able to trigger acute oral systemic toxicity in mice, being classified as a compound with low acute toxicity hazard (2.000mg/kg>LD50<5.000mg/kg). Therefore, this compound synthesized using green chemistry approach is promising showing potential to development of a new sunscreen product with advantage of presenting redox potential, indicating antioxidant properties.

  7. Evaluation of ATC as an Orally Administered Drug in Treatment of Cadmium Toxicity of Rat Organs

    Directory of Open Access Journals (Sweden)

    S. Nabilaldine Fatemi

    2009-01-01

    Full Text Available The effect of N-tetramethylene dithiocarbamate (ATC as a chelating agent on the excretion of cadmium was evaluated in cadmium-poisoned Wistar rats following administration through food and drink. The present research aimed to characterize the potential efficiency of ATC as an orally administered chelator drug after cadmium administration for 60 days. This chelator significantly enhanced the urinary and biliary excretion of cadmium and restored the altered levels of iron. Cadmium and iron concentrations in different tissues were determined by graphite furnace and flame atomic absorption spectrometry (GF AAS and F AAS methods, respectively. The chelation therapy results show that ATC is able to remove cadmium ions from different tissues while iron concentration returned to the normal level and the clinical symptoms were also reduced. In summary, we conclude that ATC is able to mobilize and promote the excretion of cadmium in rat organs and reduce the side effects and general symptoms of toxicity caused by cadmium and might be useful for preliminary testing of the efficacy of chelating agents in human body. However, these results should be confirmed in different experimental models before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for evaluating the efficiency of chelating agents in cadmium toxicity.

  8. The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse.

    Science.gov (United States)

    Molyneux, Gemma; Gibson, Frances M; Chen, Christabelle M; Marway, Harpal K; McKeag, Sean; Mifsud, Charles V J; Pilling, Andrew M; Whayman, Matthew J; Turton, John A

    2008-04-01

    Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

  9. Toxicidad oral a 60 días del aceite de sacha inchi (Plukenetia volubilis L. y linaza (Linum usitatissimum L. y determinación de la dosis letal 50 en roedores Oral toxicity at 60-days of sacha inchi oil (Plukenetia volubilis L. and linseed (Linum usitatissimum L., and determination of lethal dose 50 in rodents

    Directory of Open Access Journals (Sweden)

    Arilmi Gorriti

    2010-09-01

    Full Text Available Objetivos. Evaluar la toxicidad oral a 60 días y determinar la dosis letal 50 (DL 50 de los aceites crudos de sacha inchi (Plukenetia volubilis L. y linaza (Linum ussitatisimum en ratas Holtzman y en ratones cepa Balb C57, respectivamente. Materiales y métodos. Para la evaluación de la toxicidad oral a dosis repetida por 60 días se utilizó 24 ratas macho Holtzman divididos en tres grupos de ocho cada uno, los grupos fueron: solución salina fisiológica 4 mL/kg (SSF, aceite de sacha inchi 0,5 mL/kg (SI05 y aceite de linaza 0,5 mL/kg (L05, durante el experimento se controló semanalmente el peso corporal y signos de toxicidad en los grupos investigados, así como colesterol total, HDL, triglicéridos, glucosa, urea, TGP y fosfatasa alcalina a los 30 y 60 días de iniciado el experimento. Para la evaluación de la DL50 se usó ratones macho cepa Balb C57 en grupos de diez animales, se administró por vía oral dosis crecientes de aceites crudos hasta alcanzar 1 mL/kg (37 g/kg; Resultados. Los parámetros séricos en las ratas indican que no existe toxicidad alguna a los 60 días y que la administración de los aceites disminuyeron los niveles de colesterol, triglicéridos e incrementaron el HDL con respecto al grupo control. La DL50 muestra que los aceites crudos de sacha inchi y linaza presentan dosis por encima de los 37 g/kg de masa corporal. Conclusiones. Los aceites de sacha inchi y linaza son inocuos a 60 días y presentan una DL50 por encima de los 37 g/kg de animal.Objectives. To evaluate the oral toxicity at 60 days and to determine the lethal dose 50 (LD 50 of raw sacha inchi (Plukenetia volubilis L. and linseed (Linum ussitatisimum oils in Holtzman rats and mice of the strain Balb C57 respectively. Materials and methods. For the evaluation of the oral toxicity of repeated doses for 60 days, 24 male Holtzman rats were used, divided in three groups of 8 each, the groups were: physiologic saline solution 4 mL/kg (FSS, sacha inchi oil

  10. PRELIMINARY PHYTOCHEMICAL SCREENING AND ACUTE ORAL TOXICITY STUDY OF THE FLOWER OF PHLOGACANTHUS THYRSIFLORUS NEES IN ALBINO MICE

    Directory of Open Access Journals (Sweden)

    Chakravarty Sharmistha

    2012-04-01

    Full Text Available Medicinal plants contains a variety of chemical substances with important therapeutic properties that can be utilised in the treatment of human diseases. Phlogacanthus thyrsiflorus Nees of family Acanthaceae is used in folklore remedies for treatment of Cough, Bronchitis, Fever, Asthama, Cancer and many other ailments. The present investigation was carried out to assess the qualitative phytochemical analysis of aqueous extract of the flower of Phlogacanthus thyrsiflorus Nees. The phytochemical screening reveals the presence of Tannin, Saponin, Flavonoid, Steroid, Triterpenoid, Phenol. For Acute Oral Toxicity study aqueous extract of the flower was used. The Acute Oral Toxicity test showed no mortality upto 1000 mg/kg body weight. The presence of these phytochemicals reveals its medicinal properties and non toxic nature of the plant indicated the value of the plant as medicine. This result suggests that the flower of Phlogacanthus thyrsiflorus can be used to cure various ailments.

  11. Developmental toxicity of N-methylaniline following prenatal oral administration in rats

    Directory of Open Access Journals (Sweden)

    Krystyna Sitarek

    2016-06-01

    Full Text Available Objectives: The objective of the study was to assess prenatal toxicity of N-methylaniline (NMA administered by gavage to pregnant female rats. Material and Methods: Pregnant female rats were administered N-methylaniline in corn oil by gavage at daily doses of 0.8 mg/kg of body weight (b.w., 4 mg/kg b.w., 20 mg/kg b.w. and 100 mg/kg b.w. from implantation (the 5th day post mating to the day prior to the scheduled caesarean section (the 20th day of pregnancy. General behavior, body weight, food and water consumption, hematological, biochemical analyses and pathomorphological changes of the dams were recorded. Results: All the females survived until the end of the study. The test substance was toxic to pregnant females, even at the lowest of the used doses, i.e., 0.8 mg/kg b.w./day. Lower weight gain during pregnancy and significantly higher NMA-dose-dependent absolute weight of the organs were noted in the exposed females. The females from the groups exposed at doses of 20 mg/kg b.w./day and 100 mg/kg b.w./day developed anemia and showed higher concentrations of free thyroxine (FT3 and free triiodothyronine (FT4 thyroid hormones. Total protein concentration exhibited an increase in all the exposed groups of females. In the prenatal toxicity study, administration of N-methylaniline throughout the embryonic and fetal periods produced embryotoxic effects at doses ranging 4–100 mg/kg b.w./day. Conclusions: Considering the data obtained in this study, it is reasonable to assume that N-methylaniline administered orally to pregnant rats is toxic for mothers even at a low dose of 0.8 mg/kg b.w./day. However, this dose was not associated with any significant effects to their offspring. This prenatal exposure level may be considered as no-observed-adverse-effect level (NOAEL for the progeny and a dose of 4 mg/kg b.w./day as the lowest-observed-adverse-effect level (LOAEL for the progeny.

  12. Toxicokinetic assessment of methylphenidate (Ritalin) in a 13-week oral toxicity study in dogs.

    Science.gov (United States)

    Bakhtiar, Ray; Ramos, Luis; Tse, Francis L S

    2004-01-01

    Ritalin or methylphenidate (MPH) is often prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The therapeutic activity of MPH is principally due to D-threo-[2R,2'R]-MPH. Hence, in order to establish a kinetic relationship between doses and exposure levels in a non-rodent species, a 13-week oral (capsule) toxicity study of D-threo-[2R,2'R]-MPH was performed in beagle dogs. A previously reported chiral liquid chromatography tandem mass spectrometry (LC-MS/MS) with a limit of quantification (LLOQ) of 1.09 ng/ml was utilized. The results of this study indicated that MPH appeared to be rapidly absorbed in dogs following oral administration. The peak concentration was reached within 1-2 h. Based on the area under the curve (AUC) values, the plasma exposure of D-MPH was over-proportional to the dose. With the exception of two groups of animals (male/female, 7.5 mg/kg/day on day 1 and male/female, 3.0 mg/kg/day on week 7), the data showed no difference in MPH concentrations between the male and female dogs. Taking the statistical variations into account, concentrations of D-MPH that were observed after 7.5 mg/kg/day doses of D-MPH and 15 mg/kg/day doses of the racemate were similar. Following the racemate doses, the concentrations of L-MPH were consistently higher than those of the D-isomer. No accumulation of MPH was observed after 13 weeks of repeated daily administration.

  13. Evaluation of the subchronic toxicity of oral treatment with Chenopodium ambrosioides in mice.

    Science.gov (United States)

    Pereira, Wanderson S; Ribeiro, Bruno P; Sousa, Anildes I P; Serra, Izabel C P B; Mattar, Nadia S; Fortes, Thiare S; Reis, Aramys S; Silva, Lucilene A; Barroqueiro, Elizabeth S B; Guerra, Rosane N M; Nascimento, Flávia R F

    2010-02-17

    The leaves of Chenopodium ambrosioides L. (Chenopodiaceae) have been used by native people to treat many diseases. Recently, we showed that the treatment with small dose (5mg/kg) of hydroalcoholic extract (HE) from Chenopodium ambrosioides' leaves has immunestimulatory effects. The aim of this study was to investigate the subchronic toxicity of the oral treatment with this HE in preclinical assays. Swiss mice were divided into 4 groups (n=10/group). They received the HE daily at the doses of 5, 50 and 500 mg/kg by gavage during 15 days. The control group received only water. They were observed each hour for 24h and each day for 15 days, when the blood was collected. The serum was used to perform the biochemical analysis. The mice were then killed and the vital and lymphoid organs were collected and evaluated. There was neither death nor alterations in the body weight in the HE-treated groups, but there were alterations in the weight of some organs. There was an increase in the lymph node cells number in the highest two doses. The number of cells in the bone marrow was high in the HE-treated groups, but the number of peritoneal cells was smaller in the HE-treated groups when compared to the control. There was no alteration in the AST, but there was a reduction in the albumin levels in the HE500 group and in the triglycerides and VLDL in the highest doses. The subchronic treatment with HE induced punctual alterations in the groups treated with the highest doses. However, the HE treatment was not lethal and did not induce toxic alterations using the therapeutic dose, suggesting that it is safe to use this product in the adequate dose. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  14. Copper pellets simulating oral exposure to copper ammunition: Absence of toxicity in American kestrels (Falco sparverius)

    Science.gov (United States)

    Franson, J. Christian; Lahner, Lesanna L.; Meteyer, Carol U.; Rattner, Barnett A.

    2012-01-01

    To evaluate the potential toxicity of copper (Cu) in raptors that may consume Cu bullets, shotgun pellets containing Cu, or Cu fragments as they feed on wildlife carcasses, we studied the effects of metallic Cu exposure in a surrogate, the American kestrel (Falco sparverius). Sixteen kestrels were orally administered 5 mg Cu/g body mass in the form of Cu pellets (1.18–2.00 mm in diameter) nine times during 38 days and 10 controls were sham gavaged on the same schedule. With one exception, all birds retained the pellets for at least 1 h, but most (69%) regurgitated pellets during a 12-h monitoring period. Hepatic Cu concentrations were greater in kestrels administered Cu than in controls, but there was no difference in Cu concentrations in the blood between treated and control birds. Concentration of the metal-binding protein metallothionein was greater in male birds that received Cu than in controls, whereas concentrations in female birds that received Cu were similar to control female birds. Hepatic Cu and metallothionein concentrations in kestrels were significantly correlated. Histopathologic alterations were noted in the pancreas of four treated kestrels and two controls, but these changes were not associated with hepatic or renal Cu concentrations, and no lesions were seen in other tissues. No clinical signs were observed, and there was no treatment effect on body mass; concentrations of Cu, hemoglobin, or methemoglobin in the blood; or Cu concentrations in kidney, plasma biochemistries, or hematocrit. Based on the parameters we measured, ingested Cu pellets pose little threat to American kestrels (and presumably phylogenetically related species), although the retention time of pellets in the stomach was of relatively short duration. Birds expected to regurgitate Cu fragments with a frequency similar to kestrels are not likely to be adversely affected by Cu ingestion, but the results of our study do not completely rule out the potential for toxicity in

  15. Distribution, Metabolism and Toxic Effects of Beta-Cypermethrin in Lizards (Eremias argus) Following Oral Administration.

    Science.gov (United States)

    Chen, Li; Xu, Peng; Diao, Jinling; Di, Shanshan; Li, Ruiting; Zhou, Zhiqiang

    2016-04-01

    Beta-cypermethrin (BCYP), a synthetic pyrethriod (PYR) pesticide which is a mixture of the alpha- and theta- cypermethrin, have been reported various toxicological profiles to non-target organisms. But little is known about assimilation, accumulation and toxic effects of BCYP in reptiles. The present study firstly elucidated absorption, tissue distribution, excretion of BCYP in Eremias argus . Treated group were administered orally with BCYP 20mg/kg body weight (bw) dissolved in corn oil. Neurotoxicity was observed at 24h after gavage, and the poisoning symptom ameliorated at 72h. The changes of BCYP concentration depended on degradation time and tissues. Lizards had a strong capacity to eliminate BCYP with different tissue distribution. The tissues concentration of BCYP from high to low were intestine, stomach, heart, kidney, blood, lung, liver and brain. Bimodal phenomena were observed in lung, liver and kidney. These results may be due to the activities of enzymes, circadian rhythm, and enterohepatic circulation in lizards. Based on the results of organ coefficient and histopathology analysis in liver, the liver was confirmed as the main target organ.

  16. Ovarian Toxicity in Female Rats after Oral Administration of Melamine or Melamine and Cyanuric Acid.

    Science.gov (United States)

    Sun, Jiarui; Zhang, Xinchen; Cao, Yinan; Zhao, Qiling; Bao, Endong; Lv, Yingjun

    2016-01-01

    Although the toxicity of melamine to the kidneys and testes is well known, few studies have investigated the effects of melamine on female reproductive organs. Therefore, this study explores the effects of oral administration melamine or melamine and cyanuric acid for 28 days on the ovaries of female rats. Rats that were exposed to the mixture exhibited reduced ovarian and uterine weights, a shorter estrous cycle, and reduced serum estrogen and progesterone levels compared to rats that were exposed to melamine and control rats. Furthermore, morphological analysis revealed pathological changes in the ovaries of rats exposed to melamine or the mixture, such as more atretic follicles and necrosis of oocytes and granulosa cells. TUNEL staining revealed that the exposed groups had a higher proportion of TUNEL-positive granulosa cells than the control group, and the mRNA expressions of SOD1, GPX1, GPX2, P450scc, 17β-HSD I, and 17β-HSD II were reduced in the exposure groups compared with the control group. These results indicated that exposure to melamine alone or to the melamine-cyanuric acid mixture could damage the ovaries in rats.

  17. Acute Oral Toxicity Studies of Ethanol Leaf Extracts Of Derris Scandens & Pulicaria Wightiana In Albino Rats

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    Vidya Sabbani

    2015-02-01

    Full Text Available Objective: The present study was designed to find out LD50 and to ascertain the safety of ethanol extracts of leaves of Derris scan dens and Pulicaria wightiana by acute oral toxicity study in female rats as per OECD guideline 425.Methods: Rats were sequentially administered with ethanol leaf extracts of Derris scandens (Ds & Pulicaria wightiana(Pw  in single dosages of 175, 550, and 2000 mg/kg of body weight. All the animals were individually studied for mortality, wellness parameters and body weight for 14 days.Results: No mortality and no significant changes were observed in body weight and wellness parameters at 175, 550 and 2000 mg/kg body wt. doses of both Derris scandens and Pulicaria wightiana , which reveal the safety of these plants  in the doses up to 2000 mg/kg body weight.Conclusion: Conclusively, LD50 value of ethanol extracts of leaves of Derris scandens and Pulicaria wightiana were found to be more than 2000 mg/kg body weight.

  18. Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice

    OpenAIRE

    KIM, SEONG-KWAN; Shin, Soo-Jeong; YOO, YOHAN; KIM, NA-HYUN; KIM, DONG-SOON; Zhang, Dan; PARK, JIN-A; Yi, Hee; Kim, Jin-Suk; Shin, Ho-Chul

    2015-01-01

    An oral toxicity study of several pregnancy category X drugs was performed in female ICR mice. The drugs were administered orally once daily for 3 days at doses of 1, 10 and 100 ?g/kg for isotretinoin; 6.7, 67 and 670 ?g/kg for misoprostol; 83, 830 and 8,300 ?g/kg for methotrexate; 3.3, 33 and 330 ?g/kg for mifepristone; and 25, 250 and 2,500 ?g/kg for levonorgestrel. During the test period, clinical signs, mortality, body weight, hematology, serum biochemistry and necropsy findings were exam...

  19. Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis.

    Science.gov (United States)

    Mogensen, Stine; Sverrisdóttir, Eva; Sveinsdóttir, Kolbrún; Treldal, Charlotte; Jensen, Kenneth; Jensen, Anders Bonde; Kristensen, Claus Andrup; Jacobsen, Jette; Kreilgaard, Mads; Petersen, Janne; Andersen, Ove

    2017-01-01

    The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed-effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1-2 and three times higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25-mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit.

  20. Evaluation of the sub–acute oral toxic effect of methanol extract of Clinacanthus nutans leaves in rats

    Directory of Open Access Journals (Sweden)

    Xiu Wen P'ng

    2013-01-01

    Conclusions: For conclusion, repeatedly dosing of C. nutans extract at 0.3g/kg, 0.6g/kg and 0.9 g/kg up to 14 d was proven safe in male SD rats without causing any adverse effects and organ damages in male SD rats.

  1. Toxicological risk assessment of elemental gold following oral exposure to sheets and nanoparticles – A review

    DEFF Research Database (Denmark)

    Hadrup, Niels; Sharma, Anoop Kumar; Poulsen, Morten

    2015-01-01

    Elemental gold is used as a food coloring agent and in dental fillings. In addition, gold nanoparticles are gaining increasing attention due to their potential use as inert carriers for medical purposes. Although elemental gold is considered to be inert, there is evidence to suggest the release...... of gold ions from its surface. Elemental gold, or the released ions, is, to some extent, absorbed in the gastrointestinal tract. Gold is distributed to organs such as the liver, heart, kidneys and lungs. The main excretion route of absorbed gold is through urine. Data on the oral toxicity of elemental...... gold is limited. The acute toxicity of elemental gold seems to be low, as rats were unaffected by a single dose of 2000mg nanoparticles/kg of body weight. Information on repeated dose toxicity is very limited. Skin rashes have been reported in humans following the ingestion of liquors containing gold...

  2. Acute and Subchronic Toxicity Study of Euphorbia hirta L. Methanol Extract in Rats

    Directory of Open Access Journals (Sweden)

    Kwan Yuet Ping

    2013-01-01

    Full Text Available Despite Euphorbia hirta L. ethnomedicinal benefits, very few studies have described the potential toxicity. The aim of the present study was to evaluate the in vivo toxicity of methanolic extracts of E. hirta. The acute and subchronic oral toxicity of E. hirta was evaluated in Sprague Dawley rats. The extract at a single dose of 5000 mg/kg did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. Therefore, the LD 50 of this plant was estimated to be more than 5000 mg/kg. In the repeated dose 90-day oral toxicity study, the administration of 50 mg/kg, 250 mg/kg, and 1000 mg/kg/day of E. hirta extract per body weight revealed no significant difference (P>0.05 in food and water consumptions, body weight change, haematological and biochemical parameters, relative organ weights, and gross findings compared to the control group. Macropathology and histopathology examinations of all organs including the liver did not reveal morphological alteration. Analyses of these results with the information of signs, behaviour, and health monitoring could lead to the conclusion that the long-term oral administration of E. hirta extract for 90 days does not cause sub-chronic toxicity.

  3. Acute and subchronic toxicity study of Euphorbia hirta L. methanol extract in rats.

    Science.gov (United States)

    Yuet Ping, Kwan; Darah, Ibrahim; Chen, Yeng; Sreeramanan, Subramaniam; Sasidharan, Sreenivasan

    2013-01-01

    Despite Euphorbia hirta L. ethnomedicinal benefits, very few studies have described the potential toxicity. The aim of the present study was to evaluate the in vivo toxicity of methanolic extracts of E. hirta. The acute and subchronic oral toxicity of E. hirta was evaluated in Sprague Dawley rats. The extract at a single dose of 5,000 mg/kg did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. Therefore, the LD 50 of this plant was estimated to be more than 5,000 mg/kg. In the repeated dose 90-day oral toxicity study, the administration of 50 mg/kg, 250 mg/kg, and 1,000 mg/kg/day of E. hirta extract per body weight revealed no significant difference (P > 0.05) in food and water consumptions, body weight change, haematological and biochemical parameters, relative organ weights, and gross findings compared to the control group. Macropathology and histopathology examinations of all organs including the liver did not reveal morphological alteration. Analyses of these results with the information of signs, behaviour, and health monitoring could lead to the conclusion that the long-term oral administration of E. hirta extract for 90 days does not cause sub-chronic toxicity.

  4. Toxic effects of oral 2-amino-4,6-dinitrotoluene in the Western fence lizard (Sceloporus occidentalis)

    Energy Technology Data Exchange (ETDEWEB)

    McFarland, Craig A., E-mail: craig.a.mcfarland@us.army.mi [US Army Public Health Command (Prov), Aberdeen Proving Ground, MD 21010 (United States); Quinn, Michael J. [US Army Public Health Command (Prov), Aberdeen Proving Ground, MD 21010 (United States); Boyce, John [Biotechnics, LLC, Hillsborough, NC 27278 (United States); LaFiandra, Emily M.; Bazar, Matthew A. [US Army Public Health Command (Prov), Aberdeen Proving Ground, MD 21010 (United States); Talent, Larry G. [Oklahoma State University, Department of Natural Resource Ecology and Management, Stillwater, OK 74078 (United States); Johnson, Mark S. [US Army Public Health Command (Prov), Aberdeen Proving Ground, MD 21010 (United States)

    2011-02-15

    The compound 2-amino-4,6-dinitrotoluene (2A-DNT) was evaluated under laboratory conditions in the Western fence lizard (Sceloporus occidentalis) to assess the potential for reptile toxicity. Oral LD{sub 50} values were 1406 and 1867 mg/kg for male and female lizards, respectively. Based on responses from a 14-day subacute study, a 60-day subchronic experiment followed where lizards were orally dosed at 0, 5, 15, 20, 25, 30 mg/kg-d. At day 60, number of days and survivors, food consumption, and change in body weight were inversely related to dose. Signs of toxicity were characterized by anorexia and generalized cachexia. Significant adverse histopathology was observed in hepatic tissue at {>=}15 mg/kg-d, consistent with hepatocellular transdifferentiation. Based on survival, loss of body weight, diminished food intake, changes in liver, kidney, and testes, and increased blood urea nitrogen, these data suggest a LOAEL of 15 mg/kg-d and a NOAEL of 5 mg/kg-d in S. occidentalis. - Research highlights: Oral LD{sub 50} (mg/kg) values were 1406 for male and 1867 for female lizards. Dose-dependent hepatocellular transdifferentiation was observed at {>=}5 mg/kg-d. Chromaturia in 2A-DNT and the parent TNT suggest biomarkers of exposure and effect. Health effects of metabolites support comprehensive ecological risk assessments. - The Western fence lizard (Sceloporus occidentalis) is a suitable reptile model for assessing the toxicity of energetic compounds and their metabolites.

  5. Assessment of Acute Oral and Dermal Toxicity of 2 Ethyl-Carbamates with Activity against Rhipicephalus microplus in Rats

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    María Guadalupe Prado-Ochoa

    2014-01-01

    Full Text Available The acute oral and dermal toxicity of two new ethyl-carbamates (ethyl-4-bromophenyl-carbamate and ethyl-4-chlorophenyl-carbamate with ixodicide activity was determined in rats. The oral LD50 of each carbamate was 300 to 2000 mg/kg, and the dermal LD50 of each carbamate was >5000 mg/kg. Clinically, the surviving rats that had received oral doses of each carbamate showed decreased weight gain (P<0.05 and had slight nervous system manifestations. These clinical signs were evident from the 300 mg/kg dose and were reversible, whereas the 2000 mg/kg dose caused severe damage and either caused their death or was motive for euthanasia. At necropsy, these rats had dilated stomachs and cecums with diffuse congestion, as well as moderate congestion of the liver. Histologically, the liver showed slight degenerative lesions, binucleated hepatocytes, focal coagulative necrosis, and congestion areas; the severity of the lesions increased with dosage. Furthermore, an slight increase in gamma-glutamyltransferase, lactate dehydrogenase, and creatinine was observed in the plasma. The dermal application of the maximum dose (5000 mg/kg of each carbamate did not cause clinical manifestations or liver and skin alterations. This finding demonstrates that the carbamates under study have a low oral hazard and low acute dermal toxicity.

  6. Evaluation of the antinociceptive activity and acute oral toxicity of standardized ethanolic extract of the rhizome of Curcuma xanthorrhiza Roxb.

    Science.gov (United States)

    Devaraj, Sutha; Esfahani, Azadeh Sabetghadam; Ismail, Sabariah; Ramanathan, Surash; Yam, Mun Fei

    2010-04-22

    Ethanolic extract of Curcuma xanthorrhiza was used to evaluate the analgesic and toxicity effects in vivo. The extract was standardized using GC-MS, which showed that 1 mg of Curcuma xanthorrhiza ethanolic extract contains 0.1238 mg of xanthorrhizol. The analgesic activity was studied in rats using three different models, namely the hot plate test, tail flick test and formalin-induced pain test. The acute oral toxicity was examined by the oral administration of standardized Curcuma xanthorrhiza ethanolic extract in mice at doses ranging from 300-5,000 mg/kg and observation for 14 days. Standardized Curcuma xanthorrhiza ethanolic extract did not show significant analgesic effect in the hot plate and tail flick tests. However, in the formalin-induced pain test, Curcuma xanthorrhiza ethanolic extract significantly (P Curcuma xanthorrhiza ethanolic extract did not show any toxic effects in mice at 5 g/kg. These experimental results suggest that the standardized Curcuma xanthorrhiza ethanolic extract showed peripheral and central antinociceptive activity associated with neurogenic pain as well as a relative absence of toxic effects which could compromise the medicinal use of this plant in folk medicine.

  7. In vitro anti oxidant activity and acute oral toxicity of Terminalia paniculata bark ethanolic extract on Sprague Dawley rats

    Institute of Scientific and Technical Information of China (English)

    Ramgopal Mopuri; Balaji Meriga

    2014-01-01

    Objective: To ensure the safety and evaluate the anti oxidant activity of Terminalia paniculata (T.paniculata) ethanolic extract in Sprague Dawley rats. Methods: The solvent extracts (hexane, ethyl acetate and ethanol) of T. paniculata were subjected to phytochemical analysis and their DPPH radical scavenging activity was assayed. The oral acute toxicity was evaluated using ethanolic extract of T. paniculata. Results:Ethyl acetate and ethanolic extracts showed more phytochemicals, whereas highest DPPH scavenging activity was found in ethanolic extract. In an acute toxicity study, T. paniculata ethanolic extract was orally administered (1 000 mg/kg body weight) to rats and observed for 72 h for any toxic symptoms and the dose was continued up to 14 d. On the 15th day rats were sacrificed and blood samples were collected from control and test animals and analyzed for some biochemical parameters. We did not observe any behavioral changes in test groups in comparison with their controls. Also, there were no significant alterations in biochemical, hematological (hemoglobin content and blood cells count) and liver function parameters such as serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, alkaline phosphatase, total proteins, albumin and bilirubin levels between T. paniculata ethanolic extract treated and normal control groups. Conclusions:Together our results demonstrated that T. paniculata ethanolic possessed potent antioxidant activity and it was safer and non toxic to rats even at higher doses and therefore could be well considered for further investigation for its medicinal and therapeutic efficacy.

  8. Subchronic oral toxicity study with regular and enzymatically depolymerized sodium carboxymethylcellulose in rats.

    Science.gov (United States)

    Bär, A; Til, H P; Timonen, M

    1995-11-01

    Enzymatically depolymerized sodium carboxymethylcellulose (CMC-ENZ) is a new functional food ingredient which has a lower molecular weight and viscosity than regular sodium carboxymethylcellulose (CMC). Both compounds are known not to be absorbed to a significant extent, and the human safety of CMC as a thickening agent and stabilizer in food is well established. In the present study, the subchronic oral toxicity of CMC-ENZ was examined and compared with that of CMC in Wistar rats. Seven groups of 20 rats/sex were fed diets with 0 (controls), 2.5, 5 and 10% CMC and 2.5, 5 and 10% CMC-ENZ for a 3-month period. There was only one death that was unrelated to the treatment. Water intake, urine production and urinary sodium excretion increased with increasing doses of CMC and CMC-ENZ due to their sodium content of about 7-8%. The treatment-related occurrence of diarrhoea and caecal enlargement in the mid- and high-dose groups, a slight increase of plasma alkaline phosphatase, and increased urinary calcium and citrate excretions were considered to be generic effects that typically are observed in rodent studies with low digestible carbohydrates. The increased occurrence of nephrocalcinosis and hyperplasia of the urothelial epithelium in some of the treated groups was interpreted as an indirect consequence of a more alkaline urine coupled with an increased calcium excretion. As the frequency and severity of all these changes did not differ between corresponding CMC and CMC-ENZ dose groups, it is concluded that the two products have a similar toxicological profile.

  9. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients

    NARCIS (Netherlands)

    Brand, W.; Schutte, M.E.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2006-01-01

    The transcellular transport of ingested food ingredients across the intestinal epithelial barrier is an important factor determining bioavailability upon oral intake. This transcellular transport of many chemicals, food ingredients, drugs or toxic compounds over the intestinal epithelium can be high

  10. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients

    NARCIS (Netherlands)

    Brand, W.; Schutte, M.E.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2006-01-01

    The transcellular transport of ingested food ingredients across the intestinal epithelial barrier is an important factor determining bioavailability upon oral intake. This transcellular transport of many chemicals, food ingredients, drugs or toxic compounds over the intestinal epithelium can be high

  11. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group.

    Science.gov (United States)

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  12. Efficacy and toxicity of an accelerated hypofractionated radiation therapy protocol in cats with oral squamous cell carcinoma.

    Science.gov (United States)

    Poirier, Valérie J; Kaser-Hotz, Barbara; Vail, David M; Straw, Rodney C

    2013-01-01

    Squamous cell carcinoma (SCC) is the most common feline oral tumor. Standard radiation protocols have been reported to achieve tumor control durations of 1.5-5.5 months (45-165 days). The purpose of this study was to describe the efficacy and toxicity of an accelerated hypofractionated radiation therapy protocol in cats with oral SCC. Twenty-one cats with histologically confirmed oral SCC and T1-3N0M0 were treated with 10 once-daily fractions (Monday-Friday) of 4.8 Gy. Seventeen cats had macroscopic disease and four were microscopic after incomplete excision. Acute toxicity consisted of grade 2 mucositis in all cats and this was effectively managed using esophageal or gastric tube feeding, pain medication, and antibiotics. Late toxicity effects for cats with available follow-up data included alopecia (4 cats), leukotricia (6), tongue ulceration (1), and oronasal fistula (1). Response could be assessed in 17 cats (seven complete response and five partial response). Four cats (19%) developed metastatic disease without evidence of local progression. The median progression-free survival (PFS) was 105 days (1 year PFS of 23%), median local progression-free survival (LPFS) was 219 days (1 year LPFS of 41%), and median overall survival (OS) was 174 days (1 year OS of 29%). Only tumor stage was prognostic, with T1 having a median PFS of 590 days. Findings indicated that this accelerated hypofractionated radiation therapy protocol was well tolerated in cats with oral SCC, with manageable adverse events. Tumor response was observed in most cats and long tumor control durations were achieved in some cats.

  13. Safety evaluation of Morinda citrifolia (noni leaves extract: assessment of genotoxicity, oral short term and subchronic toxicity

    Directory of Open Access Journals (Sweden)

    Alicia Lagarto

    2013-02-01

    Full Text Available Morinda citrifolia L (noni is an evergreen or small tree that grows in many tropical regions of the world. The use of the noni leaves has not been so studied however; there are reports of its pharmacological benefits. Aims: The objective of this investigation was to assess the genotoxicity, short-term, and subchronic oral toxicity of Morinda citrifolia L leaves aqueous extract. Methods: The genotoxicity of the M. citrifolia extract was investigated by measuring the frequency of micronuclei in mice bone marrow cells. The animals were treated with three doses of the extract (500, 1000, and 2000 mg/kg. For short-term toxicity, both sexes Wistar rats received 1000 mg/kg/day for 28 days. Animals were sacrificed for hematological and biochemical evaluation. For the subchronic study, Wistar rats were administered with three doses of M. citrifolia extract (100, 300, and 1000 mg/kg by oral route for 90 days. Mortalities, clinical signs, body weight changes, food and water consumption, hematological and biochemical parameters, gross findings, organ weights, and histological examination were monitored during the study period. Results: Genotoxicity and short-term toxicity test resulted in absence of toxicity at doses between 500 and 2000 mg/kg. Significant differences were observed in hemoglobin, and differential leukocyte count after subchronic dosing of the extract. Histology evaluation did not reveal treatment-related abnormalities. Variations observed were within to normal range and reversible. Conclusions: In summary, 1000 mg/kg orally was the NOAEL for M. citrifolia extract for effects other than transient variations in some hematological parameters within normal range. [J Intercult Ethnopharmacol 2013; 2(1.000: 15-22

  14. Sub-chronic (13-week) oral toxicity study in rats with recombinant human lactoferrin produced in the milk of transgenic cows

    NARCIS (Netherlands)

    Appel, M.J.; Veen, H.A. van; Vietsch, H.; Salaheddine, M.; Nuijens, J.H.; Ziere, B.; Loos, F. de

    2006-01-01

    The oral toxicity of recombinant human lactoferrin (rhLF) produced in the milk of transgenic cows was investigated in Wistar rats by daily administration via oral gavage for 13 consecutive weeks, 7 days per week. The study used four groups of 20 rats/sex/dose. The control group received physiologica

  15. Thirteen-week oral dose toxicity study of Oligonol containing oligomerized polyphenols extracted from lychee and green tea.

    Science.gov (United States)

    Kitadate, Kentaro; Homma, Kohei; Roberts, Ashley; Maeda, Takahiro

    2014-02-01

    Oligonol is a functional food containing catechin-type monomers and proanthocyanidin oligomer converted from polymer forms via a novel manufacturing process. The catechin component of green tea extract has been associated with nasal toxicity in rats following subchronic exposure. To assess the potential for Oligonol to induce nasal toxicity a 13-week repeated oral dose toxicity study was conducted in rats using doses of 100, 300, and 1000 mg/kg/d. Clinical signs and mortality were not affected by Oligonol treatment. Compound-colored stools and an increase in food consumption were observed in some treated groups; however, there were no treatment-related differences in terminal body weights or with respect to the results of the gross postmortem examinations. Histopathological evaluation of the nasal cavity tissues revealed no treatment-related lesions. The results from this toxicity study indicate that Oligonol does not induce nasal toxicity and further supports the results of previous studies demonstrating the safety of Oligonol for human consumption.

  16. Acute toxicity of some synthetic cyanogens in rats and their response to oral treatment with alpha-ketoglutarate.

    Science.gov (United States)

    Bhattacharya, R; Satpute, R M; Hariharakrishnan, J; Tripathi, H; Saxena, P B

    2009-09-01

    Oral toxicity of several cyanogens and their reversal by alpha-ketoglutarate (A-KG; oral) were studied in rats. LD(50) of acetonitrile (ATCN), acrylonitrile (ACN), malononitrile (MCN), propionitrile (PCN), sodium nitroprusside (SNP), and succinonitrile (SCN) was 4891, 143.3, 69.8, 122.9, 69.8 and 488.7 mg/kg, respectively while the protection index of A-KG (ratio of LD(50) of cyanogens in the presence or absence of A-KG) was>2.0 against MCN (7.6), PCN (2.7) and SNP (3.6) only. We further studied the efficacy of A-KG against acute toxicity of these three cyanogens (0.75 LD(50)) on various hematological and biochemical variables in blood and soft tissues 24h post-exposure. We observed increase in white blood cells (SNP), plasma alanine (PCN, SNP) and aspartate (PCN) aminotransferase, lactate dehydrogenase (MCN, PCN, SNP), Na(+) (MCN, PCN) and cyanide (PCN), and decrease in K(+) (MCN, SNP) accompanied by an increase in brain, kidney and liver malondialdehyde (PCN), decrease in brain glutathione peroxidase, glutathione reductase (PCN, SNP), reduced glutathione (MCN, PCN, SNP) and cytochrome oxidase (PCN), liver rhodanese (PCN, SNP), and kidney cytochrome oxidase (PCN). The study indicates that (i) PCN was most toxic among all the cyanogens and (ii) beside cyanide, A-KG could be considered as an effective antidote for cyanogens.

  17. Technetium-99m-labeled deoxynivalenol from Fusarium mycotoxin alters organ toxicity in BALB/c mice by oral and intravenous route

    Directory of Open Access Journals (Sweden)

    P Chattopadhyay

    2012-01-01

    Full Text Available The toxicity of deoxynivalenol, both intravenously and orally, was investigated in male and female BALB/c mice. Technetium-99m (99m Tc-labeled deoxynivalenol was administered to mice by tail vein injection and orally dosed. Distribution of labeled deoxynivalenol at 26 hours was monitored by gamma-scintigraphy. In the evaluated organs, the accumulation of radioactive deoxynivalenol was correlated with the amount of radioactivity. In addition, the toxicity of deoxynivalenol was measured by biochemical assays followed by histopathological findings. Kidney and hepatic marker enzymes were significantly increased in intravenously administered deoxynivalenol as compared to orally treated mice. Intravenously treated mice showed severe damage in liver and kidney when compared to those orally exposed. Biodistribution of 99mTc-labeled deoxynivalenol differed between oral and intravenous treatment. In intravenously exposed mice, deoxynivalenol was distributed primarily in the liver and kidney whereas in oral exposure, it was found in the stomach and intestines after 26 hours. Deoxynivalenol toxicity, associated with its biodistribution and organ toxicity, was greatest where it had accumulated. The results show that the toxicity of deoxynivalenol is associated with organ accumulation.

  18. Technetium-99m-labeled deoxynivalenol from Fusarium mycotoxin alters organ toxicity in BALB/c mice by oral and intravenous route

    Energy Technology Data Exchange (ETDEWEB)

    Chattopadhyay, P; Pandey, A; Goyary, D; Chaurasia, A; Singh, L; Veer, V. [Division of Pharmaceutical Technology, Defence Research Laboratory, Assam (India); Department of Life Sciences, Defense Research Development and Organization, New Delhi (India)

    2012-07-01

    The toxicity of deoxynivalenol, both intravenously and orally, was investigated in male and female BALB/c mice. Technetium-99m ({sup 99m} Tc)-labeled deoxynivalenol was administered to mice by tail vein injection and orally dosed. Distribution of labeled deoxynivalenol at 26 hours was monitored by gamma scintigraphy. In the evaluated organs, the accumulation of radioactive deoxynivalenol was correlated with the amount of radioactivity. In addition, the toxicity of deoxynivalenol was measured by biochemical assays followed by histopathological findings. Kidney and hepatic marker enzymes were significantly increased in intravenously administered deoxynivalenol as compared to orally treated mice. Intravenously treated mice showed severe damage in liver and kidney when compared to those orally exposed. Biodistribution of {sup 99m}Tc-labeled deoxynivalenol differed between oral and intravenous treatment. In intravenously exposed mice, deoxynivalenol was distributed primarily in the liver and kidney whereas in oral exposure, it was found in the stomach and intestines after 26 hours. Deoxynivalenol toxicity, associated with its biodistribution and organ toxicity, was greatest where it had accumulated. The results show that the toxicity of deoxynivalenol is associated with organ accumulation. (author)

  19. Acute Toxicity of Fengshigubi Oral Liquid%风湿骨痹口服液急性毒性研究

    Institute of Scientific and Technical Information of China (English)

    辛玲歌

    2014-01-01

    目的:观察小鼠灌胃风湿骨痹口服液的急性毒性反应,测定半数致死量( LD50)及最大给药量,为临床安全用药提供依据。方法小鼠给予风湿骨痹口服液灌胃,通过预试验测定 LD50及最大给药量。结果 LD50未测出;小鼠最大给药量为1236 g生药/kg,相当于临床人用量的1799倍,在此剂量下灌胃对小鼠无急性毒性反应。结论风湿骨痹口服液毒性较低,在临床规定用法用量下安全可靠。%Objective To observe the acute toxicity reaction of Fengshigubi Oral Liquid by gastric gavage in mice,and to determine LD50 and the maximum dosage to provide the basis for clinical safe medication. Methods The mice were given Fengshigubi Oral Liq-uid by gastric gavage. The median lethal dose( LD50) and the maximum dose were determined by the pre-experiment. Results LD50 was not detected out and the maximum dose in mice was 1 236 g crude drug/kg,which was equivalent to 1 799 times of human dosage in clinic,the gastric gavage of this dose had no acute toxicity in mice. Conclusion Fengshigubi Oral Liquid has low toxicity and it is safe under the clinical provision of usage and dosage.

  20. Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model.

    Science.gov (United States)

    Sivak, Olena; Gershkovich, Pavel; Lin, Molly; Wasan, Ellen K; Zhao, Jinying; Owen, David; Clement, John G; Wasan, Kishor M

    2011-08-08

    The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

  1. Tropically stable novel oral lipid formulation of amphotericin B (iCo-010: biodistribution and toxicity in a mouse model

    Directory of Open Access Journals (Sweden)

    Owen David

    2011-08-01

    Full Text Available Abstract Background The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010. Methods BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone® 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. Results The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone® resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone® treatment induced necrotic changes in hepatic and kidney tissues. Conclusions Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

  2. Subacute and Reproductive Oral Toxicity Assessment of the Hydroethanolic Extract of Jacaranda decurrens Roots in Adult Male Rats

    Directory of Open Access Journals (Sweden)

    Joyce Alencar Santos

    2013-01-01

    Full Text Available Jacaranda decurrens subsp. symmetrifoliolata Farias & Proença (Bignoniaceae is a species traditionally used for the treatment of inflammatory and infectious diseases. Previous findings from our group reported scientifically that J. decurrens has anti-inflammatory efficacy. However, more toxicological studies are needed to support and ensure its safe use. The present study was carried out to evaluate the toxic effects of a prolonged treatment with hydroethanolic root extract of J. decurrens (EJD on hematological, biochemical, and reproductive parameters in adult male rats. The animals received by oral gavage 0; 250; 500; or 1000 mg/kg body weight of EJD for 28 days. After the treatment, biochemical, hematological, histopathological, and reproductive parameters were analyzed. The EJD treatment did not cause adverse effects on body weight gain, feed and water consumption, hematological and biochemical profiles, or histopathological analysis of liver and kidney. Similarly, there were no statistically significant differences in reproductive parameters, such as sperm production, number of sperm in the epididymis, and sperm morphology. These results demonstrate the absence of subacute toxicity as a result of the oral treatment with EJD for 28 days in adult male rats. However, other studies should be performed to evaluate the total safety of this plant.

  3. A Quantitative Structure Activity Relationship for acute oral toxicity of pesticides on rats: Validation, domain of application and prediction.

    Science.gov (United States)

    Hamadache, Mabrouk; Benkortbi, Othmane; Hanini, Salah; Amrane, Abdeltif; Khaouane, Latifa; Si Moussa, Cherif

    2016-02-13

    Quantitative Structure Activity Relationship (QSAR) models are expected to play an important role in the risk assessment of chemicals on humans and the environment. In this study, we developed a validated QSAR model to predict acute oral toxicity of 329 pesticides to rats because a few QSAR models have been devoted to predict the Lethal Dose 50 (LD50) of pesticides on rats. This QSAR model is based on 17 molecular descriptors, and is robust, externally predictive and characterized by a good applicability domain. The best results were obtained with a 17/9/1 Artificial Neural Network model trained with the Quasi Newton back propagation (BFGS) algorithm. The prediction accuracy for the external validation set was estimated by the Q(2)ext and the root mean square error (RMS) which are equal to 0.948 and 0.201, respectively. 98.6% of external validation set is correctly predicted and the present model proved to be superior to models previously published. Accordingly, the model developed in this study provides excellent predictions and can be used to predict the acute oral toxicity of pesticides, particularly for those that have not been tested as well as new pesticides.

  4. Toxicity profiling of water contextual zinc oxide, silver, and titanium dioxide nanoparticles in human oral and gastrointestinal cell systems.

    Science.gov (United States)

    Giovanni, Marcella; Tay, Chor Yong; Setyawati, Magdiel Inggrid; Xie, Jianping; Ong, Choon Nam; Fan, Rongli; Yue, Junqi; Zhang, Lifeng; Leong, David Tai

    2015-12-01

    Engineered nanoparticles (ENPs) are increasingly detected in water supply due to environmental release of ENPs as the by-products contained within the effluent of domestic and industrial run-off. The partial recycling of water laden with ENPs, albeit at ultra-low concentrations, may pose an uncharacterized threat to human health. In this study, we investigated the toxicity of three prevalent ENPs: zinc oxide, silver, and titanium dioxide over a wide range of concentrations that encompasses drinking water-relevant concentrations, to cellular systems representing oral and gastrointestinal tissues. Based on published in silico-predicted water-relevant ENPs concentration range from 100 pg/L to 100 µg/L, we detected no cytotoxicity to all the cellular systems. Significant cytotoxicity due to the NPs set in around 100 mg/L with decreasing extent of toxicity from zinc oxide to silver to titanium dioxide NPs. We also found that noncytotoxic zinc oxide NPs level of 10 mg/L could elevate the intracellular oxidative stress. The threshold concentrations of NPs that induced cytotoxic effect are at least two to five orders of magnitude higher than the permissible concentrations of the respective metals and metal oxides in drinking water. Based on these findings, the current estimated levels of NPs in potable water pose little cytotoxic threat to the human oral and gastrointestinal systems within our experimental boundaries.

  5. Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis

    Directory of Open Access Journals (Sweden)

    Donald Albert

    2013-05-01

    Full Text Available Introduction: There are few reports summarizing the effectiveness of oral and intravenous (IV acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L when treated with oral and IV acetylcysteine.Methods: Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment.Results: We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity.Conclusion: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration. [West J Emerg Med. 2013;14(3:218–226.

  6. A Study on the Single-dose Oral Toxicity of Super Key in Sprague-Dawley Rats

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    Jinhee Kim

    2015-09-01

    Full Text Available Objectives: This study was performed to analyze the single-dose oral toxicity of the super key (processed sulfur. Methods: All experiments were conducted at Medvill, an institution authorized to perform non-clinical studies, under the Good Laboratory Practice (GLP regulations. In order to investigate the oral toxicity of super key We administered it orally to Sprague-Dawley (SD rats. The SD rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of super key 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg were administered to the experimental groups, and a dose of normal saline solution, 10 mL/kg, was administered to the control group. We examined the survival rates, weights, clinical signs, gross findings and necropsy findings. This study was conducted under the approval of the Institutional Animal Ethics Committee. (Approval number: A01-14018. Results: No deaths or abnormalities occurred in any of the four groups. Although slight decreases in the weights of some female rats were noted, no significant changes in weights or differences in the gross findings between the control group and the experimental groups were observed. To check for abnormalities in organs, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs. Conclusion: The results of this research showed that administration of 500 ─ 2,000 mg/kg of super key did not cause any changes in the weights or in the results of necropsy examinations. Neither did it result in any mortalities. The above findings suggest that treatment with super key is relatively safe. Further studies on this subject are needed to yield more concrete evidence.

  7. The Acute Oral Toxicity of Black Garlic%黑蒜经口急性毒性试验研究

    Institute of Scientific and Technical Information of China (English)

    王月明; 刘宇峰; 马若波; 韩秋菊

    2015-01-01

    The acute oral toxicity of black garlic was tested based on "Health Food Inspection and Evaluation of Technical Specifications" by the People's Republic of China Ministry of Health. The Kunming mice was administered intragastrically with black garlic at a dose of 20 000mg/kg twice within 24 hours. Mice had no toxicity symptom and no death within 14 days, the results showed that the MTD of acute toxic test was higher than the dosage of 20 000 mg/kg. Conclusion: the black garlic is an actually nonpoisonous material.%为研究黑蒜的经口急性毒性,按中华人民共和国卫生部《保健食品检验与评价技术规范》规定的方法。将黑蒜于24h 内两次经口灌胃给予昆明种小鼠20000 mg/kg·BW,对小鼠的生存状态进行观察和记录14d。在14d 观察期内,未见小鼠有任何中毒症状,更无死亡,表明黑蒜对昆明种小鼠的经口急性毒性剂量大于20000mg/kg·BW。说明黑蒜属实际无毒物质。

  8. Intensive cisplatin/oral etoposide for epithelial ovarian cancer: the Cambridge Gynae-Oncology Centre experience: too toxic for relapse?

    Science.gov (United States)

    Gounaris, Ioannis; Iddawela, Mahesh; Parkinson, Christine; Pratt, Jennie; Hatcher, Helen; Basu, Bristi; Tan, Li Tee; Brenton, James D; Earl, Helena M

    2016-03-01

    Intensive cisplatin and oral etoposide for relapsed epithelial ovarian cancer (EOC), commonly known as the van der Burg (VDB) protocol, has been reported to improve response rates and progression-free survival. We report on all patients with relapsed EOC treated on the VDB protocol at the Cambridge Gynae-Oncology Centre. From the institutional databases, we identified all patients treated since 2001. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used Cox regression to identify predictors of survival. A total of 35 patients were treated on the VDB protocol. Toxicity was significant, with grade 3/4 fatigue, nausea and vomiting affecting 46, 46 and 29% of patients, respectively. Six patients had grade 3/4 infection and four (11%) deaths occurred on treatment. Efficacy was encouraging, with a radiological response rate of 43%, a median progression-free survival of 5.8 months and a median overall survival of 14.1 months. No significant difference in efficacy was seen between platinum-resistant and sensitive patients. We report significant activity of the VDB protocol in a routine clinical setting. However, the high rates of serious toxicity and treatment-related deaths among patients treated with palliative intent proved unacceptable. The Cambridge Gynae-Oncology Centre no longer uses this regimen in women with relapsed EOC.

  9. 40 CFR 799.9310 - TSCA 90-day oral toxicity in rodents.

    Science.gov (United States)

    2010-07-01

    ... displaying each type of lesion. (ii) When applicable, all observed results, qualitative and quantitative... obtained by acute testing. The subchronic oral study has been designed to permit the determination of the... be used throughout the duration of the study and the research sample should be stored under...

  10. Oral toxicity of silver ions, silver nanoparticles and colloidal silver – a review

    DEFF Research Database (Denmark)

    Hadrup, Niels; Lam, Henrik Rye

    2014-01-01

    Orally administered silver has been described to be absorbed in a range of 0.4-18% in mammals with a human value of 18%. Based on findings in animals, silver seems to be distributed to all of the organs investigated, with the highest levels being observed in the intestine and stomach. In the skin...

  11. Ninety-day oral toxicity study of lycopene from Blakeslea trispora in rats

    NARCIS (Netherlands)

    Jonker, D.; Kuper, C.F.; Fraile, N.; Estrella, A.; Rodríguez Otero, C.

    2003-01-01

    Lycopene, as a suspension in sunflower oil (20% w/w), was tested for subchronic toxicity by administration at dietary concentrations of 0, 0.25, 0.50, and 1.0% to groups of 20 male and 20 female Wistar rats for a period of 90 days. The lycopene examined in this study was derived from a fungal biomas

  12. Oral two-generation reproduction toxicity study with NM-200 synthetic amorphous silica in Wistar rats

    NARCIS (Netherlands)

    Wolterbeek, A.; Oosterwijk, T.; Schneider, S.; Landsiedel, R.; Groot, D. de; Ee, R. van; Wouters, M.; Sandt, H. van de

    2015-01-01

    Synthetic amorphous silica (SAS) like NM-200 is used in a wide variety of technological applications and consumer products. Although SAS has been widely investigated the available reproductive toxicity studies are old and do not cover all requirements of current OECD Guidelines. As part of a CEFIC-L

  13. Acute and subacute oral toxicity evaluation of Tephrosia purpurea extract in rodents

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    Talib Hussain

    2012-04-01

    Full Text Available Objective: To evaluate the acute and subacute toxicity of 50% ethanolic extract of Tephrosia purpurea (T. purpurea in rodents. Methods: The acute toxicity test was conducted in Swiss albino mice. The extract of T. purpurea was administrated in single doses of 50, 300 and 2000 mg/ kg and observed for behavioral changes and mortality, if any. In subacute toxicity study, Wistar rats of either sex were administered two doses of T. purpurea i.e., 200 and 400 mg/kg (One-tenth and one-fifth of the maximum tolerated dose, p.o. for 4 weeks. During 28 days of treatment, rats were observed weekly for any change in their body weight, food and water intake. At the end of 28 days, rats were sacrificed for hematological, biochemical and histopathology study. Results: In the acute toxicity study, T. purpurea was found to be well tolerated upto 2 000 mg/kg, produced neither mortality nor changes in behavior in mice. In subacute toxicity study, T. purpurea at dose level of 200 and 400 mg/kg did not produce any significant difference in their body weight, food and water intake when compared to vehicle treated rats. It also showed no significant alteration in hematological and biochemical parameters in experimental groups of rats apart from a decrease in aspartate transaminase, alanine transaminase and alkaline phosphate content at the dose of 400 mg/kg. Histopathological study revealed normal architecture of kidney and liver of T. purpurea treated rats. Conclusions: These results demonstrated that there is a wide margin of safety for the therapeutic use of T. purpurea and further corroborated the traditional use of this extract as an anti hepatocarcinogenic agent

  14. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

    Science.gov (United States)

    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

    2014-01-01

    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  15. Evaluation of arecoline hydrobromide toxicity after a 14-day repeated oral administration in Wistar rats.

    Directory of Open Access Journals (Sweden)

    Xiaojuan Wei

    Full Text Available A subchronic toxicity test was conducted in rats on the basis of a previous acute toxicity test to evaluate the safety of arecoline hydrobromide (Ah, to systematically study its pharmacological effects and to provide experimental support for a safe clinical dose. Eighty rats were randomly divided into four groups: a high-dose group (1000 mg/kg, medium-dose group (200 mg/kg, low-dose group (100mg/kg and blank control group. The doses were administered daily via gastric lavage for 14 consecutive days. There were no significant differences in the low-dose Ah group compared to the control group (P>0.05 with regard to body weight, organ coefficients, hematological parameters and histopathological changes. The high-dose of Ah influenced some of these parameters, which requires further study. The results of this study indicated that a long-term, continuous high dose of Ah was toxic. However, it is safe to use Ah according to the clinically recommended dosing parameters. The level of Ah at which no adverse effects were observed was 100 mg/kg/day under the present study conditions.

  16. Evaluation of arecoline hydrobromide toxicity after a 14-day repeated oral administration in Wistar rats.

    Science.gov (United States)

    Wei, Xiaojuan; Zhang, Jiyu; Niu, Jianrong; Zhou, Xuzheng; Li, Jianyong; Li, Bing

    2015-01-01

    A subchronic toxicity test was conducted in rats on the basis of a previous acute toxicity test to evaluate the safety of arecoline hydrobromide (Ah), to systematically study its pharmacological effects and to provide experimental support for a safe clinical dose. Eighty rats were randomly divided into four groups: a high-dose group (1000 mg/kg), medium-dose group (200 mg/kg), low-dose group (100mg/kg) and blank control group. The doses were administered daily via gastric lavage for 14 consecutive days. There were no significant differences in the low-dose Ah group compared to the control group (P>0.05) with regard to body weight, organ coefficients, hematological parameters and histopathological changes. The high-dose of Ah influenced some of these parameters, which requires further study. The results of this study indicated that a long-term, continuous high dose of Ah was toxic. However, it is safe to use Ah according to the clinically recommended dosing parameters. The level of Ah at which no adverse effects were observed was 100 mg/kg/day under the present study conditions.

  17. Cytotoxicity and Acute Gastrointestinal Toxicity of Bacterial Cellulose-Poly (acrylamide-sodium acrylate Hydrogel: A Carrier for Oral Drug Delivery

    Directory of Open Access Journals (Sweden)

    Manisha Pandey 1,2 * , Hira Choudhury 1, Mohd Cairul Iqbal Mohd Amin 2

    2016-12-01

    Full Text Available Background: Preliminary safety evaluation of polymer intended to use as drug delivery carrier is essential. Methods: In this study polyacrylamide grafted bacterial cellulose (BC/AM hydrogel was prepared by microwave irradiation initiated free radical polymerization. The synthesized hydrogel was subjected to in vitro cytotoxicity and acute gastrointestinal toxicity studies to evaluate its biological safety as potential oral drug delivery carrier. Results: The results indicate that hydrogel was non cytotoxic and did not show any histopathological changes in GI tract after a high dose of oral administration. Conclusion: The results revealed that hydrogel composed of bacterial cellulose and polyacrylamide is safe as oral drug delivery carrier.

  18. Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice.

    Science.gov (United States)

    Kim, Seong-Kwan; Shin, Soo-Jeong; Yoo, Yohan; Kim, Na-Hyun; Kim, Dong-Soon; Zhang, Dan; Park, Jin-A; Yi, Hee; Kim, Jin-Suk; Shin, Ho-Chul

    2015-03-01

    An oral toxicity study of several pregnancy category X drugs was performed in female ICR mice. The drugs were administered orally once daily for 3 days at doses of 1, 10 and 100 μg/kg for isotretinoin; 6.7, 67 and 670 μg/kg for misoprostol; 83, 830 and 8,300 μg/kg for methotrexate; 3.3, 33 and 330 μg/kg for mifepristone; and 25, 250 and 2,500 μg/kg for levonorgestrel. During the test period, clinical signs, mortality, body weight, hematology, serum biochemistry and necropsy findings were examined. Following administration of methotrexate at 8,300 μg/kg, a number of animals exhibited decreased spontaneous activity, and one animal died. In the hematological analysis, compared with those treated with the control, the animals treated with the drugs exhibited similar significant decreases in the number of granulocytes and granulocyte differentiation, and increases in lymphocyte differentiation. In the serum biochemical analysis, animals receiving high doses of the five drugs demonstrated significant changes in uric acid, glucose, alkaline phosphatase, total bilirubin, lipase, total cholesterol and calcium. At necropsy, intestinal redness was frequently observed in animals that received the high dose of methotrexate. Uterus enlargement and ovary dropsy were also detected in the groups receiving mifepristone and levonorgestrel. Despite the short-term exposure, these drugs exhibited significant side effects, including white blood cell toxicity, in the mouse model. Category X drugs can be traded illegally via the internet for the purpose of early pregnancy termination. Thus, illegal abuse of the drugs should be further discouraged to protect mothers.

  19. Acute and sub-chronic oral toxicity studies of an aqueous stem bark extract of Pterocarpus soyauxii Taub (Papilionaceae) in rodents.

    Science.gov (United States)

    Tchamadeu, M C; Dzeufiet, P D D; Nana, P; Kouambou Nouga, C C; Ngueguim Tsofack, F; Allard, J; Blaes, N; Siagat, R; Zapfack, L; Girolami, J P; Tack, I; Kamtchouing, P; Dimo, T

    2011-01-27

    Pterocarpus soyauxii Taub (Papilionaceae) is used in Cameroonian traditional medicine and pharmacopoeia to treat hypertension, diabetes, gastrointestinal parasitizes and cutaneous diseases. The present investigation was carried out to evaluate the safety of an aqueous stem bark extract of Pterocarpus soyauxii by determining toxicity after acute and sub-chronic oral administration in male and female rodents. The acute toxicity test was conducted in mice. An aqueous extract of barks was administrated by gavage in single doses of 2.5-12.5 g/kg. General behaviour and mortality were examined for up to 7 days. The sub-chronic toxicity test was performed in rats. The plant extract was administered by daily gavage of 150-600 mg/kg for 42 days. Body weight, food and water intakes were followed weekly. Haematological, biochemical and organ parameters were determined at the end of the 42-day administration. In the acute study in mice, oral administration of the aqueous extract of Pterocarpus soyauxii caused dose-dependent general behaviour adverse effects and mortality. The no-observed adverse effect level (NOAEL) of the extract was 5.0 g/kg. The lowest-observed adverse effect level (LOAEL) was 7.5 mg/kg. Mortality increased with the dose, LD(50) was>10.75 g/kg for the mouse. In the sub-chronic study in rats, daily oral administration of the aqueous extract of Pterocarpus soyauxii did not result in death or significant changes in haematological or biochemical parameters, excepted increased hepatic catalase activity (PPterocarpus soyauxii Taub had very low toxicity in oral acute high dose administration and no toxicity in oral sub-chronic low dose administration and indicate that the plant could be considered safe for oral medication. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Evaluation of acute and sub-acute toxicity of Pinus eldarica bark extract in Wistar rats

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    Akram Ghadirkhomi

    2016-08-01

    Full Text Available Objective: Pinus eldarica (P. eldarica is one of the most common pines in Iran which has various bioactive constituents and different uses in traditional medicine. Since there is no documented evidence for P. eldarica safety, the acute and sub-acute oral toxicities of hydroalcoholic extract of P. eldarica bark were investigated in male and female Wistar rats in this study. Materials and Methods: In the acute study, a single dose of extract (2000 mg/kg was orally administered and animals were monitored for 7 days. In the sub-acute study, repeated doses (125, 250 and 500 mg/kg/day of the extract were administered for 28 days and biochemical, hematological and histopathological parameters were evaluated. Results: Our results showed no sign of toxicity and no mortality after single or repeated administration of P. eldarica. The median lethal dose (LD50 of P. eldarica was determined to be higher than 2000 mg/kg. The mean body weight and most of the biochemical and hematological parameters showed normal levels.  There were only significant decreases in serum triglyceride levels at the doses of 250 and 500 mg/kg of the extract in male rats (pConclusion: Oral administration of the hydroalcoholic extract of P. eldarica bark may be considered as relatively non-toxic particularly at the doses of 125 and 250 mg/kg.

  1. Preliminary toxicity study of dichloromethane extract of Kielmeyera coriacea stems in mice and rats.

    Science.gov (United States)

    Obici, Simoni; Otobone, Fernanda Jacques; da Silva Sela, Vânia Ramos; Ishida, Kelly; da Silva, José Carlos; Nakamura, Celso Vataru; Garcia Cortez, Diógenes Aparício; Audi, Elisabeth Aparecida

    2008-01-01

    Kielmeyera coriacea Mart. (Clusiaceae), known as "Pau Santo" or "Saco de Boi" in the central Brazilian plateau region, is used to treat several tropical diseases. The present study evaluated the toxic effects of dichloromethane (DcM) extract of Kielmeyera coriacea stems, administered to rodents. In the acute toxicity tests, mice receiving doses of this extract by the oral and intraperitoneal routes, showed reversible effects, with LD50 values of 1503.0 and 538.8 mg/kg, respectively. In the repeated-dose oral (90 days) toxicity tests, male and female Wistar rats were treated by gavage with different doses of DcM extract (5, 25 or 125 mg/kg). In biochemical and haematological evaluations, the results varied widely in respect to dose and sex, with no linear profile, and did not show clinical correlations. In the histopathological examinations, the groups exhibited some changes, but there were no significant differences between the groups compared to the controls. In conclusion, these investigations appeared to indicate the safety of acute and repeated oral administration of the DcM extract of Kielmeyera coriacea stems, which can therefore be continuously used with safety.

  2. Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in Children

    Science.gov (United States)

    Choonara, Imti; Conroy, Sharon

    2017-01-01

    Background Long courses of oral corticosteroids are commonly used in children in the management of chronic conditions. Various adverse drug reactions (ADRs) are known to occur with their use. This systematic review aimed to identify the most common and serious ADRs and to determine their relative risk levels. Methods A literature search of Embase, Medline, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions in order to identify studies where oral corticosteroids were administered to patients aged 28 days to 18 years of age for at least 15 days of treatment. Each database was searched from their earliest dates to January 2016. All studies providing clear information on ADRs were included. Results One hundred and one studies including 33 prospective cohort studies; 21 randomised controlled trials; 21 case series and 26 case reports met the inclusion criteria. These involved 6817 children and reported 4321 ADRs. The three ADRs experienced by the highest number of patients were weight gain, growth retardation and Cushingoid features with respective incidence rates of 21.1%, 18.1% and 19.4% of patients assessed for these ADRs. 21.5% of patients measured showed decreased bone density and 0.8% of patients showed osteoporosis. Biochemical HPA axis suppression was detected in 269 of 487 patients where it was measured. Infection was the most serious ADR, with twenty one deaths. Varicella zoster was the most frequent infection (9 deaths). Conclusions Weight gain, growth retardation and Cushingoid features were the most frequent ADRs seen when long-course oral corticosteroids were given to children. Increased susceptibility to infection was the most serious ADR. PMID:28125632

  3. Anti-Osteoporotic Effects of Angelica sinensis (Oliv. Diels Extract on Ovariectomized Rats and Its Oral Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    Dong Wook Lim

    2014-10-01

    Full Text Available Angelica sinensis root is one of the herbs most commonly used in China; it is also often included in dietary supplements for menopause in Europe and North America. In the present study, we examined the anti-osteoporotic effects of A. sinensis extract in an ovariectomized (OVX rat model of osteoporosis as well as toxicity of the extract after repeated oral administration. The OVX rats were treated with 17β-estradiol (10 μg/kg i.p. once daily or A. sinensis extract (30, 100, and 300 mg/kg, p.o. once daily for four weeks. The bone (femur mineral density (BMD of rats treated with the extract (300 mg/kg was significantly higher than that of the OVX-control, reaching BMD of the estradiol group. Markers of bone turnover in osteoporosis, serum alkaline phosphatase, collagen type I C-telopeptide and osteocalcin, were significantly decreased in the extract group. The body and uterus weight and serum estradiol concentration were not affected, and no treatment-related toxicity was observed during extract administration in rats. The results obtained indicate that A. sinensis extract can prevent the OVX-induced bone loss in rats via estrogen-independent mechanism.

  4. Automation of an in vitro cytotoxicity assay used to estimate starting doses in acute oral systemic toxicity tests.

    Science.gov (United States)

    Bouhifd, Mounir; Bories, Gilles; Casado, Juan; Coecke, Sandra; Norlén, Hedvig; Parissis, Nicholaos; Rodrigues, Robim M; Whelan, Maurice P

    2012-06-01

    Application of High Throughput Screening (HTS) to the regulatory safety assessment of chemicals is still in its infancy but shows great promise in terms of facilitating better understanding of toxicological modes-of-action, reducing the reliance on animal testing, and allowing more data-poor chemicals to be assessed at a reasonable cost. To promote the uptake and acceptance of HTS approaches, we describe in a stepwise manner how a well known cytotoxicity assay can be automated to increase throughput while maintaining reliability. Results generated with selected reference chemicals compared very favourably with data obtained from a previous international validation study concerning the prediction of acute systemic toxicity in rodents. The automated assay was then included in a formal ECVAM validation study to determine if the assay could be used for binary classification of chemicals with respect to their acute oral toxicity, using a threshold equivalent to a dose of 2000 mg/kg b.w. in a rodent bioassay (LD50). This involved the blind-testing of 56 reference chemicals on the HTS platform to produce concentration-response and IC50 data. Finally, the assay was adapted to a format more suited to higher throughput testing without compromising the quality of the data obtained. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Quantitative structure-activity relationship modelling of oral acute toxicity and cytotoxic activity of fragrance materials in rodents.

    Science.gov (United States)

    Papa, E; Luini, M; Gramatica, P

    2009-10-01

    Fragrance materials are used as ingredients in many consumer and personal care products. The wide and daily use of these substances, as well as their mainly uncontrolled discharge through domestic sewage, make fragrance materials both potential indoor and outdoor air pollutants which are also connected to possible toxic effects on humans (asthma, allergies, headaches). Unfortunately, little is known about the environmental fate and toxicity of these substances. However, the use of alternative, predictive approaches, such as quantitative structure-activity relationships (QSARs), can help in filling the data gap and in the characterization of the environmental and toxicological profile of these substances. In the proposed study, ordinary least squares regression-based QSAR models were developed for three toxicological endpoints: mouse oral LD(50), inhibition of NADH-oxidase (EC(50) NADH-Ox) and the effect on mitochondrial membrane potential (EC(50) DeltaPsim). Theoretical molecular descriptors were calculated by using DRAGON software, and the best QSAR models were developed according to the principles defined by the Organization for Economic Co-operation and Development.

  6. Exposición infantil a plastificantes potencialmente tóxicos en productos de uso oral Infant exposure to potentially toxic plasticizers in products for oral use

    Directory of Open Access Journals (Sweden)

    Lilia Patricia Bustamante-Montes

    2004-12-01

    Full Text Available OBJETIVO: Determinar la prevalencia en el uso de productos infantiles orales entre menores de tres años de edad y medir su concentración de ftalatos, sustancias potencialmente tóxicas. MATERIAL Y MÉTODOS: Se realizó, en 1999, una entrevista domiciliaria a 199 madres de niños del área metropolitana de la ciudad de Toluca. Por cromatografía de gases se identificaron y cuantificaron diversos ftalatos de productos de uso oral empleados por los niños participantes y se estimó la contribución de estas fuentes a la ingesta diaria de ftalatos. RESULTADOS: La prevalencia de uso de estos productos fue de 13%, siendo mayor entre los niños, menores de 18 meses de edad, pertenecientes al estrato socioeconómico bajo. Las concentraciones variaron desde trazas hasta 67.0% del peso. La exposición media calculada proveniente de los productos manufacturados con policloruro de vinilo y ftalatos fue de 13.94 µg/ kg de peso/día, IC 95% (9.08, 18.89. CONCLUSIONES: La exposición a ftalatos proveniente de productos para chupar o morder se encuentra dentro de los límites reportados en otros países; sin embargo, otras fuentes pueden incrementarla. Dado que algunos ftalatos han mostrado ser tóxicos en el sistema reproductivo, y este potencial efecto es plausible en el hombre, es necesaria la investigación de otras fuentes y determinar la exposición total a través de biomarcadores.OBJECTIVE: To estimate the prevalence of oral product use in children less than three years of age, and to measure the concentration of phthalates as potentially toxic products. MATERIAL AND METHODS: In 1999, 199 mothers of children living in the city of Toluca agreed to household interviews. Samples of oral products used by the children were taken and analyzed by gas chromatography to identify and quantify phthalate concentrations, to estimate the daily intake of phthalates from this source. RESULTS: The prevalence of oral product use was 13%. Male infants less than 18

  7. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

  8. Six Month Oral Toxicity Study of WR238605 Succinate in Rats. Volume 2

    Science.gov (United States)

    1996-02-02

    STUDY MO: 1!>2 ABBR: HCV SEX: FEMALE UNITS: fL Animal ID Week U Week 13 Week 26 GROUP: 1-F:0 mg base/kg/day 426 57.8 55.4 57.9 427 58.8 55.5 57.5...Microscopic (Micro) Findings (Section V). The codes used as entries in these tables are explained in the Report Codes Table. The results of the bone...TOXICITY STUDY OF WR23 8605 SUCCINATE IN RATS SUMMARY OF CLINICAL CHEMISTRY TESTS TEST: Creatine Kinase [uj Ul STUDY ID: UIC-15B STUDY NO

  9. Influence of Food on the Bioavailability of an Enteric-Coated Tablet Formulation of Omeprazole 20 mg Under Repeated Dose Conditions

    Directory of Open Access Journals (Sweden)

    ABR Thomson

    1997-01-01

    Full Text Available The objective of this study was to investigate the influence of food on the bioavailability of omeprazole (20 mg given as an enteric-coated tablet under repeated dose conditions. This open randomized crossover study consisted of three seven-day treatment periods, each separated by a drug-free period. During each treatment period an enteric-coated tablet of omeprazole was taken once daily either under fasting conditions, or immediately before or after a standardized breakfast. On the last day of each treatment period, blood samples for the determination of plasma omeprazole concentrations were collected at baseline and at predetermined intervals over the 24 h period following drug administration. Fifty-seven male and female subjects, aged 18 to 52 years, completed the study according to the protocol. No statistically significant differences were found when comparing either the before breakfast or after breakfast treatment regimens with the fasting regimen for the estimated mean area under the plasma concentration-time curve (AUC. The maximum plasma concentration was not found to differ significantly among any of the treatment regimens. However, the lower limit of the CI for the comparison of fasting/before breakfast was not contained within the limits of bioequivalence. The time to reach maximum plasma concentration was significantly different when fasting and after breakfast regimens were compared. Thus, under repeated dose conditions, food has no influence on the bioavailability (expressed as AUC of omeprazole given as the enteric-coated tablet formulation.

  10. Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity.

    Directory of Open Access Journals (Sweden)

    Kwangkook Lee

    Full Text Available Botulinum neurotoxins (BoNTs are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs to become highly potent oral poisons. Here, we report the structure of a ∼760 kDa 14-subunit large PTC of serotype A (L-PTC/A and reveal insight into its absorption mechanism. Using a combination of X-ray crystallography, electron microscopy, and functional studies, we found that L-PTC/A consists of two structurally and functionally independent sub-complexes. A hetero-dimeric 290 kDa complex protects BoNT, while a hetero-dodecameric 470 kDa complex facilitates its absorption in the harsh environment of the gastrointestinal tract. BoNT absorption is mediated by nine glycan-binding sites on the dodecameric sub-complex that forms multivalent interactions with carbohydrate receptors on intestinal epithelial cells. We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry.

  11. Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats

    NARCIS (Netherlands)

    Hempenius, R.A.; Lina, B.A.R.; Haggitt, R.C.

    2000-01-01

    Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm, 15,

  12. Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats

    NARCIS (Netherlands)

    Hempenius, R.A.; Lina, B.A.R.; Haggitt, R.C.

    2000-01-01

    Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm,

  13. Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats

    NARCIS (Netherlands)

    Hempenius, R.A.; Lina, B.A.R.; Haggitt, R.C.

    2000-01-01

    Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm, 15,

  14. Preparation of five 3-MCPD fatty acid esters and the effects of their chemical structures on acute oral toxicity in Swiss mice

    Science.gov (United States)

    Fatty acid esters of 3-monochloro-1, 2-propanediol (3-MCPDEs), including 1-stearic, 1-oleic, 1-linoleic, 1-linoleic-2-palmitic and 1-palmitic-2-linoleic acid esters, were synthetized and examined for their acute oral toxicities in Swiss mice. 3-MCPDEs were obtained through the reaction of 3-MCPD and...

  15. Repeated-Dose and Reproductive/Developmental Toxicity of NTO (3-Nitro-1,2,4-Triazol-5-One) in the Rat

    Science.gov (United States)

    2014-03-21

    than 5000 milligrams per kilogram (mg/kg) . In addition, NTO was reported to be a mild skin and eye irritant but was not a dermal sensitizer (Los...pancreas; testes; uterus; aorta; esophagus; stomach; duodenum; jejunum; ileum; caecum; colon ; rectum; urinary bladder; representative lymph node...adrenals; pancreas; testes; uterus; aorta; esophagus; stomach; duodenum; jejunum; ileum; cecum; colon ; rectum; urinary bladder; representative lymph

  16. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.

    Science.gov (United States)

    Cheng, Yaofeng; Chen, Shenjue; Freeden, Chris; Chen, Weiqi; Zhang, Yueping; Abraham, Pamela; Nelson, David M; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2017-09-01

    The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  17. Ninety Day Toxicity and Toxicokinetics of Fluorochloridone after Oral Administration in Rats

    Directory of Open Access Journals (Sweden)

    Suhui Zhang

    2015-05-01

    Full Text Available The ninety day toxicity and toxicokinetics of fluorochloridone (FLC were accessed in Wistar rats. Animals were gavaged with FLC at doses of 31.25 mg/kg, 125 mg/kg and 500 mg/kg for ninety days, followed by thirty days for recovery. On the 1st, 60th, 75th and 90th days of the dosing phase, plasma of ten animals of all groups treated with FLC was collected for toxicokinetic analysis of FLC by an UPLC-MS/MS method. Numerous changes in body weight, hematology, serum chemistry, and organ weight ratios were observed by the 45th and 90th dosing day. Most changes in groups treated with FLC were absent on the last recovery day. Testis and epididymis lesions were consistently seen in histopathological observations on the 45th, 90th dosing day and the last recovery day. Repeated administration of FLC increased the level of testosterone in serum in male rats on the 90th dosing day. FLC plasma concentrations could be detected in all animal drug-treated groups during the dosing phase, and a dose proportional relationship was seen between FLC dose and AUC or Cmax. This study will support future studies on the mechanism of FLC-induced toxicity.

  18. Clinical effectiveness, toxicity, and failure patterns of helical tomotherapy for postoperative oral cavity cancer patients

    Directory of Open Access Journals (Sweden)

    Hsieh CH

    2014-03-01

    Full Text Available Chen-Hsi Hsieh,1–3 Pei-Wei Shueng,1,4 Li-Ying Wang,5 Li-Jen Liao,6 Yu-Chin Lin,7 Ying-Shiung Kuo,8 Wu-Chia Lo,6 Chien-Fu Tseng,8 Hui-Ju Tien,1 Hsiu-Ling Chou,9,10 Yen-Ping Hsieh,11 Le-Jung Wu,1 Yu-Jen Chen3,12–14 1Department of Radiation Oncology, Far Eastern Memorial Hospital, 2Department of Medicine, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Department of Radiation Oncology, National Defense Medical Center, 5School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, 6Department of Otolaryngology, 7Division of Medical Oncology and Hematology, Department of Internal Medicine, 8Department of Dentistry and Oral Surgery, 9Department of Nursing, Far Eastern Memorial Hospital, 10Department of Nursing, Oriental Institute of Technology, Taipei, 11Department of Senior Citizen Service Management, National Taichung University of Science and Technology, Taichung, 12Department of Radiation Oncology, 13Department of Medical Research, Mackay Memorial Hospital, 14Graduate Institute of Sport Coaching Science, Chinese Culture University, Taipei, Taiwan Background: The outcome of postoperative high- and intermediate-risk oral cavity cancer (OCC patients receiving helical tomotherapy (HT remains limited. Materials and methods: Between November 2006 and November 2012, 53 postoperative high- and intermediate-risk OCC patients treated with HT were enrolled. Results: The 4-year locoregional, local, and regional control rates were 66%, 76.4%, and 94.3%, respectively. The 4-year locoregional control rates of oral tongue and buccal mucosa cancer were 88.3% and 37.1%, respectively (P=0.012. Eleven (20.8% patients experienced locoregional failure. In-field failure occurred in six of 53 (11.3% in the primary area and three of 53 (5.7% in the regional lymph-node area. No marginal failure was noted. Two of 53 (3.8% experienced out-of-field failure. The rates of grade 3 dermatitis

  19. Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid.

    Science.gov (United States)

    Stine, Cynthia B; Reimschuessel, Renate; Keltner, Zachary; Nochetto, Cristina B; Black, Thomas; Olejnik, Nicholas; Scott, Michael; Bandele, Omari; Nemser, Sarah M; Tkachenko, Andriy; Evans, Eric R; Crosby, Tina C; Ceric, Olgica; Ferguson, Martine; Yakes, Betsy J; Sprando, Robert

    2014-06-01

    The industrial chemical melamine was used in 2007 and 2008 to raise the apparent protein content in pet feed and watered down milk, respectively. Because humans may be exposed to melamine via several different routes into the human diet as well as deliberate contamination, this study was designed to characterize the effect of high dose melamine or cyanuric acid oral exposure on the pregnant animal and developing fetus, including placental transfer. Clear rectangular crystals formed following a single triazine exposure which is a different morphology from the golden spherulites caused by combined exposure or the calculi formed when melamine combines with endogenous uric acid. Crystal nephropathy, regardless of cause, induces renal failure which in turn has reproductive sequelae. Specifically, melamine alone-treated dams had increased numbers of early and late fetal deaths compared to controls or cyanuric acid-treated dams. As melamine was found in the amniotic fluid, this study confirms transfer of melamine from mammalian mother to fetus and our study provides evidence that cyanuric acid also appears in the amniotic fluid if mothers are exposed to high doses.

  20. Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression

    Energy Technology Data Exchange (ETDEWEB)

    Hoffmann, Peter, E-mail: peterk.hoffmann@novartis.com [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Beckman, David; McLean, Lee Anne [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Yan, Jing-He [Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States)

    2014-02-15

    Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300 mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day-old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3 mg/kg i.v.) pharmacokinetic study in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. Oral administration of aliskiren at 100 and 300 mg/kg caused unexpected mortality and severe morbidity in 8-day-old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21 days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure. - Highlights: • Aliskiren was orally administered to juvenile rats. • Unexpected severe toxicity and acute mortality occurred in rats aged 8 days. • Toxicity was associated with increased aliskiren plasma and tissue exposure. • Developmental changes of exposure correlated with ontogeny of transporters. • Immaturity of MDR1 in enterocytes causes increased exposure in very young rats.

  1. A 90-day oral (dietary) toxicity study of rebaudioside A in Sprague-Dawley rats.

    Science.gov (United States)

    Nikiforov, Andrey I; Eapen, Alex K

    2008-01-01

    Rebaudioside A is one of several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) stevia that has been identified as a potential sweetener. The present study (initiated in April 2006 and completed in October 2006) evaluated the safety of this sweetener when administered as a dietary admix at target exposure levels of 500, 1000, and 2000 mg/kg/day to Sprague-Dawley rats for 90 days. There were no treatment-related effects on the general condition and behavior of the animals as determined by clinical observations, functional observational battery, and locomotor activity assessments. Evaluation of clinical pathology parameters revealed no toxicologically relevant, treatment-related effects on hematology, serum chemistry, or urinalysis. Macroscopic and microscopic findings revealed no treatment-related effects on any organ evaluated. Lower mean body weight gains were noted in males in the 2000 mg/kg/day group throughout the study, which was considered to be test article related; however, given the small magnitude of the difference as compared to controls, this effect was not considered to be adverse. Results of this study clearly demonstrate that dietary administration of high concentrations of rebaudioside A for 90 consecutive days to Sprague-Dawley rats was not associated with any signs of toxicity.

  2. Evaluation of cardiovascular toxicity of carbon nanotubes functionalized with sodium hyaluronate in oral regenerative medicine

    Energy Technology Data Exchange (ETDEWEB)

    Joviano-Santos, J.V.; Sá, M.A.; De Maria, M.L.A.; Almeida, T.C.S. [Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Geraldo, V.; Oliveira, S.; Ladeira, L.O. [Departamento de Física, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ferreira, A.J. [Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2014-05-23

    It has been demonstrated that carbon nanotubes (CNTs) associated with sodium hyaluronate (HY-CNTs) accelerate bone repair in the tooth sockets of rats. Before clinical application of HY-CNTs, it is important to assess their biocompatibility. Moreover, cardiac toxicity may be caused by the translocation of these particles to the blood stream. The aim of this study was to evaluate possible changes in cardiovascular function in male Wistar rats whose tooth sockets were treated with either CNTs or HY-CNTs (100 μg/mL, 0.1 mL). Blood pressure and heart rate were monitored in conscious rats 7 days after treatment. Cardiac function was evaluated using the Langendorff perfusion technique. The data showed no changes in blood pressure or heart rate in rats treated with either CNTs or HY-CNTs, and no significant changes in cardiac function were found in any of the groups. To confirm these findings, experiments were conducted in rats injected intraperitoneally with a high concentration of either CNTs or HY-CNTs (0.75 mg/kg). The same parameters were analyzed and similar results were observed. The results obtained 7 days following injection indicate that the administration of low concentrations of CNTs or HY-CNTs directly into tooth sockets did not cause any significant change in cardiovascular function in the rats. The present findings support the possibility of using these biocomposites in humans.

  3. Evaluation of cardiovascular toxicity of carbon nanotubes functionalized with sodium hyaluronate in oral regenerative medicine

    Directory of Open Access Journals (Sweden)

    J.V. Joviano-Santos

    2014-07-01

    Full Text Available It has been demonstrated that carbon nanotubes (CNTs associated with sodium hyaluronate (HY-CNTs accelerate bone repair in the tooth sockets of rats. Before clinical application of HY-CNTs, it is important to assess their biocompatibility. Moreover, cardiac toxicity may be caused by the translocation of these particles to the blood stream. The aim of this study was to evaluate possible changes in cardiovascular function in male Wistar rats whose tooth sockets were treated with either CNTs or HY-CNTs (100 μg/mL, 0.1 mL. Blood pressure and heart rate were monitored in conscious rats 7 days after treatment. Cardiac function was evaluated using the Langendorff perfusion technique. The data showed no changes in blood pressure or heart rate in rats treated with either CNTs or HY-CNTs, and no significant changes in cardiac function were found in any of the groups. To confirm these findings, experiments were conducted in rats injected intraperitoneally with a high concentration of either CNTs or HY-CNTs (0.75 mg/kg. The same parameters were analyzed and similar results were observed. The results obtained 7 days following injection indicate that the administration of low concentrations of CNTs or HY-CNTs directly into tooth sockets did not cause any significant change in cardiovascular function in the rats. The present findings support the possibility of using these biocomposites in humans.

  4. Evaluation of the subchronic toxicity of kefir by oral administration in Wistar rats

    Directory of Open Access Journals (Sweden)

    Damiana Diniz Rosa

    2014-06-01

    Full Text Available Introduction: Kefir is obtained by fermentation of milk with complex microbial populations present in kefir grains. Several health-promoting benefits have been attributed to kefir consumption. Objective: The objective of this work was to conduct a subchronic toxicity study, offering the rats normal or high-doses of kefir and evaluating growth, hematology and blood chemistry, as well as assessing bacterial translocation and the integrity of the intestinal mucosa of animals. Methods: Wistar rats were randomly divided into three groups (n = 6/group: control group received 0.7 mL of water, kefir group received 0.7 mL/day of kefir, (normodose, and Hkefir group received 3.5 mL/day of kefir (fivefold higher dose. Feeding was carried out by gavage. The animals were housed in individual cages and maintained under standard conditions for 4 weeks. Results: The normodose and high-dose of kefir supplementation did not harm the animals since growth, hematology and blood chemistry in rats, as well as the potential pathogenicity in tissues were within normal limits, demonstrating that consumption of normodose and highdose of kefir are safe. In addition, administration of the normodose of kefir reduced cholesterol levels and improved the intestinal mucosa of the rats. Conclusion: These results demonstrate that the consumption of kefir is safe. Importantly, while damages are not seen for the high-dose, the normodose consumption is recommended due to the pronounced beneficial effects, as safety is concerned.

  5. Acute oral toxicity study of ethanol extract of Ceiba pentandra leaves as a glucose lowering agent in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Hadiza Lami Muhammad; Adamu Yusuf Kabiru; Musa Bola Busari; Abdullah Mann; Abubakar Siddique Abdullah; Abdulrazaq Taye Usman; Usman Adamu

    2016-01-01

    Objective: To evaluate the use of Ceiba pentandra (C. pentandra) as a glucose lowering agent and the attendant physiological changes in albino rats. Methods: Acute oral toxicity study of the extract was carried out by the administration of 10, 100, 1 000, 1 600, 2 900, and 5 000 mg/kg body weight of C. pentandra to rats in their respective groups. Twenty healthy albino rats weighing between 140 and 150 g were randomly allotted to five groups of four rats each. 100 mg/kg body weight of alloxan monohydrate was i.p. administered to rats and rats with blood glucose ? 200 mg/dL were considered diabetic. 5 mg/kg body weight of standard drug, 200 and 400 mg/kg body weight of ethanol extract of C. pentandra were orally administered to diabetic rats in their respective groups once daily for 12 days while the control groups received 0.1 mL of normal saline for the same period. The blood glucose was checked after every 4 days and the experiment was terminated on the 17th day. Results: The safe dose (LD50) of the extract was greater than 5 000 mg/kg body weight. The extract treated groups exhibited a remarkable reduction in blood glucose [(87.72 ± 7.67) mg/dL for 200 mg/kg body weight dose and (86.33 ± 4.54) mg/dL for 400 mg/kg body weight dose] competitively with the normoglycemic group [(88.71 ± 4.56) mg/dL]. The body weight of the extract and standard drug treated groups appreciated significantly (P Conclusions: Ethanol extract of C. pentandra has glucose lowering effect and can ameliorate the biochemical abnormalities associated with diabetes mellitus.

  6. Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate

    Directory of Open Access Journals (Sweden)

    Douglas Rossi Jesus

    2015-01-01

    Full Text Available The large consumption of biodegradable films from cassava starch acetate (FCSA as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm.

  7. Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate

    Science.gov (United States)

    Jesus, Douglas Rossi; Barbosa, Lorena Neris; Prando, Thiago Bruno Lima; Martins, Leonardo Franco; Gasparotto, Francielli; Guedes, Karla Moraes Rocha; Dragunski, Douglas Cardoso; Lourenço, Emerson Luiz Botelho; Dalsenter, Paulo Roberto; Gasparotto Junior, Arquimedes

    2015-01-01

    The large consumption of biodegradable films from cassava starch acetate (FCSA) as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm. PMID:26451154

  8. Acute Toxicity Test of Kushencangshu Oral Liquid%苦参苍术口服液急性毒性研究

    Institute of Scientific and Technical Information of China (English)

    高艳艳; 周德刚; 高富红

    2014-01-01

    In order to evaluate the actue toxicity of Kushencangshu oral liquid,the experiment was conducted in accordance with acute toxicity requirements in compilation of veterinary drug registration data. The acute toxicity of Kushencangshu oral liquid was studied in mice in this experiment,the toxicity of Kushencangshu oral liquid was demonstrated by the minimal lethal dose and the LD50 of mice. The results showed that the LD50 of the Kushencangshu oral liquid was 20.51 mL/kg,equal to 68.91 g/kg of the crude drug every day,it had light poi-sonous; the minimal lethal dose ranged between 16.37 and 25.9 mL/kg,which was equivalent to from 27.3 to 43.2 times of daily dosage of poultry. Kushencangshu oral liquid was relatively safe in clinical application.%为了考察苦参苍术口服液的安全性,按《兽药注册资料汇编》的要求,选用小白鼠进行了急性毒性试验。结果显示,苦参苍术口服液灌胃给药的LD50为20.51 mL/kg,相当于生药量68.91 mL/kg,可判断苦参苍术口服液为小毒。95%可信限(可信区间)范围为16.37~25.90 mL/kg,相当于禽临床用量的27.3~43.2倍,说明苦参苍术口服液临床使用安全。

  9. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

    Science.gov (United States)

    Guo, RX; Anaclet, C; Roberts, JC; Parmentier, R; Zhang, M; Guidon, G; Buda, C; Sastre, JP; Feng, JQ; Franco, P; Brown, SH; Upton, N; Medhurst, AD; Lin, JS

    2009-01-01

    Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg−1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg−1), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg−1) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies. PMID:19413575

  10. Evaluation of the subchronic toxicity of kefir by oral administration in Wistar rats.

    Science.gov (United States)

    Diniz Rosa, Damiana; Gouveia Peluzio, Maria do Carmo; Pérez Bueno, Tania; Vega Cañizares, Ernesto; Sánchez Miranda, Lilian; Mancebo Dorbignyi, Betty; Chong Dubí, Dainé; Espinosa Castaño, Ivette; Marcin Grzes Kowiak, Lukasz; Fortes Ferreira, Célia Lucia de Luces

    2014-06-01

    Introducción: El kéfir es obtenido por fermentación de la leche con una población microbiana compleja presente en sus granos. Al consumo de kéfir se le atribuyen múltiples efectos beneficiosos sobre la salud. Objetivo: Evaluar la toxicidad subcrónica del kéfir en ratas Wistar, administrado por vía oral en dosis normal (normodosis) y sobredosis. Se evaluaron además, los parámetros de peso corporal, hematología, química sanguínea, translocación bacteriana e integridad de la mucosa intestinal. Métodos: Se conformaron tres grupos de seis animales de manera aleatoria: grupo control, recibió 0,7 mL de agua; grupo kéfir recibió 0,7 mL/día de kéfir (normodosis) y grupo Hkéfir recibió 3,5 mL/día de kéfir (dosis cinco veces superior). La administración se llevó a cabo mediante sonda. Los animales se alojaron individualmente, y se mantuvieron bajo las mismas condiciones de manejo y alimentación durante 4 semanas. Resultados: La administración de kéfir en dosis normal y sobredosis no afectó los parámetros evaluados en los animales, el peso corporal, indicadores hematológicos, de química sanguínea, y la patogenicidad potencial en los tejidos se encontraron dentro de límites normales, lo que demostró que el consumo de kéfir en dosis normal y sobredosis es seguro. Además, se evidenció que la administración de normodosis de kéfir redujo los niveles de colesterol y mejoró la mucosa intestinal de las ratas. Conclusión: Se demostró que el consumo de kéfir es seguro. Destacar que, la administración de sobredosis no evidenció daños, no obstante, se recomienda el consumo de normodosis, debido a los marcados efectos beneficiosos y de seguridad.

  11. Toxicological assessment of enzyme-treated asparagus extract in rat acute and subchronic oral toxicity studies and genotoxicity tests.

    Science.gov (United States)

    Ito, Tomohiro; Ono, Tomoko; Sato, Atsuya; Goto, Kazunori; Miura, Takehito; Wakame, Koji; Nishioka, Hiroshi; Maeda, Takahiro

    2014-03-01

    The safety of enzyme-treated asparagus extract (ETAS) developed as a novel anti-stress functional material was assessed in acute and subchronic studies and genotoxicity assays. In the acute oral dose toxicity study, all rats survived during the test period and ETAS did not influence clinical appearance, body weight gain and necropsy findings at a dosage of 2000mg/kg body weight. Thus, the 50% lethal dose (LD50) of ETAS was determined to be greater than 2000mg/kg. The 90-day subchronic study (500, 1000 and 2000mg/kg body weight, delivered by gavage) in rats reported no significant adverse effects in food consumption, body weight, mortality, urinalysis, hematology, biochemistry, necropsy, organ weight and histopathology. In the micronucleus test of mice, the incidence of micronuclei in ETAS-administered groups (500, 1000 and 2000mg/kg/day, injected twice) was equivalent to that of the negative control group, while the positive control group receiving mitomycin C showed a high incidence. The potential of ETAS to induce gene mutation was tested using four Salmonella typhimurium strains and Escherichia coli WP2uvrA. The test sample was not mutagenic to the test strains. These results support the safety of ETAS as food and dietary supplement.

  12. An oral bioassay for the toxicity of hydramethylnon to individual workers and queens of Argentine ants, Linepithema humile.

    Science.gov (United States)

    Hooper-Bùi, L M; Rust, M K

    2001-11-01

    We have developed an oral bioassay to determine the toxicity of hydramethylnon to individual workers and queens of the Argentine ant, Linepithema humile. We fed seven concentrations of hydramethylnon in suspension to individual workers or queens, determined the amount of hydramethylnon ingested and evaluated the individual ants for mortality 14 days later. At concentrations > or = 0.37 g liter-1, the amount of liquid the queens ingested decreased dramatically, indicating that Argentine ant queens may detect hydramethylnon. Significantly larger volumes of the two highest concentrations of the hydramethylnon suspension were ingested by the workers, compared to the lower concentrations, suggesting that hydramethylnon may act as a feeding stimulant for the workers. Worker mortality was higher than queen mortality at the highest concentrations tested. The highest worker mortality resulted when the ants ingested 1.03 micrograms of hydramethylnon per mg of ant tissue. At the highest concentration (1.0 g liter-1) tested, workers ingested almost 12 times as much active ingredient per mg of body weight as did queens, suggesting that, in order to increase mortality of queens, multiple feedings must occur.

  13. Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50 and No Observed Adverse Effect Level (NOAEL

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    Paula Abal

    2017-02-01

    Full Text Available Tetrodotoxin (TTX is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50 and the No Observed Adverse Effect Level (NOAEL in mice by using an accurate well-characterized TTX standard.

  14. Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL)

    Science.gov (United States)

    Abal, Paula; Louzao, M. Carmen; Antelo, Alvaro; Alvarez, Mercedes; Cagide, Eva; Vilariño, Natalia; Vieytes, Mercedes R.; Botana, Luis M.

    2017-01-01

    Tetrodotoxin (TTX) is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard. PMID:28245573

  15. A fusion protein containing a lepidopteran-specific toxin from the South Indian red scorpion (Mesobuthus tamulus and snowdrop lectin shows oral toxicity to target insects

    Directory of Open Access Journals (Sweden)

    Fitches Elaine

    2006-03-01

    Full Text Available Abstract Background Despite evidence suggesting a role in plant defence, the use of plant lectins in crop protection has been hindered by their low and species-specific insecticidal activity. Snowdrop lectin (Galanthus nivalis agglutinin; GNA is transported to the haemolymph of insects after oral ingestion, and can be used as a basis for novel insecticides. Recombinant proteins containing GNA expressed as a fusion with a peptide or protein, normally only toxic when injected into the insect haemolymph, have the potential to show oral toxicity as a result of GNA-mediated uptake. Results A gene encoding a toxin, ButaIT, from the red scorpion (Mesobuthus tamulus was synthesised and assembled into expression constructs. One construct contained ButaIT alone, whereas the other contained ButaIT fused N-terminally to a GNA polypeptide (ButaIT/GNA. Both recombinant proteins were produced using the yeast Pichia pastoris as an expression host, and purified. Recombinant ButaIT and ButaIT/GNA were acutely toxic when injected into larvae of tomato moth (Lacanobia oleracea, causing slow paralysis, leading to mortality or decreased growth. ButaIT/GNA was chronically toxic when fed to L. oleracea larvae, causing decreased survival and weight gain under conditions where GNA alone was effectively non-toxic. Intact ButaIT/GNA was detected in larval haemolymph from insects fed the fusion protein orally, demonstrating transport of the linked polypeptide across the gut. Proteolysis of the fusion protein was also observed. ButaIT/GNA was significantly more toxic that GNA alone when fed to the homopteran Nilaparvata lugens (rice brown planthopper in liquid artificial diet. Conclusion The ButaIT/GNA recombinant fusion protein is toxic to lepidopteran larvae both when injected and when fed orally, showing the utility of GNA as a carrier to transport potentially toxic peptides and proteins across the insect gut. Although ButaIT has been claimed to be lepidopteran

  16. Toxicity of 100 nm zinc oxide nanoparticles: a report of 90-day repeated oral administration in Sprague Dawley rats

    Directory of Open Access Journals (Sweden)

    Kim YR

    2014-12-01

    /kg, respectively. Both ZnO NPs had significant changes in hematological and blood biochemical analysis, which could correlate with anemia-related parameters, in the 500 mg/kg groups of both sexes. Histopathological examination showed significant adverse effects (by both test articles in the stomach, pancreas, eye, and prostate gland tissues, but the particle charge did not affect the tendency or the degree of the lesions. We speculate that this inflammatory damage might result from continuous irritation caused by both test articles. Therefore, the target organs for both ZnOAE100(- and ZnOAE100(+ are considered to be the stomach, pancreas, eye, and prostate gland. Also, the no observed adverse effect level for both test articles was identified as 31.25 mg/kg for both sexes, because the adverse effects were observed at all doses greater than 125 mg/kg. Keywords: zinc oxide nanoparticles, surface charge, 90-day oral dose toxicity, no observed adverse effect level

  17. Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).

    Science.gov (United States)

    Gershkovich, Pavel; Sivak, Olena; Wasan, Ellen K; Magil, Alex B; Owen, David; Clement, John G; Wasan, Kishor M

    2010-12-01

    The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

  18. Short-Term Effects of Oral Administration of Pistacia Lentiscus Oil on Tissue-Specific Toxicity and Drug Metabolizing Enzymes in Mice

    OpenAIRE

    Samir Attoub; Karam, Sherif M.; Abderrahim Nemmar; Kholoud Arafat; Annie John; Wafa Al-Dhaheri; Mahmood Ahmed Al Sultan; Haider Raza

    2014-01-01

    Background: Pistacia lentiscus (Anacardiaceae) is a flowering plant traditionally used in the treatment of various skin, respiratory, and gastrointestinal disorders. The aim of this study was to assess whether Pistacia lentiscus oil has any short term toxic effects in vivo and in vitro. Methods: Pistacia lentiscus oil (100µl) was administered orally into mice for 5 days. Results: Measurements of body weight did not show any weight loss. Serum concentration of LDH did not show any significant ...

  19. Acute toxicity of some synthetic cyanogens in rats: time-dependent cyanide generation and cytochrome oxidase inhibition in soft tissues after sub-lethal oral intoxication.

    Science.gov (United States)

    Rao, Pooja; Singh, Poonam; Yadav, Shiv Kumar; Gujar, Niranjan L; Bhattacharya, Rahul

    2013-09-01

    Cyanogens include complex nitrile-containing compounds that can generate free cyanide of toxicological significance. Acute toxicity, time-dependent cyanide generation and cytochrome oxidase (CYTOX) inhibition in soft tissues, and urinary thiocyanate levels were measured after acute cyanogen intoxication in rats. Order of cyanogens in terms of LD₅₀ was: malononitrile (MCN)>propionitrile (PCN)≈sodium nitroprusside (SNP)>acrylonitrile (ACN)>succinonitrile (SCN)>acetonitrile (ATCN) for oral, and SNP>MCN>ACN>PCN>SCN>ATCN for intraperitoneal and subcutaneous routes. MCN was most toxic by oral (LD₅₀=66.4 mg/kg) and SNP by intraperitoneal (LD₅₀=16.7 mg/kg) and subcutaneous (LD₅₀=11.9 mg/kg) routes. Minimum survival time (25 min) was recorded after 4.0 LD₅₀ ATCN. Order of cyanogens (0.75 LD₅₀; oral) on the basis of maximum blood cyanide and time of peak cyanide generation were: ATCN>SNP>SCN>PCN>MCN>ACN, and MCN (30 min)PCN≈ACN (8h)toxicity of different cyanogens, suitable therapeutic windows can be designed for their management.

  20. 78 FR 66700 - Toxic Substances Control Act Chemical Testing; Receipt of Test Data

    Science.gov (United States)

    2013-11-06

    ... Mammals; Bacterial Reverse Mutation Assay; Chromosomal Aberrations; Combined Repeated Dose Toxicity with... heat set, cold Study in Zebra Fish set, and sheet-fed (Brachydanio rerio). applications. Acute Toxicity Study in Daphnia Magna with C.I. Pigment Blue 61 (Static). Fresh Water Algal Growth 0442,...

  1. Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

    Science.gov (United States)

    Kishi, Y; Murashige, N; Kami, M; Miyakoshi, S; Shibagaki, Y; Hamaki, T; Takaue, Y; Taniguchi, S

    2005-06-01

    Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

  2. NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration

    Energy Technology Data Exchange (ETDEWEB)

    Bu Qian; Lin Hongjun; Xu Youzhi; Cao Zhixing; Zhou Tian; Zhao Yinglan [State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041 (China); Yan Guangyan; Cen Xiaobo [National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041 (China); Deng Pengchi [Analytical and Testing Center, Sichuan University, Chengdu 610041 (China); Peng Feng [Department of Thoracic Oncology of Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041 (China); Xue Aiqin [Institute of Bioengineering, Zhejiang Sci-Tech University Road 2, Xiasha, Hangzhou 310018 (China); Wang Yanli, E-mail: alancenxb@sina.com [Tianjin Children' s Hospital, Tianjin 300074 (China)

    2010-03-26

    As titanium dioxide nanoparticles (TiO{sub 2} NPs) are widely used commercially, their potential toxicity on human health has attracted particular attention. In the present study, the oral toxicological effects of TiO{sub 2} NPs (dosed at 0.16, 0.4 and 1 g kg{sup -1}, respectively) were investigated using conventional approaches and metabonomic analysis in Wistar rats. Serum chemistry, hematology and histopathology examinations were performed. The urine and serum were investigated by {sup 1}H nuclear magnetic resonance (NMR) using principal components and partial least squares discriminant analysis. The metabolic signature of urinalysis in TiO{sub 2} NP-treated rats showed increases in the levels of taurine, citrate, hippurate, histidine, trimethylamine-N-oxide (TMAO), citrulline, {alpha}-ketoglutarate, phenylacetylglycine (PAG) and acetate; moreover, decreases in the levels of lactate, betaine, methionine, threonine, pyruvate, 3-D-hydroxybutyrate (3-D-HB), choline and leucine were observed. The metabonomics analysis of serum showed increases in TMAO, choline, creatine, phosphocholine and 3-D-HB as well as decreases in glutamine, pyruvate, glutamate, acetoacetate, glutathione and methionine after TiO{sub 2} NP treatment. Aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) were elevated and mitochondrial swelling in heart tissue was observed in TiO{sub 2} NP-treated rats. These findings indicate that disturbances in energy and amino acid metabolism and the gut microflora environment may be attributable to the slight injury to the liver and heart caused by TiO{sub 2} NPs. Moreover, the NMR-based metabolomic approach is a reliable and sensitive method to study the biochemical effects of nanomaterials.

  3. NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration

    Science.gov (United States)

    Bu, Qian; Yan, Guangyan; Deng, Pengchi; Peng, Feng; Lin, Hongjun; Xu, Youzhi; Cao, Zhixing; Zhou, Tian; Xue, Aiqin; Wang, Yanli; Cen, Xiaobo; Zhao, Ying-Lan

    2010-03-01

    As titanium dioxide nanoparticles (TiO2 NPs) are widely used commercially, their potential toxicity on human health has attracted particular attention. In the present study, the oral toxicological effects of TiO2 NPs (dosed at 0.16, 0.4 and 1 g kg - 1, respectively) were investigated using conventional approaches and metabonomic analysis in Wistar rats. Serum chemistry, hematology and histopathology examinations were performed. The urine and serum were investigated by 1H nuclear magnetic resonance (NMR) using principal components and partial least squares discriminant analysis. The metabolic signature of urinalysis in TiO2 NP-treated rats showed increases in the levels of taurine, citrate, hippurate, histidine, trimethylamine-N-oxide (TMAO), citrulline, α-ketoglutarate, phenylacetylglycine (PAG) and acetate; moreover, decreases in the levels of lactate, betaine, methionine, threonine, pyruvate, 3-D-hydroxybutyrate (3-D-HB), choline and leucine were observed. The metabonomics analysis of serum showed increases in TMAO, choline, creatine, phosphocholine and 3-D-HB as well as decreases in glutamine, pyruvate, glutamate, acetoacetate, glutathione and methionine after TiO2 NP treatment. Aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) were elevated and mitochondrial swelling in heart tissue was observed in TiO2 NP-treated rats. These findings indicate that disturbances in energy and amino acid metabolism and the gut microflora environment may be attributable to the slight injury to the liver and heart caused by TiO2 NPs. Moreover, the NMR-based metabolomic approach is a reliable and sensitive method to study the biochemical effects of nanomaterials.

  4. Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion.

    Science.gov (United States)

    Gorain, Bapi; Choudhury, Hira; Tekade, Rakesh Kumar; Karan, Saumen; Jaisankar, P; Pal, Tapan Kumar

    2016-12-01

    Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Avaliação da toxicidade oral subcrônica da bixina para ratos Oral toxicity assessment of annatto in rats

    Directory of Open Access Journals (Sweden)

    Ana Rita Pedreira Lapa Bautista

    2004-06-01

    Full Text Available A bixina em pó (30% de bixina, proveniente das sementes de urucum (Bixa orellana L., foi administrada, por gavagem, a ratos Wistar, 10 animais de cada sexo, na concentração de 0,01±0,006% de bixina/dia, em óleo de milho, cinco dias por semana, durante 13 semanas, com o objetivo de verificar a toxicidade da substância-teste para essa espécie animal. A grupos controle (10 animais por sexo, foi administrado óleo de milho, para comparação. Durante o período de exposição, foram registrados o peso absoluto corpóreo, o ganho de peso, o consumo de ração e a eficiência alimentar, bem como realizadas as avaliações clínica e oftalmoscópica. Antes da eutanásia, os animais foram anestesiados (éter etílico e submetidos a exames hematológicos de rotina e bioquímicos (glicose, creatinina, colesterol total, triglicérides, asparagina transaminase e g-glutamil transaminase. Durante o exame necroscópico, fígado, rins, baço, adrenais e testículos foram excisados e pesados. O estudo histológico foi realizado em amostras de fígado e rins dos animais expostos e respectivos controles. A análise estatística dos parâmetros de peso, hematológicos e bioquímicos mostrou algumas diferenças significativas entre os grupos teste e controle, as quais não parecem estar relacionadas à exposição. Não foram observadas alterações clínicas, comportamentais, necroscópicas e histológicas. Nas condições do estudo, a bixina não produziu efeitos tóxicos nos animais expostos.The aim of the investigation was to determine the possible health hazards of bixin (30% from annatto (Bixa orellana L. origin to rats. A concentration of 0.01±0.006%/day of bixin in corn oil was administered to 20 Wistar rats (10 per sex, through the oral route (gavage over a period of 13 weeks. A group of untreated animal (10 per sex acting as a control (corn oil was used for comparision. Body weight, body weight gain, feed consumption and feed efficiency were

  6. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats.

    Science.gov (United States)

    Institóris, L; Siroki, O; Undeger, U; Basaran, N; Banerjee, B D; Dési, I

    2001-06-21

    In the present study, an immunotoxicity test system, containing general toxicological (body weight gain, organ weights), haematological (WBC,RBC, Ht, mean cell volume of the RBCs, cell content of the femoral bone marrow), and immune function (PFC assay, DTH reaction) investigations, was used for detection the effects of a 4 weeks repeated low dose combined oral exposure of male Wistar rats with propoxur and the heavy metals arsenic or mercury. Two doses of the compounds were used: a higher one (the lowest dose which resulted in significant change of at least one parameter examined in previous dose-effect experiments), and a lower one (the highest dose which proved to be non-effective). The applied doses were: 8.51 and 0.851 mg kg(-1) of propoxur, 13.3 and 3.33 mg kg(-1) of NaAsO(2), and 3.20 and 0.40 mg kg(-1) of HgCl(2). In the combination treatment, the high dose of propoxur was combined with the low dose of arsenic or mercury, and the high doses of each heavy metals were combined with the low dose of propoxur. The main finding of this study was that some of the combinations significantly altered the relative weight of liver, adrenals and kidneys, related to both the untreated and the high dose internal control. Among the immune functions examined, only the PFC content of the spleen showed a trend of changes in certain combinations versus the corresponding high dose control. According to the present results, combined exposure with propoxur and the heavy metals examined can modify the detection limit of the single compounds and/or may alter their toxic effects.

  7. Relationship between coumarin-induced hepatocellular toxicity and mitochondrial function in rats.

    Science.gov (United States)

    Tanaka, Yasuhiro; Fujii, Wataru; Hori, Hisako; Kitagawa, Yoshinori; Ozaki, Kiyokazu

    2016-04-01

    The manifestation of coumarin-induced hepatocellular toxicity may differ and depends on the frequency of administration to rats. A single coumarin dose induces hepatocellular necrosis while repeated doses induce only hepatocyte degeneration. However, the mechanism underlying these effects remains unclear. Therefore, we investigated the mechanism of coumarin-induced hepatotoxicity in rats. Coumarin was administered to male rats as a single dose or for 4 consecutive days, and samples were obtained 4 or 24 h after a single dose or 24 h after the repeated doses. A single coumarin dose significantly induced hepatocellular necrosis in rats; however, toxicity was attenuated after repeated dosing. With a single dose, hepatocellular necrosis was preceded by increased mitochondrial number and size and decreased mitochondrial function. An increased expression of granular cytochrome P450 (CYP) 2E1 protein was observed in the cytoplasm and mitochondria of coumarin-treated rats compared to the expression in the untreated controls. Nevertheless, repeated dosing showed mitochondrial function that was equivalent to that of the control while enlarged CYP2E1 protein droplets were distributed outside the mitochondria. These results suggest that mitochondrial function and CYP2E1 expression might be involved in coumarin-induced hepatocellular toxicity in rats. A reduction in mitochondrial CYP2E1 might be implicated in the acquisition of coumarin resistance after repeated doses.

  8. Styrene maleic acid-encapsulated paclitaxel micelles: antitumor activity and toxicity studies following oral administration in a murine orthotopic colon cancer model

    Directory of Open Access Journals (Sweden)

    Parayath NN

    2016-08-01

    Full Text Available Neha N Parayath,1 Hayley Nehoff,1 Samuel E Norton,2 Andrew J Highton,2 Sebastien Taurin,1,3 Roslyn A Kemp,2 Khaled Greish1,4 1Department of Pharmacology and Toxicology, 2Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand; 3Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA; 4Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Oral administration of paclitaxel (PTX, a broad spectrum anticancer agent, is challenged by its low uptake due to its poor bioavailability, efflux through P-glycoprotein, and gastrointestinal toxicity. We synthesized PTX nanomicelles using poly(styrene-co-maleic acid (SMA. Oral administration of SMA-PTX micelles doubled the maximum tolerated dose (60 mg/kg vs 30 mg/kg compared to the commercially available PTX formulation (PTX [Ebewe]. In a murine orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 mg/kg and 60 mg/kg reduced tumor weight by 54% and 69%, respectively, as compared to the control group, while no significant reduction in tumor weight was observed with 30 mg/kg of PTX (Ebewe. In addition, toxicity of PTX was largely reduced by its encapsulation into SMA. Furthermore, examination of the tumors demonstrated a decrease in the number of blood vessels. Thus, oral delivery of SMA-PTX micelles may provide a safe and effective strategy for the treatment of colon cancer. Keywords: oral delivery, anticancer nanomedicine, CT-26, enhanced permeability and retention (EPR effect, HUVEC, antiangiogenic

  9. Tolerance and toxicity of neoadjuvant docetaxel, cisplatin and 5 fluorouracil regimen in technically unresectable oral cancer in resource limited rural based tertiary cancer center

    Directory of Open Access Journals (Sweden)

    V M Patil

    2014-01-01

    Full Text Available Background: Recent studies indicate neoadjuvant chemotherapy (NACT can result in R0 resection in a substantial proportion of patients with technically unresectable oral cavity cancers. However, data regarding the efficacy and safety of docetaxel, cisplatin and 5 fluorouracil (TPF NACT in our setting is lacking. The present audit was proposed to evaluate the toxicities encountered during administration of this regimen. It was hypothesized that TPF NACT would be considered feasible for routine administration if an average relative dose intensity (ARDI of ≥0.90 or more in at least 70% of the patients. Materials and Methods: Technically unresectable oral cancers with Eastern Cooperative Oncology Group PS 0-2, with biopsy proven squamous cell carcinoma underwent two cycles of NACT with TPF regimen. Toxicity and response rates were noted following the CTCAE 4.03 and RECIST criteria. Descriptive analysis of completion rates (completing 2 cycles of planned chemotherapy with ARDI of 0.85 or more, reason for delay, toxicity, and response are presented. Results: The NACT was completed by all patients. The number of subjects who completed all planned cycles of chemotherapy are with the ARDI of the delivered chemotherapy been equal to or >0.85 was 11 (91.67%. All toxicity inclusive Grade 3-5 toxicity was seen in 11 patients (91.67%. The response rate of chemotherapy was 83.33%. There were three complete response, seven partial response, and two stable disease seen post NACT in this study. Conclusion: Docetaxel, cisplatin and 5 fluorouracil regimen can be routinely administered at our center with the supportive care methods and precautionary methods used in our study.

  10. A chronic oral toxicity study of marine collagen peptides preparation from chum salmon (Oncorhynchus keta) skin using Sprague-Dawley rat.

    Science.gov (United States)

    Liang, Jiang; Pei, Xin-Rong; Zhang, Zhao-Feng; Wang, Nan; Wang, Jun-Bo; Li, Yong

    2012-01-01

    Due to the increased consumption of marine collagen peptides preparation (MCP) as ingredients in functional foods and pharmaceuticals, it was necessary to carry out safety requirements in the form of an oral chronic toxicity assessment. In order to define the oral chronic toxicity of MCP, a 24-month feeding study of MCP was carried out. Sprague-Dawley (S-D) rats at the age of four-week of both sexes were treated with MCP at the diet concentrations of 0%, 2.25%, 4.5%, 9% and 18% (wt/wt). The actual food intake and bodyweight of the individual animals were recorded periodically until sacrifice. Blood and urine samples were collected for serum chemistry evaluations and urinalysis. Throughout the experimental period, there was no toxicologically significant difference between the vehicle and MCP-treated animals with respect to the survival rate, body weight, food consumption, urinalysis, clinical biochemistry parameter and relative organ weight in either sex. Moreover, incidences of non-neoplastic lesions in MCP-treated groups did not significantly increase compared with the control group. Under the present experimental conditions, no higher risk of chronic toxic effects was observed in MCP-treated rats at the diet concentrations of 2.25%, 4.5%, 9% and 18% (wt/wt) than in the rats fed with basal rodent diet.

  11. Mammalian Toxicity of Munitions Compounds. Phase I. Acute Oral Toxicity, Primary Skin and Eye Irritation, Dermal Sensitization, Disposition and Metabolism and Ames Tests of Additional Compounds

    Science.gov (United States)

    1978-12-08

    Assay of 300 Chemicals, Proc. Nat. Acad. Sci., 72:5135-5139, 1975. 17. Wang, C. Y., K. Muraoka, and G. T. Bryan, Yatagenicity of Nitrofurans ...L. H. DiSalvo, and J. Ng, Toxicity and Mutagenicity of 2,4,6-Trinitrotoluene and Its Microbial Metabolites , Appl. Environ. Microbiol., 31:576-580

  12. Polymer coated liposomes for use in the oral cavity - A study of the in vitro toxicity, effect on cell permeability and interaction with mucin

    DEFF Research Database (Denmark)

    Klemetsrud, Therese; Kjøniksen, Anna-Lena; Hiorth, Marianne

    2016-01-01

    (NIPAAM-co-MAA)), hydrophobically modified hydroxyethyl cellulose (HM-HEC), and hydrophobically modified ethyl hydroxyethyl cellulose (HM-EHEC). With chitosan as an exception, all the systems exhibited no significant effect on cell viability and permeability at the considered concentrations. Additionally, all the formulations...... formulations promising for oromucosal administration. Although the chitosan coated liposomes affected the cell viability, this formulation also influenced the cell permeability, which makes it an interesting candidate for systemic drug delivery from the oral cavity.......In this study we investigated the in vitro toxicity, impact on cell permeability and mucoadhesive potential of polymer coated liposomes intended for use in the oral cavity. A TR146 cell line was used as a model. The overall aim was to end up with a selection of safe polymer coated liposomes...

  13. A recombinant fusion protein containing a spider toxin specific for the insect voltage-gated sodium ion channel shows oral toxicity towards insects of different orders.

    Science.gov (United States)

    Yang, Sheng; Pyati, Prashant; Fitches, Elaine; Gatehouse, John A

    2014-04-01

    Recombinant fusion protein technology allows specific insecticidal protein and peptide toxins to display activity in orally-delivered biopesticides. The spider venom peptide δ-amaurobitoxin-PI1a, which targets insect voltage-gated sodium channels, was fused to the "carrier" snowdrop lectin (GNA) to confer oral toxicity. The toxin itself (PI1a) and an amaurobitoxin/GNA fusion protein (PI1a/GNA) were produced using the yeast Pichia pastoris as expression host. Although both proteins caused mortality when injected into cabbage moth (Mamestra brassicae) larvae, the PI1a/GNA fusion was approximately 6 times as effective as recombinant PI1a on a molar basis. PI1a alone was not orally active against cabbage moth larvae, but a single 30 μg dose of the PI1a/GNA fusion protein caused 100% larval mortality within 6 days when fed to 3rd instar larvae, and caused significant reductions in survival, growth and feeding in 4th - 6th instar larvae. Transport of fusion protein from gut contents to the haemolymph of cabbage moth larvae, and binding to the nerve chord, was shown by Western blotting. The PI1a/GNA fusion protein also caused mortality when delivered orally to dipteran (Musca domestica; housefly) and hemipteran (Acyrthosiphon pisum; pea aphid) insects, making it a promising candidate for development as a biopesticide.

  14. Subchronic oral toxicity evaluation of ethanolic whole plant extract of Eleucine indica on haematological and biochemical indices in Wistar albino rats

    Institute of Scientific and Technical Information of China (English)

    Ette Okon Ettebong; PaulAlozie Nwafor

    2016-01-01

    Objective: To evaluate the effect of ingestion of ethanolic whole plant extract of Eleucine indica on haematological and biochemical parameters of Wistar albino rats. Methods: Subchronic toxicity study was carried out by oral administration of different doses (200, 400 and 600 mg/kg body weight) of the extract on alternate-day basis to different groups of rats for 28 days. The animals were subsequently sacrificed and blood samples were collected by cardiac puncture for haematological and biochemical analyses. Results: Haematological indices were preserved and the extract showed significant (P Conclusions: The results obtained indicated that ingestion of Eleucine indica whole plant extract for a long period of time reduces both bleeding and clotting times, reduces blood sugar and shows no apparent toxic effect on liver and kidneys. The results of this study may be useful as a basis for clinical trials in humans.

  15. Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

    Science.gov (United States)

    Xu, Zhi; Huang, Chun-Ming; Shao, Zhe; Zhao, Xiao-Ping; Wang, Meng; Yan, Ting-Lin; Zhou, Xiao-Cheng; Jiang, Er-Hui; Liu, Ke; Shang, Zheng-Jun

    2017-01-01

    Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 μg). Cisplatin toxicity (IC50, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 μg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway. PMID:28257034

  16. PUNARNAVA MANDUR: TOXICITY STUDY OF CLASSICAL AYURVEDIC FORMULATION IN WISTAR RATS

    Directory of Open Access Journals (Sweden)

    P. S. Jamadagni

    2013-06-01

    Full Text Available Punarnava Mandur is an iron containing classical Ayurvedic formulation which was studied for repeated dose oral toxicity study in Wistar rats for 90 days. Total 48 Wistar rats (24 male and 24 female were selected based on the body weight and were randomly distributed into four groups followed by administration of Punarnava Mandur at the dose of 0, 90, 450, 900 mg/kg body weight for 90 consecutive days. Body weight, Weekly Feed and Water consumption, Clinical Chemistry, Hematology, Differential leukocyte Count, Reticulocyte count and Organ weights were recorded and analyzed statistically. At termination, rats were sacrificed, examined for gross pathological changes, organs were collected, weighed and processed for histopathological evaluation. There was no effect on body weights and feed consumption, no abnormal findings in the histopathological evaluation of high dose group animals but there was significant increase in weight of liver in females of high dose group as compared to control. Hence, the dose level 450 mg/kg of Punarnava Mandur was found as NOAEL (No Observable Adverse Effect Level. However, the NOEL (No Observed Effect Level could not be established. It was suggested to carry out a toxicity study at possible higher doses so as to establish target organ of toxicity.

  17. Essential and Toxic Metals in Oral Fluid-a Potential Role in the Diagnosis of Periodontal Diseases.

    Science.gov (United States)

    Herman, Malgorzata; Golasik, Magdalena; Piekoszewski, Wojciech; Walas, Stanislaw; Napierala, Marta; Wyganowska-Swiatkowska, Marzena; Kurhanska-Flisykowska, Anna; Wozniak, Anna; Florek, Ewa

    2016-10-01

    Recently, many studies have investigated the relationship between the level of metals in the body and various diseases. The objective of this study was to examine any possible influence of periodontal disease upon the concentration of metals in oral fluid and blood and to explore the usability of applying cluster analysis coupled with the analysis of selected elements in oral fluid, calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), zinc (Zn), cadmium (Cd) and lead (Pb), for effectively distinguishing people affected by periodontitis from healthy individuals. The quantification of eight metals in oral fluid and blood samples was performed by two inductively coupled plasma techniques-inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). Most of the examined elements were detected at elevated concentration in the oral fluid of periodontal patients. However, the differences were statistically significant in the case of three metals: Cu, Mg and Mn (p oral fluid of the periodontal patients compared to the controls. Cluster analysis confirmed the statistical significance of the differences in the level of metals in the oral fluid between the two groups in most cases, plus enabled the correct classification of the subjects into patients and controls. The relationship between concentrations of metals and periodontal disease may in the future serve to prevent the development of such disease.

  18. Overview of Chronic Oral Toxicity Values for Chemicals Present in Hydraulic Fracturing Fluids, Flowback and Produced Waters

    Science.gov (United States)

    as part of EPA's Hydraulic Fracturing Drinking Water Assessment, EPA is summarizing existing toxicity data for chemicals reported to be used in hydraulic fracturing fluids and/or found in flowback or produced waters from hydraulically fractured wells

  19. Spontaneous and Dosing Route-related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies: Differentiation from Compound-induced Lesions.

    Science.gov (United States)

    Mukaratirwa, Sydney; Garcia, Begonya; Isobe, Kaori; Petterino, Claudio; Bradley, Alys

    2016-10-01

    This study was conducted to characterize lung microscopic lesions in control beagle dogs from inhalation and oral gavage toxicity studies, to determine differences associated with the route of administration, and to discuss distinguishing features from compound-induced lung lesions. Samples from 138 control dogs from oral gavage studies and 124 control dogs from inhalation (vehicle control) studies were evaluated microscopically. There was no significant sex-related difference in the incidence of all lesions. Perivascular mononuclear cell infiltration, centriacinar mixed cell infiltration, bronchopneumonia, subpleural septal fibrosis, and alveolar macrophage accumulation were the most common lesions. Aspiration pneumonia was more common in dogs from gavage studies, suggesting reflux after gavage dosing or accidental administration of test formulation as possible causes. Centriacinar mixed cell infiltration was more common in dogs from inhalation studies, suggesting mild irritation by the vehicles used. Vascular lesions, which included pulmonary arteriopathy and smooth muscle mineralization, were observed in a few animals. Some of the spontaneous lesions are similar to lesions induced by test compounds. Compared to spontaneous lesions, compound-induced lesions tend to be multifocal or diffuse, follow a pattern of distribution (e.g., centriacinar, perivascular, and interstitial), show a dose response in the incidence and severity, and may show cell-specific toxicity.

  20. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

    Science.gov (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S

    2001-09-15

    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  1. Four common pesticides, their mixtures and a formulation solvent in the hive environment have high oral toxicity to honey bee larvae.

    Science.gov (United States)

    Zhu, Wanyi; Schmehl, Daniel R; Mullin, Christopher A; Frazier, James L

    2014-01-01

    Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L.) health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax--fluvalinate, coumaphos, chlorothalonil, and chloropyrifos--tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common 'inert' ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated.

  2. Four Common Pesticides, Their Mixtures and a Formulation Solvent in the Hive Environment Have High Oral Toxicity to Honey Bee Larvae

    Science.gov (United States)

    Zhu, Wanyi; Schmehl, Daniel R.; Mullin, Christopher A.; Frazier, James L.

    2014-01-01

    Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L.) health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax - fluvalinate, coumaphos, chlorothalonil, and chloropyrifos - tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common ‘inert’ ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated. PMID:24416121

  3. Four common pesticides, their mixtures and a formulation solvent in the hive environment have high oral toxicity to honey bee larvae.

    Directory of Open Access Journals (Sweden)

    Wanyi Zhu

    Full Text Available Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L. health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax--fluvalinate, coumaphos, chlorothalonil, and chloropyrifos--tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common 'inert' ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated.

  4. Evaluation of acute and sub-acute toxicity of Pinus eldarica bark extract in Wistar rats

    Science.gov (United States)

    Ghadirkhomi, Akram; Safaeian, Leila; Zolfaghari, Behzad; Agha Ghazvini, Mohammad Reza; Rezaei, Parisa

    2016-01-01

    Objective: Pinus eldarica (P. eldarica) is one of the most common pines in Iran which has various bioactive constituents and different uses in traditional medicine. Since there is no documented evidence for P. eldarica safety, the acute and sub-acute oral toxicities of hydroalcoholic extract of P. eldarica bark were investigated in male and female Wistar rats in this study. Materials and Methods: In the acute study, a single dose of extract (2000 mg/kg) was orally administered and animals were monitored for 7 days. In the sub-acute study, repeated doses (125, 250 and 500 mg/kg/day) of the extract were administered for 28 days and biochemical, hematological and histopathological parameters were evaluated. Results: Our results showed no sign of toxicity and no mortality after single or repeated administration of P. eldarica. The median lethal dose (LD50) of P. eldarica was determined to be higher than 2000 mg/kg. The mean body weight and most of the biochemical and hematological parameters showed normal levels. There were only significant decreases in serum triglyceride levels at the doses of 250 and 500 mg/kg of the extract in male rats (p<0.05 and p<0.01, respectively) and in monocyte counts at the highest dose of the extract in both male and female rats (p<0.05). Mild inflammation was also found in histological examination of kidney and liver tissues at the highest dose of extract. Conclusion: Oral administration of the hydroalcoholic extract of P. eldarica bark may be considered as relatively non-toxic particularly at the doses of 125 and 250 mg/kg. PMID:27761426

  5. 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs.

    Science.gov (United States)

    Yimam, Mesfin; Lee, Young Chul; Jia, Qi

    2016-07-01

    The needs for relatively safe botanical alternatives to relieve symptoms associated to arthritis have continued to grow in parallel with the ageing population. UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, has been used as over the counter joint care dietary supplements and a prescription medical food. Significant safety data have been documented in rodents and human for this composition. Here we evaluated the potential adverse effects of orally administered UP446 in beagle dogs following a 26-week repeated oral dose toxicity study. UP446 at doses of 250, 500 and 1000 mg/kg/day were administered orally to beagle dogs for 26 weeks. A 4-week recovery group from the high dose (1000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, ophthalmological examinations, electrocardiograms, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Emesis, loose feces and diarrhea were noted in both genders at the 1000 mg/kg treatment groups. These clinical signs were considered to be reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP446 was considered to be 500 mg/kg/day both in male and female beagle dogs.

  6. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    OpenAIRE

    Collaku A; Yue Y.; Reed K

    2017-01-01

    Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly ass...

  7. Once-daily oral administration of cyclosporine in a lung transplant patient with a history of renal toxicity of calcineurin inhibitors.

    Science.gov (United States)

    Matsuda, Yuya; Chen, Fengshi; Miyata, Hitomi; Date, Hiroshi

    2014-07-01

    Cyclosporine is usually administered orally in two divided doses every 12 h in transplant patients. However, some patients have difficulty in achieving therapeutic levels after transplantation. In fact, cyclosporine is reportedly administered once daily in renal and liver transplantation cases, but not in lung transplantation cases. We report a patient with a history of calcineurin inhibitor-induced renal toxicity who successfully underwent living-donor lobar lung transplantation (LDLLT) with the novel immunosuppressive strategy of once-daily administration of cyclosporine. An 18-year old man with progressive respiratory insufficiency after bone marrow transplantation was referred to our hospital for lung transplantation. He had a history of renal toxicity due to calcineurin inhibitors. Based on his history of tacrolimus- and cyclosporine-induced renal toxicity, we decided to initiate basiliximab as induction therapy, followed by once-daily cyclosporine administration to obtain high enough blood cyclosporine concentrations at 2 h post-dose (C2) and lowered trough blood concentrations (C0) for protection of renal function as maintenance therapy. LDLLT was successfully performed, and the postoperative course was uneventful and free of rejection episodes. Cyclosporine dosing was adjusted with intensive therapeutic drug monitoring of blood cyclosporine levels. One year after LDLLT, the patient is alive and well with no problems with daily life activities. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  8. [Toxicity effects of phthalate substitute plasticizers used in toys].

    Science.gov (United States)

    Hirata-Koizumi, Mutsuko; Takahashi, Mika; Matsumoto, Mariko; Kawamura, Tomoko; Ono, Atsushi; Hirose, Akihiko

    2012-01-01

    Phthalate esters are widely used as plasticizers in polyvinyl chloride products. Because of human health concerns, regulatory authorities in Japan, US, Europe and other countries control the use of di(2-ethylhexyl) phthalate, diisononyl phthalate, di-n-butyl phthalate, butylbenzyl phthalate, diisodecyl phthalate and di-n-octyl phthalate for the toys that can be put directly in infants' mouths. While these regulatory actions will likely reduce the usage of phthalate esters, there is concern that other plasticizers that have not been sufficiently evaluated for safety will be used more frequently. We therefore collected and evaluated the toxicological information on di(2-ethylhexyl) terephthalate (DEHT), 1,2-cyclohexanedicarboxylic acid, diisononyl ester (DINCH), diisononyl adipate (DINA), 2,2,4-trimetyl-1,3-pentanediol diisobutyrate (TXIB), tri-n-butyl citrate (TBC) and acetyl tri-n-butyl citrate (ATBC) which were detected at a relatively high frequency in toys. The collected data have shown that chronic exposure to DEHT affects the eye and nasal turbinate, and DINCH exerts effects on the thyroid and kidney in rats. DINA and TXIB have been reported to have hepatic and renal effects in dogs or rats, and ATBC slightly affected the liver in rats. The NOAELs for repeated dose toxicity are relatively low for DINCH (40 mg/kg bw/day) and TXIB (30 mg/kg bw/day) compared with DEHT, DINA and ATBC. DEHT, TXIB and ATBC have been reported to have reproductive/developmental effects at relatively high doses in rats. For DINA and TBC, available data are insufficient for assessing the hazards, and therefore, adequate toxicity studies should be conducted. In the present review, the toxicity information on 6 alternatives to phthalate plasticizers is summarized, focusing on the effects after oral exposure, which is the route of most concern.

  9. Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

    Energy Technology Data Exchange (ETDEWEB)

    Lozano, Omar, E-mail: omar.lozanogarcia@fundp.ac.be [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Laloy, Julie; Alpan, Lütfiye [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Mejia, Jorge [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Rolin, Stéphanie [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Toussaint, Olivier [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Laboratory of Biochemistry and Cellular Biology (URBC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Dogné, Jean-Michel [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); and others

    2012-10-15

    Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup −1}, while the subacute doses were 0.5 and 50 mg·kg{sup −1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup −1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ► SiC nanoparticles were orally administered to rats in acute and subacute doses. ► SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ► SiC excretion rate, feces and organ elemental composition change with time. ► No morphological alteration were found on GI tract, liver, kidneys

  10. Analysis of the toxicity and histopathology induced by the oral administration of Pseudanabaena galeata and Geitlerinema splendidum (cyanobacteria) extracts to mice.

    Science.gov (United States)

    Rangel, Marisa; Martins, Joyce C G; Garcia, Angélica Nunes; Conserva, Geanne A A; Costa-Neves, Adriana; Sant'Anna, Célia Leite; de Carvalho, Luciana Retz

    2014-01-22

    Cyanobacteria are common members of the freshwater microbiota in lakes and drinking water reservoirs, and are responsible for several cases of human intoxications in Brazil. Pseudanabaena galeata and Geitlerinema splendidum are examples of the toxic species that are very frequently found in reservoirs in Sao Paulo, which is the most densely populated area in Brazil. In the search for toxic strains collected from water reservoirs and maintained in the Cyanobacterial Culture Collection (CCIBt) of the Institute of Botany of Brazil, the acetic acid extracts (AE) of P. galeata CCIBt 3082 and G. splendidum CCIBt 3223 were analyzed by planar chromatography, which indicated the absence of cyanotoxins. Animal tests were then carried out, and both extracts were found to induce toxic effects in mice when administered intraperitoneally. The present study aimed to investigate whether the oral ingestion of the above mentioned cyanobacteria extracts would also induce toxic effects in mice. Necropsy and histopathological studies were conducted using tissue samples from the animals, which were euthanized one week after the administration of the extracts. The AE of P. galeata did not cause death but did induce transient symptoms, including eyebrow ptosis, straub tail, and pain. The euthanized animals presented hemorrhage in the liver, whereas the histological analysis showed disorganization of the hepatic parenchyma, necrosis, hyperemia, and proximity of the centrilobular vein in the liver. In addition, alterations in the convoluted tubules of the kidneys were observed, and the lungs were unaffected. The AE of G. splendidum caused only one death, and induced transient symptoms, such as dyspnea, paralysis, and pain, in the other mice. The necropsy of the euthanized mice showed hemorrhage in the lungs and liver. The lungs presented hemorrhagic focuses, alveolar collapse, and granulomatous foci. The liver presented hemorrhagic and enlarged sinusoids, hyperemia, proximity of the

  11. Analysis of the Toxicity and Histopathology Induced by the Oral Administration of Pseudanabaena galeata and Geitlerinema splendidum (Cyanobacteria Extracts to Mice

    Directory of Open Access Journals (Sweden)

    Marisa Rangel

    2014-01-01

    Full Text Available Cyanobacteria are common members of the freshwater microbiota in lakes and drinking water reservoirs, and are responsible for several cases of human intoxications in Brazil. Pseudanabaena galeata and Geitlerinema splendidum are examples of the toxic species that are very frequently found in reservoirs in Sao Paulo, which is the most densely populated area in Brazil. In the search for toxic strains collected from water reservoirs and maintained in the Cyanobacterial Culture Collection (CCIBt of the Institute of Botany of Brazil, the acetic acid extracts (AE of P. galeata CCIBt 3082 and G. splendidum CCIBt 3223 were analyzed by planar chromatography, which indicated the absence of cyanotoxins. Animal tests were then carried out, and both extracts were found to induce toxic effects in mice when administered intraperitoneally. The present study aimed to investigate whether the oral ingestion of the above mentioned cyanobacteria extracts would also induce toxic effects in mice. Necropsy and histopathological studies were conducted using tissue samples from the animals, which were euthanized one week after the administration of the extracts. The AE of P. galeata did not cause death but did induce transient symptoms, including eyebrow ptosis, straub tail, and pain. The euthanized animals presented hemorrhage in the liver, whereas the histological analysis showed disorganization of the hepatic parenchyma, necrosis, hyperemia, and proximity of the centrilobular vein in the liver. In addition, alterations in the convoluted tubules of the kidneys were observed, and the lungs were unaffected. The AE of G. splendidum caused only one death, and induced transient symptoms, such as dyspnea, paralysis, and pain, in the other mice. The necropsy of the euthanized mice showed hemorrhage in the lungs and liver. The lungs presented hemorrhagic focuses, alveolar collapse, and granulomatous foci. The liver presented hemorrhagic and enlarged sinusoids, hyperemia

  12. Toxicity of zinc oxide nanoparticles in rats treated by two different routes: single intravenous injection and single oral administration.

    Science.gov (United States)

    Choi, Jonghye; Kim, Heyjin; Kim, Pilje; Jo, Eunhye; Kim, Hyun-Mi; Lee, Moo-Yeol; Jin, Seon Mi; Park, Kwangsik

    2015-01-01

    Toxicokinetics of zinc oxide nanoparticles (ZnONP) was studied in rats via a single intravenous (iv) injection and a single oral administration (3 mg/kg or 30 mg/kg), respectively. Blood concentrations of zinc (Zn) were monitored for 7 d and tissue distribution were determined in liver, kidneys, lung, spleen, thymus, brain, and testes. To ascertain the excretion of ZnONP, Zn levels in urine and feces were measured for 7 d. ZnONP were not readily absorbed from the gastrointestinal tract (GIT) after oral administration and were excreted mostly in feces. When the nanoparticles were injected iv to rats at a dose of 30 mg/kg, peak concentration appeared at 5 min but returned to normal range by d 2 (48 h after injection). ZnONP were distributed mainly to liver, kidneys, lung, and spleen, but not to thymus, brain, and testes. The distribution level was significantly decreased to normal by d 7. Feces excretion levels after iv injection supported biliary excretion of ZnONP. In rats injected iv with 30 mg/kg, mitotic figures in hepatocytes were significantly increased and multifocal acute injuries with dark brown pigment were noted in lungs, while no significant damage was observed in rats treated orally with the same dosage.

  13. [Gymnema sylvestre leaf extract: a 52-week dietary toxicity study in Wistar rats].

    Science.gov (United States)

    Ogawa, Yukio; Sekita, Kiyoshi; Umemura, Takashi; Saito, Minoru; Ono, Atsushi; Kawasaki, Yasushi; Uchida, Osayuki; Matsushima, Yuko; Inoue, Tohru; Kanno, Jun

    2004-02-01

    A 52-week study of oral-repeated-dose toxicity for the extraction powder of Gymnema sylvestre (GS), Indian-native genus, Metaplexis japonica, was conducted in both genders of Wistar rats. The rats were administered a graded dose of GS at 0.01, 0.10 and 1.00% of basal powder diet, along with a group fed solely with the basal powder diet without GS, for 52 weeks. General conditions were recorded daily. Body weights and food consumptions were recorded weekly up to 12 weeks, and thereafter at longer intervals. At 26 weeks, for an intermediate examination, and 52 weeks, for the final examination, animals were subjected to hematology, serum chemistry, and pathological examination. None of the animals died in the period up to 52 weeks. No exposure-related changes in body-weight, in the food consumption, in the hematological examinations, or in the serum biochemical examinations were recognized. No histopathological alterations were seen. Thus, it was concluded that there was no toxic effect in rats treated with GS at up to 1.00% in the diet for 52 weeks. The no-observable-effect level from this study is 1.00% GS, i.e., 504 mg/kg/day for male and 563 mg/kg/day for female as mean daily intake, for 52 weeks.

  14. Fourteen-Day Subchronic Oral Toxicity Study of 4-Nitrophenyl Methyl (Phenyl) Phosphinate in Male and Female Rats.

    Science.gov (United States)

    1982-09-01

    Lewis-- 14 a ~1 A Lewis--15 TEST SUBSTANCE 1. Chemical name: 4-Nitrophenyl Methyl (Phenyl) Phosphinate Chemical Abstract Service Registry No.: None...11.25 2. Chemical name: Polysorbate 80 (Tween 80) Chemical Abstract Service Registry No.: 9005-65-6 Molecular structure: HO(C 2 40) ( C 2 H 4 )XOH...particularly in chronic toxicity studies in experimental data. APPENDIX A (Cant) Lewis--17 3. Chemical name: Citric Acid, monohydrate Chemical Abstract Service

  15. Acute and subacute oral toxicity assessment of the oil extracted from Attalea phalerata Mart ex Spreng. pulp fruit in rats.

    Science.gov (United States)

    Freitas de Lima, Fernando; Traesel, Giseli Karenina; Menegati, Sara Emilia Lima Tolouei; Santos, Ariany Carvalho Dos; Souza, Roosevelt Isaias Carvalho; de Oliveira, Vinícius Soares; Sanjinez-Argandoña, Eliana Janet; Cardoso, Claudia Andrea Lima; Oesterreich, Silvia Aparecida; Vieira, Maria do Carmo

    2017-01-01

    Attalea phalerata Mart. ex Spreng., popularly known as "bacuri", is a native plant from the brazilian Cerrado and used in folk medicine as a pulmonary decongestant, an anti-inflammatory for joints and antipyretic. There is an expectation about the use in chronic disease of the Attalea phalerata oil since its composition is high in carotenoids and beneficial fatty acids. The aim of the study was to evaluate the toxicological profile of the oil extracted from Attalea phalerata Mart. ex Spreng. pulp (APO). Acute and subacute toxicity studies were performed in male and female Wistar rats according to the OECD - Guidelines 425 and 407. For the acute toxicity, one single dose of the APO (2000mg/kg) was administered by gavage to five female rats. In the subacute toxicity, four different doses (125, 250, 500 and 1000mg/kg) of the APO were administered to male and female rats for 28 consecutive days. No deaths or behavioral changes were observed during both experiments as well as no changes in organ weights, hematological, histopathological parameters. The biochemical parameters showed changes in phosphatase alkaline and albumin levels, however these values are within the normal range for the species. A significant reduction in cholesterol and triglycerides was also observed in some of the animals treated with the APO. Therefore, the LD50 is higher than 2000mg/kg and the APO oil can be considered safe at the doses tested in rats. However, further assessments are required in order to proceed to clinical studies in humans.

  16. Subchronic oral toxicity evaluation of ethanolic whole plant extract of Eleucine indica on haematological and biochemical indices in Wistar albino rats

    Directory of Open Access Journals (Sweden)

    Ette Okon Ettebong

    2016-02-01

    Full Text Available Objective: To evaluate the effect of ingestion of ethanolic whole plant extract of Eleucine indica on haematological and biochemical parameters of Wistar albino rats. Methods: Subchronic toxicity study was carried out by oral administration of different doses (200, 400 and 600 mg/kg body weight of the extract on alternate-day basis to different groups of rats for 28 days. The animals were subsequently sacrificed and blood samples were collected by cardiac puncture for haematological and biochemical analyses. Results: Haematological indices were preserved and the extract showed significant (P < 0.01–0.001 haemostatic potentials. There was significant reduction (P < 0.05–0.001 in total bilirubin, aspartate aminotransferase (P < 0.001, alanine transaminase (P < 0.05, alkaline phosphatase (P < 0.001 and blood glucose (P < 0.001 compared to control. The level of total protein increased significantly (P < 0.05–0.001. Kidney functions were, however, intact. Conclusions: The results obtained indicated that ingestion of Eleucine indica whole plant extract for a long period of time reduces both bleeding and clotting times, reduces blood sugar and shows no apparent toxic effect on liver and kidneys. The results of this study may be useful as a basis for clinical trials in humans.

  17. Evaluation of the Genotoxic Potential against H2O2-Radical-Mediated DNA Damage and Acute Oral Toxicity of Standardized Extract of Polyalthia longifolia Leaf

    Directory of Open Access Journals (Sweden)

    Subramanion L. Jothy

    2013-01-01

    Full Text Available Medicinal plants have been used in medicoculturally diverse countries around the world, where it is a part of a time-honoured tradition that is respected even today. Polyalthia longifolia leaf extract has been previously reported as an efficient antioxidant in vitro. Hence, the genotoxic effects of P. longifolia leaf were investigated by using plasmid relation, comet, and Allium cepa assay. In the presence of  ∙OH radicals, the DNA in supercoil was start nicked into open circular form, which is the product of the single-stranded cleavage of supercoil DNA and quantified as fragmented separate bands on agarose gel in plasmid relation assay. In the plasmid relation and comet assay, the P. longifolia leaf extract exhibited strong inhibitory effects against H2O2-mediated DNA damage. A dose-dependent increase of chromosome aberrations was also observed in the Allium cepa assay. The abnormalities scored were stickiness, c-mitosis, bridges, and vagrant chromosomes. Micronucleated cells were also observed at the interphase. The results of Allium cepa assay confirmed that the methanol extracts of P. longifolia exerted no significant genotoxic or mitodepressive effects at 100 μg/mL. Thus, this study demonstrated that P. longifolia leaf extract has a beneficial effect against oxidative DNA damage. This experiment is the first report for the protective effect of P. longifolia on DNA damage-induced by hydroxyl radicals. Additionally in acute oral toxicity study, female rats were treated at 5000 mg/kg body weight of P. longifolia leaf extract and observed for signs of toxicity for 14 days. P. longifolia leaf extract did not produce any treatment-related toxic effects in rats.

  18. Evaluation of the Genotoxic Potential against H2O2-Radical-Mediated DNA Damage and Acute Oral Toxicity of Standardized Extract of Polyalthia longifolia Leaf

    Science.gov (United States)

    Jothy, Subramanion L.; Chen, Yeng; Kanwar, Jagat R.; Sasidharan, Sreenivasan

    2013-01-01

    Medicinal plants have been used in medicoculturally diverse countries around the world, where it is a part of a time-honoured tradition that is respected even today. Polyalthia longifolia leaf extract has been previously reported as an efficient antioxidant in vitro. Hence, the genotoxic effects of P. longifolia leaf were investigated by using plasmid relation, comet, and Allium cepa assay. In the presence of  ∙OH radicals, the DNA in supercoil was start nicked into open circular form, which is the product of the single-stranded cleavage of supercoil DNA and quantified as fragmented separate bands on agarose gel in plasmid relation assay. In the plasmid relation and comet assay, the P. longifolia leaf extract exhibited strong inhibitory effects against H2O2-mediated DNA damage. A dose-dependent increase of chromosome aberrations was also observed in the Allium cepa assay. The abnormalities scored were stickiness, c-mitosis, bridges, and vagrant chromosomes. Micronucleated cells were also observed at the interphase. The results of Allium cepa assay confirmed that the methanol extracts of P. longifolia exerted no significant genotoxic or mitodepressive effects at 100 μg/mL. Thus, this study demonstrated that P. longifolia leaf extract has a beneficial effect against oxidative DNA damage. This experiment is the first report for the protective effect of P. longifolia on DNA damage-induced by hydroxyl radicals. Additionally in acute oral toxicity study, female rats were treated at 5000 mg/kg body weight of P. longifolia leaf extract and observed for signs of toxicity for 14 days. P. longifolia leaf extract did not produce any treatment-related toxic effects in rats. PMID:23878610

  19. Short-Term Effects of Oral Administration of Pistacia Lentiscus Oil on Tissue-Specific Toxicity and Drug Metabolizing Enzymes in Mice

    Directory of Open Access Journals (Sweden)

    Samir Attoub

    2014-05-01

    Full Text Available Background: Pistacia lentiscus (Anacardiaceae is a flowering plant traditionally used in the treatment of various skin, respiratory, and gastrointestinal disorders. The aim of this study was to assess whether Pistacia lentiscus oil has any short term toxic effects in vivo and in vitro. Methods: Pistacia lentiscus oil (100µl was administered orally into mice for 5 days. Results: Measurements of body weight did not show any weight loss. Serum concentration of LDH did not show any significant statistical difference when compared to control mice. Similarly, blood, kidney or liver function tests showed no toxicity with Pistacia lentiscus oil when compared to the control group. Examination of gastrointestinal tissues sections revealed similar structural features with no difference in cell proliferation. In this context, pharmacological dilutions of Pistacia lentiscus oil (10-6 - 10-3 did not affect the viability (cell death and proliferation of mouse gastric stem cells, human colorectal cancer cells HT29, human hepatoma cells HepG2. However, it appears that at the dose and time point studied, Pistacia lentiscus oil treatment has targeted various cytochrome P450s and has specifically inhibited the activities and the expression of CYP2E1, CYP3A4, CYP1A1 and CYP1A2 differentially in different tissues. Our results also demonstrate that there is no appreciable effect of Pistacia lentiscus oil on the GSH-dependent redox homoeostasis and detoxification mechanism in the tissues. Conclusion: These data suggest a good safety profile of short term oral use of Pistacia lentiscus oil as a monotherapy in the treatment of various skin, respiratory, and gastrointestinal disorders. However, due to its inhibitory effect of various cytochrome P450s and mainly CYP3A4, this might have implications on the bioavailability and metabolism of drugs taken in combination with Pistacia lentiscus oil. More attention is needed when Pistacia lentiscus oil is intended to be uses in

  20. A 56-Day Oral Toxicity Study of the Aqueous Extract of Rapanea melanophloeos (L.) Mez in Rats

    Science.gov (United States)

    Mbaria, James M.; Thaiyah, Andrew G.; Thoithi, Grace N.; Gathumbi, Peter K.

    2016-01-01

    Rapanea melanophloeos is a tropical tree that is extensively utilized in African traditional medicine to treat helminthiases, tuberculosis, and heart-water. As with many other medicinal plants, there is insufficient information regarding the safety of therapeutic R. melanophloeos extracts. An aqueous extract of R. melanophloeos stem bark was administered to Sprague Dawley rats at doses of 100 mg/kg, 300 mg/kg, and 1000 mg/kg for 56 days to characterize its potential toxicity after prolonged dosing. Blood samples were obtained fortnightly for serum chemistry and hematology, while organs were collected at the end of the study. The extract caused an increase in organ weight indices of the kidneys and testis at 300 mg/kg and 1000 mg/kg. Hematological and biochemical examination revealed a drop in leukocyte counts and the hematocrit at 1000 mg/kg dose level, while there was a general but nondose-related elevation in alkaline phosphatase activity. There were time-associated variations in the hematological and clinical chemistry parameters at days 28, 42, and 56 in all dose levels, but most values remained within physiological limits. No pathological lesions were evident at histopathology after treatment with the extract. Our data shows that the aqueous extract of R. melanophloeos is not likely to be toxic at the doses tested and provides support to its medicinal use. PMID:28105062

  1. A 90-day oral (dietary) toxicity and mass balance study of corn starch fiber in Sprague Dawley rats.

    Science.gov (United States)

    Crincoli, Christine M; Nikiforov, Andrey I; Rihner, Marisa O; Lambert, Elizabeth A; Greeley, Melanie A; Godsey, Justin; Eapen, Alex K; van de Ligt, Jennifer L G

    2016-11-01

    The potential toxicity of corn starch fiber was assessed and compared to polydextrose, a commonly used bulking agent with a long history of safe use in the food supply. Groups of male and female Crl:CD(SD) rats were fed 0 (control), 1,000, 3,000, or 10,000 mg/kg-bw/day corn starch fiber in the diet for 90 days. The polydextrose reference article was offered on a comparable regimen at 10,000 mg/kg-bw/day. Following a single gavage dose of [(14)C]-corn starch fiber on study day 13 or 90, the mass balance of the test article was assessed by analysis of excreta samples collected from 0 to 168 h post-dose. There were no toxicologically or biologically relevant findings in any of the test article-treated groups. The few minor differences observed between the corn starch fiber and polydextrose exposed groups were considered to be due to normal biological variation. Following [(14)C]-corn starch fiber dosing, nearly complete excretion of the administered dose occurred over 168 h post-dosing, with the majority excreted in the feces. The dietary no-observed-adverse-effect level of corn starch fiber after 90 days was 10,000 mg/kg-bw/day. Similar toxicity profiles for corn starch fiber and polydextrose were observed due to the structural and compositional similarities of these materials.

  2. A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

    Science.gov (United States)

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2014-04-01

    3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

  3. Six-month oral toxicity of D-004, a lipid extract from Roystonea regia fruits, in Sprague Dawley rats

    Directory of Open Access Journals (Sweden)

    Balia Pardo

    2009-01-01

    Full Text Available El D-004 es un extracto lipídico obtenido del fruto de la palma real (Roystonea regia que consiste en una mezcla de ácidos grasos, en la cual los ácidos oleico, palmítico, láurico y mirístico son los más abundantes. El tratamiento oral con D-004 inhibe significativamente la hiperplasia prostática inducida por testosterona en roedores. Este ensayo se realizó para investigar la toxicidad inducida por el D-004 en ratas Sprague Dawley (SD. Las ratas de ambos sexos fueron distribuidas al azar en cuatro grupos experimentales (24 ratas sexo/grupo, un control que recibió el vehículo tween 65/agua y tres grupos tratados con D-004 a las dosis de 500, 750 y 1 000 mg/(kg · d, respectivamente. Las observaciones clínicas se realizaron diariamente. El peso corporal y el consumo de alimentos se determinaron semanalmente durante las primeras 13 semanas y mensualmente hasta el final del estudio. Los animales fueron sacrificados en atmósfera de éter. Ninguna evidencia de efectos tóxicos fue detectada en relación con el tratamiento. Las observaciones clínicas, peso corporal, consumo de alimentos, indicadores de bioquímica y hematología sanguínea, peso de órganos y hallazgos histopatológicos no arrojaron diferencias significativas entre grupos tratados y control. Las lesiones histopatológicas encontradas en este estudio fueron comunes a esta especie y línea. Basado en los presentes resultados, la mayor dosis investigada (1 000 mg/kg durante la administración oral del D-004 durante seis meses a ratas SD, se comportó como un nivel de dosis que no produjo efectos tóxicos, lo que hace pensar que esta sustancia presenta una toxicidad oral potencialmente baja.

  4. Does use of oral contraceptives enhance the toxicity of carbon disulfide through interactions with pyridoxine and tryptophan metabolism?

    Science.gov (United States)

    Calabrese, E J

    1980-01-01

    It is proposed that oral contraceptive (OC) users are at increased risk to experiencing adverse psychological disorders (e.g. irritability, depression) from exposures to elevated levels of carbon disulfide (CS2). This theory is based on studies indicating that both OCs and CS2 induce either a vitamin B6 deficiency and/or enhance its requirement. Since disruptions of B6 metabolism are thought to explain, at least in part, the adverse psychological effects of OCs and CS2, it is speculated that joint exposure to these substances may result in an exaggerated disruption of B6 metabolism with the development of CS2 induced adverse psychological effects occurring at exposure levels below those normally associated with adverse effects.

  5. Toxic influence of chronic oral administration of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice

    Institute of Scientific and Technical Information of China (English)

    REN Jin-peng; ZHAO Yu-wu; SUN Xiao-jiang

    2009-01-01

    Background Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide, has been repeatedly suggested as a potential etiologic factor for the development of Parkinson's disease (PD), owing to its structural similarity to the known dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This study aimed to observe the influence of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice. Methods A total of 24 male C57BL/6 mice were assigned randomly to 3 groups: control group (treated by saline), PQ treated group, and MPTP treated group. Mice in PQ treated group were taken orally with PQ (10 mg/kg) daily for four months. Locomotor activity was measured. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and tyrosine hydroxylase (TH) positive neurons were detected by using immunohistochemistry. At the same time, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and the content of malondialdehyde (MDA) in substantia nigra were measured by spectrophotometry, mRNA expression of dopamine transporter (DAT) in dopaminergic neurons of substantia nigra was also determined by reverse transcription (RT)-PCR technique. Results Locomotor activities were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined. The activities of SOD and GSH-PX were decreased, and the content of MDA was increased in PQ treated mice compared with that in control group. Numbers of TH positive neurons and the mRNA expression of DAT in substantia nigra of mice were also decreased after PQ taken orally for four months.

  6. A subchronic (180-day) oral toxicity study of ethyl tertiary-butyl ether, a bioethanol, in rats.

    Science.gov (United States)

    Miyata, Katsumi; Koga, Takayuki; Aso, Sunao; Hoshuyama, Satsuki; Ajimi, Syozo; Furukawa, Kotaro

    2014-07-01

    A subchronic (180-day) toxicity study was conducted to evaluate the effects of ethyl tertiary-butyl ether (ETBE), a biomass fuel, in male and female rats. ETBE was administered at dose levels of 0, 5, 25, 100 and 400 mg/kg/body weight (b.w.)/day by gavage. No treatment-related adverse effects were observed at 5, 25 or 100 mg/kg. Centrilobular hypertrophy of hepatocytes was observed in males and females and their relative liver weights were increased, suggesting enhanced metabolic activity. From these results, we concluded that the no observed adverse effect level of ETBE was 100 mg/kg b.w./day under the conditions tested.

  7. Developmental toxicity studies with 6 forms of titanium dioxide test materials (3 pigment-different grade & 3 nanoscale) demonstrate an absence of effects in orally-exposed rats.

    Science.gov (United States)

    Warheit, D B; Boatman, R; Brown, S C

    2015-12-01

    Six different commercial forms and sizes of titanium dioxide particles were tested in separate developmental toxicity assays. The three pigment-grade (pg) or 3 ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particle-types were evaluated for potential maternal and developmental toxicity in pregnant rats by two different laboratories. All studies were conducted according to OECD Guideline 414 (Prenatal Developmental Toxicity Study). In addition, all test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 to 17 m(2)/g and 50-82 m(2)/g respectively (see Table 1). The test substances were formulated in sterile water. In all of the studies, the formulations were administered by oral gavage to time-mated rats daily beginning around the time of implantation and continuing until the day prior to expected parturition. In 3 of the studies (uf-1, uf-3, & pg-1), the formulations were administered to Crl:CD(SD) rats beginning on gestation day (GD) 6 through GD 20. In 3 additional studies (uf-2, and pg-2, pg-3 TiO2 particles), the formulations were administered to Wistar rats beginning on GD 5 through 19. The dose levels used in all studies were 0, 100, 300, or 1000 mg/kg/day; control group animals were administered the vehicle. During the in-life portions of the studies, body weights, food consumption, and clinical observations before and after dosing were collected on a daily basis. All dams were euthanized just prior to expected parturition (GD 21 for Crl:CD(SD) rats and GD 20 for Wistar rats). The gross necropsies included an examination and description of uterine contents including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. All live fetuses were sexed, weighed, and examined externally and euthanized. Following euthanasia, fresh visceral and head examinations were performed on selected fetuses. The fetal carcasses were then processed and examined for skeletal

  8. Randomized study of nutritional status and treatment toxicities of oral arginine, glutamine, and Omega-3 fatty acids during concurrent chemoradiotherapy for head and neck cancer patients

    Directory of Open Access Journals (Sweden)

    Imjai Chitapanarux

    2016-03-01

    Full Text Available Background: Patients with head and neck cancer (HNC undergoing concurrent chemoradiotherapy (CCRT are at high risk of dysphagia, malnutrition, and immunosuppression. Arginine, glutamine, and Omega-3 fatty acidsare immune-enhanced nutrition that can promote cellular immunity.We aimed to examine the impact of immunonutrition diet on nutritional status, and CCRT toxicities, in this group of patients. Methods: Forty patients with HNC who treated with curative CCRT were randomized to: group A (n = 20, patients who received a regular diet and dietary counselingby a protocol dietician; group B (n = 20, patients who received a regular diet plus immune-enhanced nutrition supplements and dietary counseling by the same protocol dietician. Outcome measures were weight loss, protein and energy intake, serum pre-albumin and albumin, and toxicities of CCRT were evaluated at baseline, weekly and at the end of treatment. Results:Both groups were well balanced at baseline.One patient from group A (1/20 withdrew consent. Seven patients from group B (7/20 withdrew from the study; 1 patient could not tolerate the side effect of chemotherapy and 6 patients could not tolerate the taste of oral immune-enhanced nutrition.A significant loss in total body weight was observed in group A patients (p<0.001, whereas not significant loss in group B (p=0.109. Median percentage change from baseline of energy intake was 19.6%, and 22.9% at the end of treatment for group A, and B, respectively. The circulating levels of nutritional markers, pre-albumin and albumin decreased after CCRT in both groups. There was a significantly decreased level of albumin in group A more than group B, at the end of treatment. During CCRT; 4 patients (20% in group A and 1 patient(5% in group B developed grade 3 mucositis, respectively. One patient (5% in group A had grade 3 radiation dermatitis. Grade 3 – 4 hematologic toxicities, mainly in absolute neutrophil count (ANC were significant higher in

  9. Duration of Acute and Chronic Toxicity Testing in Animals (ICH S4A and S4B)

    DEFF Research Database (Denmark)

    Spindler, Per; Van Cauteren, Herman

    2013-01-01

    for the ICH S4B guideline regarding the duration of non-rodent repeated dose toxicity studies is explained and lessons learned are discussed. Since the guideline was issued in 1997 changes occurred in e.g. the language of the European legislation, and the requirements for non-clinical studies to support...

  10. Toxicity and Safety Profiles of Methanolic Extract of Pistacia integerrima J. L. Stewart ex Brandis (PI for Wistar Rats

    Directory of Open Access Journals (Sweden)

    Gotmi Sharwan

    2016-09-01

    Full Text Available Objectives: The goals of this research were to evaluate acute (single-dose and sub-acute (repeated-dose toxicity profiles of methanolic extract of Pistacia integerrima J. L. Stewart ex Brandis (PI for Wistar rats and to assess the safety profile of PI by observing physiological changes, mortality, changes in body weight

  11. Distribution and toxicity of monosodium methanearsonate following oral administration of the herbicide to dairy sheep and goats.

    Science.gov (United States)

    Shariatpanahi, M; Anderson, A C

    1984-01-01

    Iranian fat-tailed sheep and dairy goats were administered the herbicide monosodium methanearsonate orally at a dose of 10 mg. MSMA (as arsenic) per kg. of body weight. The concentration time curves of MSMA in the blood of sheep and goats followed a first order composite exponential equation of the form: Cb(t) = Ae- alpha t + Be- beta t - C degrees be-kat. Absorption, distribution and elimination of MSMA, therefore, corresponds to an open two-compartment model. Arsenic from MSMA was readily absorbed from gastrointestinal tract and distributed in the body fluids and the various tissues. Approximately 90% of the arsenic was excreted in the urine within 120 hrs and small amounts were also recovered in feces. Arsenic accumulation in the tissues was low and urinary excretion was the most important exit route. Arsenic concentrations in milk were low when compared to the controls, which indicates that arsenic is not excreted in the milk to significant levels. The absorption, distribution and overall elimination rate constants for the two animal species studied were statistically different at the 0.95 level of confidence which indicates that there are apparently differences in MSMA metabolism by sheep and goats.

  12. Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney.

    Science.gov (United States)

    Sawada, Stefanie; Oberemm, Axel; Buhrke, Thorsten; Merschenz, Julia; Braeuning, Albert; Lampen, Alfonso

    2016-06-01

    3-Chloropropane-1,2-diol (3-MCPD) and its fatty acid esters are formed during thermal treatment of fat-containing foodstuff in the presence of salt. Toxicological studies indicate a carcinogenic potential of 3-MCPD, pointing to the kidney as the main target organ. It is assumed that the toxicological property of 3-MCPD esters is constituted by the release of 3-MCPD during digestion. In a repeated-dose 28-day oral toxicity study using Wistar rats, animals were treated with equimolar doses of either 3-MCPD (10 mg/kg body weight) or 3-MCPD dipalmitate (53 mg/kg body weight). A lower dose of 3-MCPD dipalmitate (13.3 mg/kg body weight) was also applied. No histopathologically visible toxicity was observed in the study. To address molecular mechanisms leading to toxicity of 3-MCPD and its esters, kidney samples were analyzed by a comparative, two-dimensional gel electrophoresis/mass spectrometry proteomic approach. After either 3-MCPD or 3-MCPD dipalmitate treatment, alterations in proteins related to various metabolic pathways, including carbohydrate, amino acid, and fatty acid metabolism, were detected. These findings confirm and complement previous data on the inhibition of glucose metabolism by 3-MCPD. Altogether, broad overlap of 3-MCPD- and 3-MCPD dipalmitate-induced proteomic changes was observed. Further analyses revealed that the observed induction of glutathione S-transferase pi 1 (Gstp1) occurred at the transcriptional level and was not related to nuclear factor (erythroid-derived 2)-like 2 activation. Overall, the results indicate common mechanisms of toxicity for 3-MCPD and its dipalmitate ester. Furthermore, data suggest Gstp1 as a sensitive marker for early 3-MCPD-induced effects in rat kidney.

  13. P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: In vitro, in situ, in vivo and in silico studies

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Cuiping, E-mail: yangsophia76@hotmail.com; Zhang, Tianhong, E-mail: wdzth@sina.com; Li, Zheng, E-mail: lizh2524@126.com; Xu, Liang, E-mail: wj24998@163.com; Liu, Fei, E-mail: liufeipharm@163.com; Ruan, Jinxiu, E-mail: ruanjx1936@yahoo.com.cn; Liu, Keliang, E-mail: keliangliu55@126.com; Zhang, Zhenqing, E-mail: zhangzhenqingpharm@163.com

    2013-12-15

    Aconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variable bioavailability of oral AC. First, the bidirectional transport of AC across Caco-2 and MDCKII-MDR1 cells was investigated. The efflux of AC across monolayers of these two cell lines was greater than its influx. Additionally, the P-gp inhibitors, verapamil and cyclosporin A, significantly decreased the efflux of AC. An in situ intestinal perfusion study in rats showed that verapamil co-perfusion caused a significant increase in the intestinal permeability of AC, from 0.22 × 10{sup −5} to 2.85 × 10{sup −5} cm/s. Then, the pharmacokinetic profile of orally administered AC with or without pre-treatment with verapamil was determined in rats. With pre-treatment of verapamil, the maximum plasma concentration (C{sub max}) of AC increased sharply, from 39.43 to 1490.7 ng/ml. Accordingly, a 6.7-fold increase in the area under the plasma concentration–time curve (AUC{sub 0–12} {sub h}) of AC was observed when co-administered with verapamil. In silico docking analyses suggested that AC and verapamil possess similar P-gp recognition mechanisms. This work demonstrated that P-gp is involved in limiting the intestinal absorption of AC and attenuating its toxicity to humans. Our data indicate that potential P-gp-mediated drug–drug interactions should be considered carefully in the clinical application of aconite and formulations containing AC. - Highlights: • Verapamil and cyclosporin A decreased the efflux of aconitine across Caco-2 cells. • Both inhibitors decreased the efflux of aconitine across MDCKII-MDR1 cells. • Co-perfusion with verapamil increased the intestinal permeability of aconitine. • Co-administration with verapamil sharply increased the C{sub max

  14. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study.

    Science.gov (United States)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At ≥120mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells.

  15. Oral administration of Moringa oleifera oil but not coconut oil prevents mercury-induced testicular toxicity in rats.

    Science.gov (United States)

    Abarikwu, S O; Benjamin, S; Ebah, S G; Obilor, G; Agbam, G

    2017-02-01

    This study was conducted to compare the effects of administration of coconut oil (CO) and Moringa oleifera oil (MO) on testicular oxidative stress, sperm quality and steroidogenesis parameters in rats treated with mercury chloride (HgCl2 ). After 15 days of oral administration of CO (2 ml kg(-1) body weight) and MO (2 ml kg(-1) body weight) along with intraperitoneal (i.p.) administration of HgCl2 (5 mg kg(-1) body weight) alone or in combination, we found that CO treatment did not protect against HgCl2 -induced poor sperm quality (motility, count) as well as decreased testosterone level and 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Treatment with CO alone decreased glutathione (GSH), and glutathione peroxidase (GSH-Px) activities and increased malondialdehyde (MDA) level in rat's testis, whereas MO did not change these parameters. Cotreatment with MO prevented HgCl2 -induced testicular catalase (CAT) and superoxide dismutase (SOD) activities, poor sperm quality and low testosterone level and also blocks the adverse effect of CO+HgCl2 (2 ml kg(-1) body weight + 5 mg kg(-1) body weight) on the investigated endpoints. In conclusion, MO and not CO decreased the deleterious effects of HgCl2 on sperm quality and steroidogenesis in rats and also strengthen the antioxidant defence of the testes. Therefore, MO is beneficial as an antioxidant in HgCl2 -induced oxidative damage.

  16. Effects of Acute Oral 5-aminotetrazole (5-AT) Exposure to Rats (Rattus norvegicus)

    Science.gov (United States)

    2015-02-12

    Micronucleus Assay (MNA) Male rats from the 5-AT study (three highest dose groups and the vehicle control) were tested for DNA damage in their peripheral...Dose Test (Sub-acute Study) - Sperm Collection and Analysis 09/25/2013 10/07/2013 14-Day Repeated Dose Test (Sub-acute Study) - Micronucleus Assay...2015 Prepared by: Valerie H Adams, Ph.D. Approved for public release; distribution unlimited. Specialty: 500C Toxicity Test Toxicity Report No. S

  17. Subacute toxicity evaluation of KR-33493, FAF1 inhibitor for a new anti-parkinson's disease agent, after oral administration in rats and dogs.

    Science.gov (United States)

    Jeong, Jong-Woo; Yu, Changsun; Lee, Jong-Hwa; Moon, Kyoung-Sik; Kim, Eunhee; Yoo, Sung-Eun; Koo, Tae-Sung

    2016-11-01

    KR33493, a newly developed FAS-associated factor 1 (FAF1) inhibitor for Parkinson's disease, is being evaluated in a Phase I clinical trial. In the present study, the subchronic toxicity of KR33493 in Sprague-Dawley (SD) rats and beagle dogs was investigated at various oral doses for 28 and 14 days, respectively. During the study, food consumption, body weights, organ weights, gross findings, and mortality were examined; and ophthalmoscopy, electrocardiography, hematology, serum biochemistry, urinalysis, histopathology, and toxicokinetics were performed. In rats, weight gain decreased in both sexes at 500 mg/kg/day, with no significant differences. In dogs, some significant differences compared with the control were found during the trial; however, at the end of recovery periods, these were no longer observed and there was no dose correlation. Some histopathological findings were observed, but these were considered as incidental changes. Since no other significant changes were observed, doses above 500 and 1000 mg/kg KR33493 in rat and dogs, respectively, caused no observed adverse effects. Therefore, based on these results, the Phase 1 clinical trial for KR33493 was approved by the Korean Food & Drug Administration.

  18. Comparative 28-day repeated oral toxicity of Longdan Xieganwan, Akebia trifoliate (Thunb.) koidz., Akebia quinata (Thunb.) Decne. and Caulis aristolochiae manshuriensis in mice.

    Science.gov (United States)

    Xue, Xiang; Xiao, Ying; Gong, Likun; Guan, Shuhong; Liu, Yongzhen; Lu, Henglei; Qi, Xinming; Zhang, Yunhai; Li, Yan; Wu, Xiongfei; Ren, Jin

    2008-09-02

    Longdan Xieganwan, which contains Aristolochia species, is a traditional Chinese prescription. It has been used for thousands of years to "enhance liver". However, many cases of Longdan Xieganwan induced nephropathy were reported recently. This study was designed to compare the possible toxic effects of Longdan Xieganwan and three different Aristolochia species, i.e. Akebia trifoliate (Thunb.) koid (Akebia trifoliate), Akebia quinata (Thunb.) Decne. (Akebia quinata) and Caulis aristolochiae manshuriensis (Aristolochia manshuriensis). Mice were orally administered these drugs for 28 days. Clinical signs, body weights, serum biochemistry, organ weights and histopathology were examined. Significantly decreased body weights and obvious nephropathy were noticed in the Aristolochia manshuriensis groups at doses higher than 0.24 g/kg/d. A few endothelial cell degenerations in renal glomerulus were observed in the Akebia trifoliate group at a high-dose of 2.00 g/kg/d. No significant changes were observed in the other groups. The no-observed-adverse-effect levels (NOAELs) for Aristolochia manshuriensis, Akebia trifoliate, Akebia quinata and Longdan Xieganwan in this study for mice were 0.06 g/kg/d, 0.40 g/kg/d, higher than 3.00 g/kg/d and higher than 10.00 g/kg/d, which were equivalent to 0.25 times, 5 times, 25 times and 10 times of normal human dose in clinical prescription, respectively.

  19. Nanostructured lipid carriers as a novel oral delivery system for triptolide: induced changes in pharmacokinetics profile associated with reduced toxicity in male rats.

    Science.gov (United States)

    Zhang, Cong; Peng, Fan; Liu, Wei; Wan, Jiangling; Wan, Chunxi; Xu, Huibi; Lam, Christopher Waikei; Yang, Xiangliang

    2014-01-01

    After oral administration in rodents, triptolide (TP), a diterpenoid triepoxide compound, active as anti-inflammatory, immunosuppressive, anti-fertility, anti-cystogenesis, and anticancer agent, is rapidly absorbed into the blood circulation (from 5.0 to 19.5 minutes after dosing, depending on the rodent species) followed by a short elimination half-life (from about 20 minutes to less than 1 hour). Such significant and rapid fluctuations of TP in plasma likely contribute to its toxicity, which is characterized by injury to hepatic, renal, digestive, reproductive, and hematological systems. With the aim of prolonging drug release and improving its safety, TP-loaded nanostructured lipid carriers (TP-NLCs), composed of Compritol® 888 ATO (solid lipid) and Capryol™ 90 (liquid lipid), were developed using a microemulsion technique. The formulated TP-NLCs were also characterized and in vitro release was evaluated using the dialysis bag diffusion technique. In addition, the pharmacokinetics and toxicology profiles of TP-NLCs were compared to free TP and TP-loaded solid lipid nanoparticles (TP-SLNs; containing Compritol 888 ATO only). Results demonstrate that TP-NLCs had mean particle size of 231.8 nm, increased drug encapsulation with a 71.6% efficiency, and stable drug incorporation for over 1-month. TP-NLCs manifested a better in vitro sustained-release pattern compared to TP-SLNs. Furthermore, TP-NLCs prolonged mean residence time (MRT)0-t (Poral delivery system for a safer use of TP.

  20. Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy.

    Science.gov (United States)

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane W; Palyada, Kiran; Shrewsbury, Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.

  1. Activity, toxicity and analysis of resistance of essential oil from Chenopodium ambrosioides after intraperitoneal, oral and intralesional administration in BALB/c mice infected with Leishmania amazonensis: a preliminary study.

    Science.gov (United States)

    Monzote, Lianet; Montalvo, Ana M; Scull, Ramón; Miranda, Migdalia; Abreu, Juan

    2007-01-01

    The World Health Organization has classified the leishmaniasis as a major tropical disease. Current therapy is toxic, expensive and cause several adverse effects. The majority of people in endemic areas of leishmaniasis depend of natural and traditional medicine. This study was developed to examine the activity of the essential oil from Chenopodium ambrosioides in BALB/c mice infected with Leishmania amazonensis. The infected animals received two cycle of treatment by different routes (intraperitoneal, oral or intralesional route). The intraperitoneal administration of the essential oil at dose of 30 mg/Kg prevented lesion development and decrease the parasite burden. Oral administration retarded the infection in the experimental model compared with untreated mice, although it was less effective that the intraperitoneal route. The administration by intralesional route did not show activity. Intraperitoneal and oral treatment at 30 mg/Kg with the essential oil had better antileishmanial effect that treatment with the reference drug, amphotericin B at 1 mg/Kg. Preliminarily, we examined the toxicity and the resistance after treatment. Signs of toxicity were evident only in the animals treated by intraperitoneal route. No resistance was detected in L. amazonensis isolates obtained from treated mice. These data clearly demonstrated that this natural product could be an alternative for the development of a new drug against cutaneous leishmaniasis based in the ethnomedical information.

  2. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Yoshida, Toshinori [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

  3. [LD 50 and selenium concentration in the organs of rabbits following oral administration of sodium selenite and testing of the toxicity of Ursoselevit-Prämix].

    Science.gov (United States)

    Berschneider, F; Hess, M; Neuffer, K; Willer, S

    1976-01-01

    LD50/24hr was established in the first of a series of experiments on 72 rabbits for orally applied sodium selenite. The dosage was 8.62 mg/kg live weight, the confidence interval being (1 - alpha = 0.95) +/- 0.13 mg/kg. The value was four times as high following intravenous application. Complete lethality was recorded from 15 mg Na2SeO3/kg live weight within 21 hours. Thirty-six animals were involved in the second experiment of the series. They had 50 or 100 per cent Ursoselevit-Prämix (30 ppm Se) in their rations. Body mass development of the test animals was superior to that recorded from the controls in the first 50 days, after which limit the former declined strongly in a few days. Their general condition worsened. Postmortem findings, following slaughter, included catarrhal enteritis, toxic liver dystrophy, scattered pulpous tumours in the spleen, and interstitial nephritis. In the third experiment (50 per cent Ursoselevit-Prämix with 60 ppm Se in the rations), the test animals developed better than the controls during the first two months, after which point they exhibited the same clinical symptoms as those observed in the second experiment, stopped to put on weight, and eventually turned cachectic. The pathomorphological findings were identical with those obtained from the second experiment. The selenium concentrations in the organs of the test animals all were much higher than those of the controls. Their amounts in excess to base values were up to eleven times in the blood, nine times in the liver, twelve times in the kidneys, and 13 times in the muscles.

  4. First-in-Human study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics and Pharmacodynamics, in Patients with Metastatic Cancer

    Science.gov (United States)

    Blagden, Sarah; Olmin, Aurelius; Josephs, Debra; Stavraka, Chara; Zivi, Andrea; Pinato, David J.; Anthoney, Alan; Decordova, Shaun; Swales, Karen; Riisnaes, Ruth; Pope, Lorna; Noguchi, Kohei; Shiokawa, Rie; Inatani, Michiyasu; Prince, Jenny; Jones, Keith; Twelves, Chris; Spicer, James; Banerji, Udai

    2014-01-01

    Purpose This Phase I dose-escalation study investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical activity of CH5132799. Patients and Methods Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily (QD) or twice daily (BID) in 28-day cycles. Results Thirty-eight patients with solid tumors received CH5132799 at 2-96 mg QD or 48-72 mg BID. The MTD was 48 mg on the BID schedule but was not reached on the QD schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/ml and 1,550 ng·hr/ml respectively, consistent with efficacious exposure based on preclinical modelling. Reduction in SUVmax with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in five of seven patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pre-treated patient with triple negative breast cancer had marked improvement in her cutaneous skin lesions lasting 6 cycles. Conclusion CH5132799 is well tolerated at the MTD dose 48 mg BID. At this dose the drug had a favorable PK and PD profile and preliminary evidence of clinical activity. PMID:25231405

  5. Differential Effects of Silver Nanoparticles and Silver Ions on Tissue Accumulation, Distribution, and Toxicity in the Sprague Dawley Rat Following Daily Oral Gavage Administration for 13 Weeks.

    Science.gov (United States)

    Boudreau, Mary D; Imam, Mohammed S; Paredes, Angel M; Bryant, Matthew S; Cunningham, Candice K; Felton, Robert P; Jones, Margie Y; Davis, Kelly J; Olson, Greg R

    2016-03-01

    There are concerns within the regulatory and research communities regarding the health impact associated with consumer exposure to silver nanoparticles (AgNPs). This study evaluated particulate and ionic forms of silver and particle size for differences in silver accumulation, distribution, morphology, and toxicity when administered daily by oral gavage to Sprague Dawley rats for 13 weeks. Test materials and dose formulations were characterized by transmission electron microscopy (TEM), dynamic light scattering, and inductively coupled mass spectrometry (ICP-MS). Seven-week-old rats (10 rats per sex per group) were randomly assigned to treatments: AgNP (10, 75, and 110 nm) at 9, 18, and 36 mg/kg body weight (bw); silver acetate (AgOAc) at 100, 200, and 400 mg/kg bw; and controls (2 mM sodium citrate (CIT) or water). At termination, complete necropsies were conducted, histopathology, hematology, serum chemistry, micronuclei, and reproductive system analyses were performed, and silver accumulations and distributions were determined. Rats exposed to AgNP did not show significant changes in body weights or intakes of feed and water relative to controls, and blood, reproductive system, and genetic tests were similar to controls. Differences in the distributional pattern and morphology of silver deposits were observed by TEM: AgNP appeared predominantly within cells, while AgOAc had an affinity for extracellular membranes. Significant dose-dependent and AgNP size-dependent accumulations were detected in tissues by ICP-MS. In addition, sex differences in silver accumulations were noted for a number of tissues and organs, with accumulations being significantly higher in female rats, especially in the kidney, liver, jejunum, and colon.

  6. Pyridostigmine Synergistic Toxicity Study.

    Science.gov (United States)

    1995-05-31

    AND DEET IN THE LABORATORY RAT 1. Executive Sum m ary .............................................................................................. 2 2...TOXICOLOGICAL STUDY 75-48-2665 ACUTE ORAL TOXICITY STUDY OF PYRIDOSTIGMINE BROMIDE. PERMETHRIN. AND DEET IN THE LABORATORY RAT 1. REFERENCES: See Appendix A... LABORATORY RAT 1. PURPOSE: The purpose of this study was to determine potential toxic interactions when pyridostigmine bromide. permethrin. and DEET are given

  7. Acute Toxicity Test of Oral Administration of Artequick in KM mice%青蒿素哌喹片对昆明种小鼠灌胃给药的急性毒性试验

    Institute of Scientific and Technical Information of China (English)

    徐勤; 李晓波; 刘婵; 袁征; 宋健平; 关业枝; 王琪

    2014-01-01

    Objective To study the acute toxicity of artequick after oral administration in mice. Methods By using the Bliss method,the LD50 and its 95 % confidence of artequick in mice were determined after single oral administration for evaluation of the toxicity within 14 days. The gross anatomy and histopathological examination for the dead mice were also carried out. Results After single oral administration,the mice showed various degrees of toxic reaction, showing as less spontaneous activities,closing eyes,face lying,incoordination,tremor,terror,forced paroxysmal spasm,and opisthotonus. The LD50 of artequick in mice was 2802.38 mg·kg-1 and its 95 % confidence was 2343.51~3520.11 mg·kg-1. No abnormal alteration was shown in the organs of all the postmortem mice after the gross anatomy. Conclusion Single oral administration of Artequick has some toxic effects in mice,and the target of toxic organs may be involved the central nervous system.%目的:研究青蒿素哌喹片(ATQ)对昆明种小鼠灌胃给药的急性毒性。方法按 Bliss 法设计试验,对小鼠单次灌胃 ATQ,测定 ATQ 对小鼠半数致死量(LD50)和 LD50的95%可信限,观察14 d 内小鼠的毒性反应和死亡情况,对小鼠进行大体解剖,肉眼观察并进行组织病理学检查。结果 ATQ 单次灌胃给药可使小鼠出现不同程度的毒性反应,包括自发活动减少、闭眼、俯卧、运动失调、震颤、惊跳、强制性-阵挛性抽搐、角弓反张。小鼠 LD50为2802.38 mg·kg-1,LD50的95%可信限为2343.51~3520.11 mg·kg-1,死亡小鼠肉眼观察未发现各脏器异常。结论 ATQ 对小鼠单次灌胃给药具有一定的毒性,涉及的毒性靶器官可能是中枢神经系统。

  8. Assessing plasma lipid levels, body weight, and hepatic and renal toxicity following chronic oral administration of a water soluble phytostanol compound, FM-VP4, to gerbils.

    Science.gov (United States)

    Wasan, K M; Najafi, S; Wong, J; Kwong, M; Pritchard, P H

    2001-01-01

    The purpose of this project was to determine the effect of a FM-VP4 when incorporated into the diet or drinking water on plasma lipids, body weight, and hepatic and renal function following chronic oral administration to gerbils. Gerbils were administered water and food daily containing either no FM-VP4 (controls; n=6), 2% or 4% FM-VP4 incorporated into the gerbil diet (n=6 each treatment group) or 2% or 4% FM-VP4 dissolved in the drinking water (n=6 each treatment group). Body weight and food and water intake were monitored weekly. Following 8 weeks of this regiment blood was obtained via a cardiac puncture and all animals were sacrificed humanely. Plasma obtained from this blood was analyzed for total cholesterol, total triglyceride and high-density lipoprotein (HDL)-cholesterol levels by standard enzymatic and precipitation techniques. Low-density lipoprotein (LDL)-cholesterol levels were determined by the Friedewald equation. The plasma was also analyzed for changes in hepatic enzyme (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and plasma creatinine (renal function) concentrations. 2% and 4% FM-VP4 administration incorporated both into the diet and in the drinking water resulted in a significant decrease in total plasma cholesterol and LDL cholesterol concentration compared to controls. Animals administered 4% FM-VP4 in either their diet or drinking water had significantly lower body weight following the 8 weeks of treatment compared to the other groups. Significant differences in daily water intake was observed in all treatment groups with the exception of the 2% FM-VP4 in diet group compared to controls. Significant differences in daily food intake were observed in gerbils administered 2% FM-VP4 in the drinking water and 4% FM-VP4 in the diet and drinking water groups compared to controls. A significant decrease in total plasma triglyceride concentration was observed in gerbils administered 4% FM-VP4 in their drinking water compared

  9. Autophagy regulated by prolyl isomerase Pin1 and phospho-Ser-GSK3αβ involved in protection of oral squamous cell carcinoma against cadmium toxicity

    Energy Technology Data Exchange (ETDEWEB)

    So, Keum-Young [Department of Anesthesiology and Pain Medicine College of Dentistry, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759 (Korea, Republic of); Ahn, Sang-Gun [Department of Pathology, College of Dentistry, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759 (Korea, Republic of); Oh, Seon-Hee, E-mail: seonh@chosun.ac.kr [Department of Premedicine, School of Medicine, College of Dentistry, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759 (Korea, Republic of)

    2015-10-23

    Prolyl isomerase Pin1 plays an important role in cell proliferation and is overexpressed in many human tumors. However, its role in autophagy induction remains undefined. Here we show that Pin1 regulates cell survival via autophagy in cadmium (Cd)-exposed oral squamous cell carcinoma (OSCC). OSCC exposure to Cd induced autophagy, as demonstrated by the formation of green fluorescent punctae in transfected cells expressing GFP-conjugated microtubule-associated protein light chain 3 (LC3) and by LC3 flux in the presence of autophagy inhibitors. Suppression of Atg5 enhanced Cd-induced apoptosis, indicating that autophagy is involved in cell protection. In dose–response experiments, cleavage of procaspase-3, PARP-1, and LC3-II was induced by Cd with an IC{sub 50} of 45 μM. Expression of Pin1 was decreased at or above the Cd IC{sub 50} value and was inversely correlated with the level of phospho(p)-Ser-GSK3αβ. Genetic or pharmacologic inhibition of Pin1 suppressed Cd-induced autophagy, but increased p-Akt-mediated p-Ser-GSK3αβ; this was reversed by overexpression of Pin1. However, suppression of GSK3αβ inhibited Cd-induced autophagy and induced apoptosis, which could be reversed by overexpression of GSK3β. The PI3K inhibitor Ly294002 blocked p-Akt-mediated increases in p-Ser-GSK3αβ and autophagy and induced apoptosis. Therefore, p-Ser-GSK3αβ can directly regulate Cd-induced autophagy, although its function is suppressed by Pin1. Collectively, the present results indicate that targeting Pin1 and GSK3αβ at the same time could be an effective therapeutic tool for Cd-induced carcinogenesis. - Highlights: • Pin1 regulated autophagy to protect cells from cadmium toxicity. • Pin1 suppression inhibited cadmium-induced autophagy and induced apoptosis. • Pin1 inhibited the function of p-Ser-GSK3αβ in autophagy regulation. • p-Ser-GSK3αβ regulated autophagy independently of Pin1.

  10. A New Way in Deciding NOAEL Based on the Findings from GLP-Toxicity Test

    OpenAIRE

    Park, Yeong-Chul; Cho, Myung-Haing

    2011-01-01

    The FDA guidance focuses on the use of the NOAEL to establish the maximum recommended starting dose. The majority of NOAEL has been described inaccurately or incompletely in final reports for 90-days repeated dose toxicity test based on GLP (good laboratory practice) regulation. This is the most serious one of reasons for why most pharmaceutical companies targeting global markets have disregarded the final report produced from GLP facilities in Korea. The problems in deciding NOAEL reflected ...

  11. Assessment of the safety of hydrogenated resistant maltodextrin: reverse mutation assay, acute and 90-day subchronic repeated oral toxicity in rats, and acute no-effect level for diarrhea in humans.

    Science.gov (United States)

    Yoshikawa, Yuko; Kishimoto, Yuka; Tagami, Hiroyuki; Kanahori, Sumiko

    2013-01-01

    A series of safety assessments were performed on hydrogenated resistant maltodextrin prepared by converting the reducing terminal glucose of resistant maltodextrin into sorbitol. The reverse mutation assay did not show mutagenicity. Acute and 90-day subchronic oral toxicity studies in rats showed no death was observed in any groups, including the group receiving the highest single dose of 10 g/kg body weight or the highest dose of 5 g/kg body weight per day for 90 days. Mucous or watery stools were observed in the hydrogenated resistant maltodextrin treatment group on the acute study, which were transient and were associated with the osmotic pressure caused by intake of the high concentrations. Subchronic study showed dose-dependent increases in the weights of cecum alone, cecal contents alone, and cecum with cecal contents as well as hypertrophy of the cecal mucosal epithelium, which are considered to be common physiological responses after intake of indigestible carbohydrates. These results indicated that the no observed adverse effect level (NOAEL) of hydrogenated resistant maltodextrin was 10 g/kg body weight or more on the acute oral toxicity study and 5.0 g/kg body weight/day or more on the 90-day subchronic repeated oral toxicity study in rats. Further study performed in healthy adult humans showed that the acute no-effect level of hydrogenated resistant maltodextrin for diarrhea was 0.8 g/kg body weight for men and more than 1.0 g/kg body weight for women. The results of the current safety assessment studies suggest that hydrogenated resistant maltodextrin is safe for human consumption.

  12. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Dulin, J; Kovács, L; Ramm, S; Horvath, F; Ebeling, L; Kohnen, R

    1998-07-01

    Sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride (Mydocalm), a centrally active muscle-relaxing agent, were evaluated in a placebo-controlled double-blind clinical trial. A total of 72 healthy young adults balanced by sex were randomized to receive 50 mg or 150 mg tolperisone hydrochloride or placebo t.i.d. for a period of 8 days. Control examinations were performed in the mornings of days 1 and 8 before intake of the morning dose and at 1.5, 4 and 6 hours postdose. The psychomotoric test battery used in this trial revealed no sedative effects of tolperisone hydrochloride in the given doses at any control examination. Subjective mood ratings quantified by the Welzel Colored Scales were not impaired either. The lack of differences in sedative potentials of tolperisone hydrochloride and placebo was confirmed by tests on differences and by tests on equivalence using 95% CI. The present study substantiates clinical experience and previous clinical trials demonstrating that tolperisone hydrochloride, though being a centrally active muscle relaxant, does not cause any sedation and does not impair reaction times.

  13. Studies on the subchronic oral toxicity of neem oil in mice%印楝油对小鼠的亚慢性经口毒性研究

    Institute of Scientific and Technical Information of China (English)

    石东霞; 蒋忠荣; 殷中琼; 龙兴发; 李太强; 贾仁勇; 徐娇; 张玉群; 杨帆

    2011-01-01

    To determine the subchronic oral toxicity of neem oil in mice,eighty mice were divided into three experiment groups and one control group at random. The mice in the 3 experiment groups were orally administrated with neem oil(mixed with 10 g/L CMC) at the doses of 177,533 and 1 600 mg/kg for 90 days respectively,and the mice in the control group were orally administrated with 10 g/L CMC at the dose of 533 mg/kg, then continued to observe for 30 days post-the last administration with neem oil. On day 90 and 120 post-beginning of administration, the general clinical manifestations, serum biochemistry, organ coefficients of the heart, liver, spleen,lung, and kidney were determined,and the histopathological changes of the heart, liver, spleen, lung, kidney and testicle were observed. The serum biochemistry and the organ coefficients of heart, liver, spleen, lung and kidney in the 3 experiment groups were not statistically different from those in the control group. On day 90 post-beginning of administration,the pathological examinations showed that 177 and 533 mg/kg doses of neem oil had low damage on each organ,such as slight vascular congestion,while 1 600 mg/kg dose of neem oil had damage on each organ to some extent,mainly degeneration on cells. After recovery for 30 days,the degree of injury to the tissues was lessened or even to be the restored. The level at which no adverse effects was 177 mg/kg for mice and the target organs of neem oil were determined to be the testicle,liver and kidneys.%为研究印楝油对小鼠的亚慢性经口毒性作用,确定印楝油的最大无作用剂量和毒作用靶器官,取健康小鼠80只,随机分成3个试验组和1个对照组,每日9点对各试验组小鼠经口给予177、533和1600mg/kg的印楝油混悬液(用10 g/L羧甲基纤维素钠与其混悬),对照组则给予533 mg/kg的10 g/L羧甲基纤维素钠溶液,连续90 d,停药后继续观察30 d.试验90 d和120 d后分别观察记录各组小鼠的一般临床

  14. Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.

    Directory of Open Access Journals (Sweden)

    Els Torreele

    of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

  15. Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy.

    Science.gov (United States)

    Chavan, Swapnil; Friedman, Ran; Nicholls, Ian A

    2015-05-21

    A k-nearest neighbor (k-NN) classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS)) database chemicals, employing two acute toxicity (LD50)-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL). We have successfully predicted the LOELs of 54 of 70 training set chemicals (77%) and 14 of 19 test set chemicals (74%) to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k-NN model predicts LD50 classes correctly for a certain chemical, then the k-analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity.

  16. Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy

    Directory of Open Access Journals (Sweden)

    Swapnil Chavan

    2015-05-01

    Full Text Available A k-nearest neighbor (k-NN classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS database chemicals, employing two acute toxicity (LD50-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL. We have successfully predicted the LOELs of 54 of 70 training set chemicals (77% and 14 of 19 test set chemicals (74% to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k-NN model predicts LD50 classes correctly for a certain chemical, then the k-analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity.

  17. Evaluation of Residual Toxic Substances in the Stomach Using Upper Gastrointestinal Endoscopy for Management of Patients With Oral Drug Overdose on Admission

    OpenAIRE

    Miyauchi, Masato; Hayashida, Makiko; Yokota, Hiroyuki

    2015-01-01

    Abstract The guidelines on the indications for gastric lavage were published in 1997, and a less-aggressive initial approach has been used for poisoned patients. Clinical studies have shown that the outcomes of retrieval of residual toxic substances in the stomach are variable and that no beneficial effect is obtained. However, the presence of residual toxic substances in the stomach before gastric lavage has not been estimated. The objective of this study was to evaluate the residual stomach...

  18. Assessment of acute and subchronic oral toxicity of ethanolic extract of Pothomorphe umbellata L. Miq (Pariparoba Avaliação da toxidade oral aguda e subcrônica de extrato etanólico de Pothomorphe umbellata L. Miq. (Parapiroba

    Directory of Open Access Journals (Sweden)

    Sonia Barros

    2005-03-01

    Full Text Available There is a high degree of concern regarding the secure use of plant extracts and, for this very reason, preclinical and clinic toxicological evaluation of these extracts are needed. With the aim to assure the quality and the safety of the extract and due to the scarcity of literature information about Pariparoba extract toxicity, our purpose was to investigate the acute and subchronic toxicity of the standardized ethanolic dried root extract of Pothomorphe umbellata L. Miq. This extract was administered orally to adult swiss mice and wistar rats and the mutagenic potencial of the extract was also evaluated. The extract showed to be non toxic.Existe uma grande preocupação quanto ao uso seguro de extratos vegetais e, por esta razão, a necessidade de estudos toxicológicos pré-clínicos e clínicos destes extratos. O objetivo deste trabalho foi o de avaliar a toxicidade aguda e subcrônica do extrato hidroalcoólico liofilizado de Pothomorphe umbellata L. Miq., administrado por via oral para animais de laboratório. O potencial mutagênico do extrato foi também avaliado pelo teste do micronúcleo. Os resultados dos estudos a curto e médio prazo demonstraram que o extrato não apresenta propriedades tóxicas.

  19. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

  20. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  1. The Acute Oral Toxicity of 300 Formulated Pesticides to Apis mellifera%300个农药制剂对蜜蜂的急性经口毒性

    Institute of Scientific and Technical Information of China (English)

    赵帅; 袁善奎; 才冰; 姜辉; 王晓军; 林荣华; 瞿唯钢; 张招荣

    2011-01-01

    [Aims] Honey bee is one of the most important insects for plant pollination, but the honey bees are underlying the phenomenon of colony collapse disorder (CCD), one of the factors causing this problem is the much use of pesticides in agricultural production. Totally 300 pesticides were tested for their acute omi toxicity to honey bee (Apis mellifera) by dietary method in the paper, the objective of this study is to understand the status of toxicity of common used pesticides.[Restults] The results indicated that the pesticides with very high toxicity, high toxicity, moderate toxicity and low toxicity pesticides accounted for 14.7, 35.6, 10.7, 39% respectively, the high toxic and very high toxic pesticide covered more than 50%, and these pesticides were mainly the insecticides, while the fungicides and herbicides with relative low toxicity.The toxicity of different pesticide formulations with the same active ingredients (AI) to zebra fish maybe varied for the difference in AI content, formulation type and processing technique. Regarding to the biological pesticides, some of them still have high toxicity to honeybee. [Conclusions] These results suggested that the pesticides with high toxicity to honey bee covered a large proportion of common used pesticides in China, therefore, some precautions should be involved as we used the pesticides, particularly for insecticides to reduce or avoid the side effects on honey bee.%[目的]蜜蜂是一种重要的传粉昆虫,近年来世界各地出现了严重的种群衰退现象,原因之一是农业生产过程中使用了大量农药.采用摄入法测定f300个农药制剂对蜜蜂的急性经口毒性,旨在了解我国常用农药对蜜蜂的毒风险情况.[结果]结果表明:对蜜蜂的急性经口毒性表现剧毒、高毒、中毒、低毒的农药制剂分别占14.7%、35.6%、10.7%、39%,高毒和剧毒农药产品达50%以上,但这些制剂主要为杀虫剂,占整个杀虫剂的74.1%,杀菌剂和除草剂

  2. Acute oral toxicity and liver oxidant/antioxidant stress of halogenated benzene, phenol, and diphenyl ether in mice: a comparative and mechanism exploration.

    Science.gov (United States)

    Shi, Jiaqi; Feng, Mingbao; Zhang, Xuesheng; Wei, Zhongbo; Wang, Zunyao

    2013-09-01

    The lethal doses (LD50s) of fluorinated, chlorinated, brominated, and iodinated benzene, phenol, and diphenyl ether in mice were ascertained respectively under the consistent condition. The acute toxicity of four benzenes orders in fluorobenzene (FB) phenols orders in 4-iodophenol≈4-bromophenol phenols, as they had lower octanol-water partition coefficients. Pathological changes in liver and liver/kidney weight changes were also observed. Hepatic superoxide dismutase, catalase activities, and malondialdehyde level were tested after a 28-day exposure, which reflects a toxicity order basically consistent with that reflected by the LD50s. By theoretical calculation and building models, the toxicity of benzene, phenol, and diphenyl ether were influenced by different structural properties.

  3. A Tutorial for Analysing the Cost-effectiveness of Alternative Methods for Assessing Chemical Toxicology: The Case of Acute Oral Toxicity Prediction

    NARCIS (Netherlands)

    Norlen, H.; Worth, A.P.; Gabbert, S.G.M.

    2014-01-01

    Compared with traditional animal methods for toxicity testing, in vitro and in silico methods are widely considered to permit a more cost-effective assessment of chemicals. However, how to assess the cost-effectiveness of alternative methods has remained unclear. This paper offers a user-oriented tu

  4. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Directory of Open Access Journals (Sweden)

    Collaku A

    2017-03-01

    Full Text Available Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0= not present to 10= unbearable recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of

  5. Comparative study of the assay of Artemia salina L. and the estimate of the medium lethal dose (LD50 value) in mice, to determine oral acute toxicity of plant extracts.

    Science.gov (United States)

    Logarto Parra, A; Silva Yhebra, R; Guerra Sardiñas, I; Iglesias Buela, L

    2001-09-01

    Artemia salina L. (Artemiidae), the brine shrimp larva, is an invertebrate used in the alternative test to determine toxicity of chemical and natural products. In this study the Medium Lethal Concentrations (LC50 value) of 20 plant extracts, Aloe vera (L.) Burm. F. (Aloeaceae), Artemisia absinthium L. (Asteraceae); Citrus aurantium L. (Rutaceae); Cymbopogon citratus (DC. Ex Nees) Stapf (Poaceae); Datura stramonium L. (Solanaceae); Justicia pectoralis Jacq. (Acanthaceae); Musa x paradisiaca L. (Musaceae); Ocimum basilicum L.; O. gratissimum L.; O. tenuiflorum L. (Lamiaceae); Pimenta dioica (L.) Merr. (Myrtaceae); Piper auritum Kunth (Piperaceae); Plantago major L. (Plantaginaceae); Plectranthus amboinicus (Lour.) Spreng. (Lamiaceae); Ruta graveolens L. (Rutaceae); Senna alata (L.) Roxb. (Fabaceae); Stachytarpheta jamaicensis (L.) Vahl (Verbenaceae); and Thuja occidentalis L. (Cupressaceae), were determined using Artemia salina L. (Artemiidae), with the objective of relating the results to the LD50 values reported in mice (tested at three concentrations: 10, 100, and 1000 microg/mL, for each extract). We found good correlation between the in vivo and the in vitro tests (r = 0.85 p < 0.05), and this method is a useful tool for predicting oral acute toxicity in plant extracts.

  6. 五种农药对中华蜜蜂和意大利蜜蜂工蜂的经口毒性比较%Oral toxicity of five pesticides to Apis cerana cerana and Apis mellifera

    Institute of Scientific and Technical Information of China (English)

    王瀛寰; 张艳峰; 张旭; 李建中; 王会利

    2012-01-01

    Two methods " small breaker" and " feeding tube" were used to measure the oral toxicity of five pesticides to Apis cerana cerana Fab. and Apis mellifera L.. The relative merits of the two methods and the sensitivity of the two kinds of honeybees to the toxicants were compared. The results showed that the LC50 values determined by " small breaker" method were lower than that by " feeding tube" method. Furthermore, comparing with A. mellifera, A. cerana cerana was more sensitive to pesticides tested, which suggested that A. cerana cerana might be more suitable for use in the toxicological evaluation of pesticides.%分别采用“小烧杯法”和“饲喂管法”测定了5种农药对中华蜜蜂和意大利蜜蜂工蜂的经口毒性.比较了2种方法的优缺点以及2个蜂种对农药毒性的敏感程度差异.结果表明:无论是“意蜂”还是“中蜂”,“小烧杯法”得到的半致死浓度( LC50)均不同程度地低于“饲喂管法”;与“意蜂”相比,“中蜂”对药剂更敏感,可能更适用于农药的毒理评价实验.

  7. Acute Oral Mammalian Toxicity and Effect of Solvents on Efficacy of Maerua edulis (Gilg. & Ben. De Wolf against Rhipicephalus (Boophilus decoloratus Koch, 1844 (Acarina: Ixodidae, Tick Larvae

    Directory of Open Access Journals (Sweden)

    Emmanuel T. Nyahangare

    2016-01-01

    Full Text Available Efficacy and toxicity of aqueous and organic solvents extracts of Maerua edulis against ticks and mice, respectively, were determined. Ground leaves were extracted separately using cold water, cold water plus surfactant (1% v/v liquid soap, hot water plus surfactant, hexane, or methanol to make 25% w/v stock solutions from which serial dilutions of 5, 10, 20, and 25% were made. For each concentration, 20 Rhipicephalus decoloratus tick larvae were put in filter papers impregnated with extracts and incubated for 48 h at 27°C and 85–90% RH for mortality observation after 24 h and 48 h. In the toxicity experiment, hot water plus surfactant treatments of 5, 10, 20, and 25% (w/v M. edulis were administered in suspension per os to sexually mature Balb/C mice and observed for clinical signs and mortality for 72 h. Larvae mortality was highest (>98% in methanol-extracted M. edulis treatments (20 and 25%, which was not different from the amitraz-based control (Tickbuster®. Mortality was also higher in the hot water than in cold water plus surfactant treatments (P<0.05. No postadministration adverse health effects were observed in the mice. These results suggest that M. edulis is an effective tick remedy best extracted using methanol or hot water plus surfactant.

  8. Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Xerostomia and trismus (Part 2). Literature review and consensus statement.

    Science.gov (United States)

    Buglione, Michela; Cavagnini, Roberta; Di Rosario, Federico; Maddalo, Marta; Vassalli, Lucia; Grisanti, Salvatore; Salgarello, Stefano; Orlandi, Ester; Bossi, Paolo; Majorana, Alessandra; Gastaldi, Giorgio; Berruti, Alfredo; Trippa, Fabio; Nicolai, Pietro; Barasch, Andrei; Russi, Elvio G; Raber-Durlacher, Judith; Murphy, Barbara; Magrini, Stefano M

    2016-06-01

    Radiotherapy alone or in combination with chemotherapy and/or surgery is a well-known radical treatment for head and neck cancer patients. Nevertheless acute side effects (such as moist desquamation, skin erythema, loss of taste, mucositis etc.) and in particular late toxicities (osteoradionecrosis, xerostomia, trismus, radiation caries etc.) are often debilitating and underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met in Milan with the aim of reaching a consensus on a clinical definition and management of these toxicities. The Delphi Appropriateness method was used for this consensus and external experts evaluated the conclusions. The paper contains 20 clusters of statements about the clinical definition and management of stomatological issues that reached consensus, and offers a review of the literature about these topics. The review was split into two parts: the first part dealt with dental pathologies and osteo-radionecrosis (10 clusters of statements), whereas this second part deals with trismus and xerostomia (10 clusters of statements). Copyright © 2016. Published by Elsevier Ireland Ltd.

  9. Assessing the mammalian toxicity of high-boiling petroleum substances under the rubric of the HPV program.

    Science.gov (United States)

    Gray, Thomas M; Simpson, Barry J; Nicolich, Mark J; Murray, F Jay; Verstuyft, Allen W; Roth, Randy N; McKee, Richard H

    2013-11-01

    In 1998, the US EPA announced the HPV Challenge Program, a voluntary chemical data collection effort. The Petroleum HPV Testing Group (PHPVTG(1)) volunteered to provide data on approximately 110 high boiling petroleum substances (HBPS), i.e. substances with final boiling points ≥ approximately 650°F (343°C). These HBPS are substances of unknown and variable composition (UVCBs) that are composed of numerous individual constituents. Toxicity studies have shown that some HBPS can produce systemic (repeat-dose) and developmental effects, and some are mutagenic under in vitro conditions. The papers in this supplement show that these effects are related to the profiles of aromatic constituents in these substances. Further, it is shown that the effects on selected repeat-dose and developmental toxicity endpoints and mutagenic activity in bacterial assays can be predicted from compositional information using models based on the aromatic-ring class profile, "ARC profile" as defined by gas chromatographic separation of the DMSO-soluble fraction of the starting materials. This chromatographic method and the predictive models provide an efficient means of characterizing for screening purposes the potential for repeat-dose, developmental effects and bacterial mutagenicity of HBPS and can reduce the number of animal tests that would be required if these tests were conducted on all 110 HBPS. Copyright © 2012. Published by Elsevier Inc.

  10. Can the oral microflora affect oral ulcerative mucositis?

    NARCIS (Netherlands)

    Laheij, A.M.G.A.; de Soet, J.J.

    2014-01-01

    Purpose of review: Oral mucositis is one of the most prevalent toxicities after hematopoietic stem cell transplantation. Mucositis is initiated by the chemotherapy or radiotherapy preceding the transplantation. It is commonly accepted that microorganisms play a role in the process of oral mucositis.

  11. Evaluación de la toxicidad aguda oral y de la actividad antimicrobiana de una mezcla de aceite de hígado de tiburones de Cuba Assessment of the oral acute toxicity and the antimicrobial activity of an oily mixture from shark's liver of Cuba

    Directory of Open Access Journals (Sweden)

    Caridad Margarita García Peña

    2010-09-01

    Full Text Available Se evaluó la toxicidad aguda oral y la actividad antimicrobiana de una mezcla de aceites de hígado de tiburón, de las especies Rhincodon typu (tiburón ballena y Galeocerdo cuvier (tiburón tigre, que habitan en zonas aledañas a las costas del litoral norte occidental de Cuba, para su posterior uso farmacéutico, debido a que presenta un alto contenido de vitaminas y de ácidos grasos, que le confieren actividad antioxidante y antiinflamatoria. El estudio de la toxicidad aguda oral demostró que la mezcla de aceites de hígado de tiburones, no provocó alteraciones macroscópicas en los órganos extraídos, ni síntomas tóxicos severos, ni mortalidad de ninguno de los animales empleados en el estudio a la dosis de 20 mL/kg. Los resultados del estudio de la actividad antimicrobiana demostraron una ligera actividad bacteriostática frente a K. pneumoniae; además una actividad antifúngica frente a Microsporum canis; y resistencia frente a C. albicans y T. mentagrophytes a las concentraciones evaluadas.The total acute toxicity and the antimicrobial activity of an oil mixtures from shark liver of Rhicodon typu (whale-shark and Galeocerdo cuvier (tigger-shark was assessed in species leaving in the adjacent costs of Cuban northern coastal for its subsequent pharmaceutical use due to its high content of vitamins and fatty acids and its antioxidant and anti-inflammatory activity. Study of oral acute toxicity demonstrated that oil mixture of shark liver hasn't macroscopic alterations in removed organs, severe toxic symptoms and on mortality of any animals used in study at 20 mL/kg dose. Study results of antimicrobial activity showed a slight bacteriostatic activity against K. pneumoniae and an antifungal activity against Microsporum canis, and a resistance against C. albicans and T. mentagrophytes at assessed concentrations.

  12. Evaluation the Oral Toxicity of Four Pesticides to Bombus hypocrita Workers and Drones%4种杀虫剂对小峰熊蜂工蜂和雄性蜂的急性经口毒性测定

    Institute of Scientific and Technical Information of China (English)

    刘佳霖; 伍翔; 廖秀丽; 和绍禹; 罗术东; 吴杰

    2012-01-01

    [Aims] Bombus hypocrita was easily affected by pesticides during pollination. And it was significant to study the influence of pesticides on B. hypocrita. [Methods] The consecutive acute oral toxicity tests were used to analyze the acute toxicity of four pesticides. [Results] The results showed that the LC50 values for B. hypocrita workers were 44.30, 0.75, 158.17 and 94.83 mg/L respectively in the first 24 h. The LC50 values for 48 h were changed to 10.68, 0.54, 31.19 and 62.82 mg/L respectively. For drone tests, the results witnessed that the LC50 values were 24.23, 2.16, 116.63 and 239.95 mg/L respectively during 24 h, and the LC50 values for 48 h were changed to 8.73, 1.47, 69.84 and 129.36 mg/L respectively. [Conclusions] The results suggested that the toxicity of imidacloprid and dinotefuran to B. hypocrita belonged to high toxicity grade, but flubendiamide and chlorantraniliprole had moderate toxicity. At the same, time, the results also indicated that the toxicities between workers and drones were different when treated with the same pesticide, and the effects of accumulation of the toxicity in workers and drones were different too.%[目的]小峰熊蜂在授粉过程中极易受到杀虫剂的影响,研究杀虫剂对小峰熊蜂的急性毒性具有重要的意义.[方法]利用连续摄入法测定了4种杀虫剂对小峰熊蜂的急性经口毒性.[结果]4种农药对小峰熊蜂工蜂24h的致死中浓度分别为44.30、0.75、158.17、94.83 mg/L,48 h的致死中浓度分别为10.68、0.54、31.19、62.82mg/L,而4种农药对小峰熊蜂雄性蜂的24 h的致死中浓度分别为24.23、2.16、116.63、239.95mg/L,48 h的致死中浓度分别为8.73、1.47、69.84、129.36mg/L.[结论]吡虫啉和呋虫胺对小峰熊蜂的毒性为高毒,而氟虫酰胺和氯虫苯甲酰胺为中等毒性;同种农药对工蜂和雄性蜂的毒力不同,在不同型蜂中的累计致死作用效果也不一样.

  13. Long-term, repeated dose in vitro neurotoxicity of the glutamate receptor antagonist L-AP3, demonstrated in rat hippocampal slice cultures by using continuous propidium iodide incubation

    DEFF Research Database (Denmark)

    Kristensen, Bjarne W; Blaabjerg, Morten; Noraberg, Jens

    2007-01-01

    ), which is known to be toxic in vivo after subchronic, but not acute, administration. Degenerative effects were monitored by measuring the cellular uptake of propidium iodide (PI; continuously present in the medium) and lactate dehydrogenase (LDH) leakage, and by using a panel of histological stains...

  14. Delayed acute toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), after oral administration, Obeys Haber's rule of inhalation toxicology.

    Science.gov (United States)

    Rozman, K K

    1999-05-01

    Eight different doses (2.5 to 10.0 mg/kg) of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) were administered acutely to a total of 272 female Sprague-Dawley rats. The doses ranged from a NOAEL for wasting/hemorrhage to supralethal doses. Dose- and time-responses of wasting/hemorrhage, anemia, and cancer were and are being studied as end points of toxicity. The experiments will be continued until the last rat dies. There was a very steep dose- and time-response between the LOAEL for wasting/hemorrhage (2.8 mg/kg) and the third highest dose (4.1 mg/kg) of HpCDD. The dose-and time-responses were nearly symmetrical, obeying Haber's Rule of inhalation toxicology (c x t = constant) even beyond 100% mortality. Introduction of a minimum of 25% body weight loss as a discriminatory criterion to separate wasting from hemorrhage as the primary cause of death reduced variability from 5.8 to 3.2%. An arithmetic plot of the dose and time data resulted in a nearly perfect hyperbola. A logarithmic plot of these data yielded a straight line of similar perfection. Dose-response data at constant times illustrate the shifting of the dose-response curve towards a liminal value, which represents the necessary observation period for this effect. Time-response data at constant doses demonstrate the shifting of the time-response curve towards a liminal value, which represents the LOAEL for the dose-response of this effect. A three-dimensional plot of dose- and time-response data depicts the surface area on which c x t is constant along hyperbolas, in terms of wasting as the end point of toxicity. Surviving rats in all groups started developing anemia 126 days after dosing, but no rat died of wasting/hemorrhage after day 74. Rats surviving anemia began to die of lung cancer as of day 397 after dosing. Thus, although the experiment has been completed as far as dose- and time-responses of wasting/hemorrhage are concerned, it will be about another 2 years before complete dose and time

  15. Toxicity effect of sub-chronic oral administration of class bitters® - a polyherbal formula on serum electrolytes and hematological indices in male Wistar albino rats

    Directory of Open Access Journals (Sweden)

    Kingsley C. Patrick-Iwuanyanwu

    2015-11-01

    Full Text Available The indiscriminate administration of readyto- use herbal formulations has become a major concern due to their potential health risk. The study investigated the effect of class bitters® (CB - a polyherbal formula prepared with Mondia whitei, Khaya senegalensis, Capparis erythrocarpus, Thoningia sanguinea and Xylopia aethiopica on serum electrolytes and hematological parameters in male Wistar albino rats. Two doses (500 and 1000 mg kg–1 of the polyherbal drugs were administered orally to male Wistar albino rats for a period of 9 weeks. The results showed that administration of 500 and 1000 mg kg–1 body weight of CB recorded a marked increase in the levels of sodium and chlorum when compared with control. However, there was a marked reduction in the levels of potassium and hydrogen carbonate. The results of the study also showed a significant (P≤0.05 decrease in the level of hematological parameters such as hemoglobin (Hb, packed cell volume (PCV, red blood cells (RBCs and platelets levels in the male Wistar albino rats, when compared with control. The marked decrease in Hb, PCV, RBCs and platelets concentrations observed in experimental rats in this study suggest that CB may have an adverse effect on erythropoiesis. These observations therefore showed that long-term administration of CB might cause renal disease and anemia.

  16. Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity.

    Science.gov (United States)

    Healing, Guy; Sulemann, Tabassum; Cotton, Peter; Harris, Jayne; Hargreaves, Adam; Finney, Rowena; Kirk, Sarah; Schramm, Carolin; Garner, Clare; Pivette, Perrine; Burdett, Lisa

    2016-01-01

    Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.

  17. Melatonin and oral cavity.

    Science.gov (United States)

    Cengiz, Murat İnanç; Cengiz, Seda; Wang, Hom-Lay

    2012-01-01

    While initially the oral cavity was considered to be mainly a source of various bacteria, their toxins and antigens, recent studies showed that it may also be a location of oxidative stress and periodontal inflammation. Accordingly, this paper focuses on the involvement of melatonin in oxidative stress diseases of oral cavity as well as on potential therapeutic implications of melatonin in dental disorders. Melatonin has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue, and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a coadjuvant in the treatment of certain conditions of the oral cavity. However, the most important effect of melatonin seems to result from its potent antioxidant, immunomodulatory, protective, and anticancer properties. Thus, melatonin could be used therapeutically for instance, locally, in the oral cavity damage of mechanical, bacterial, fungal, or viral origin, in postsurgical wounds caused by tooth extractions and other oral surgeries. Additionally, it can help bone formation in various autoimmunological disorders such as Sjorgen syndrome, in periodontal diseases, in toxic effects of dental materials, in dental implants, and in oral cancers.

  18. Melatonin and Oral Cavity

    Directory of Open Access Journals (Sweden)

    Murat İnanç Cengiz

    2012-01-01

    Full Text Available While initially the oral cavity was considered to be mainly a source of various bacteria, their toxins and antigens, recent studies showed that it may also be a location of oxidative stress and periodontal inflammation. Accordingly, this paper focuses on the involvement of melatonin in oxidative stress diseases of oral cavity as well as on potential therapeutic implications of melatonin in dental disorders. Melatonin has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue, and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a coadjuvant in the treatment of certain conditions of the oral cavity. However, the most important effect of melatonin seems to result from its potent antioxidant, immunomodulatory, protective, and anticancer properties. Thus, melatonin could be used therapeutically for instance, locally, in the oral cavity damage of mechanical, bacterial, fungal, or viral origin, in postsurgical wounds caused by tooth extractions and other oral surgeries. Additionally, it can help bone formation in various autoimmunological disorders such as Sjorgen syndrome, in periodontal diseases, in toxic effects of dental materials, in dental implants, and in oral cancers.

  19. Penetration of orally administered prulifloxacin into human prostate tissue.

    Science.gov (United States)

    Giberti, Claudio; Gallo, Fabrizio; Rosignoli, Maria T; Ruggieri, Alessandro; Barattè, Simona; Picollo, Rossella; Dionisio, Paolo

    2009-01-01

    Prulifloxacin, a fluoroquinolone antibacterial agent, may be a useful addition to the antimicrobial armamentarium against prostatitis once the ability of its active metabolite, ulifloxacin, to penetrate prostatic tissue has been determined. This study set out to evaluate ulifloxacin penetration into the prostate following administration of the oral fluoroquinolone prodrug prulifloxacin in patients undergoing transurethral resection of the prostate (TURP). This was a phase I, randomized, open-label, single-centre study involving 20 male Caucasian patients (mean age 63.1 years) requiring TURP for treatment of benign prostatic hyperplasia. Sixteen patients were randomized to receive prulifloxacin; the other four patients were not treated (controls) in order to validate the bioanalytical method. Patients in the active treatment groups were randomized to receive one or three once-daily doses of prulifloxacin 600 mg, with the last administration 3 hours prior to surgery. Central/transitional and peripheral zone prostatic tissue samples were obtained from the 6 o'clock and 9 o'clock positions in the prostate, and blood samples were collected concurrently. Ulifloxacin concentrations were determined in the tissue samples and plasma using liquid chromatography-tandem mass spectrometry. Safety was also assessed. Prostatic tissue concentrations of ulifloxacin always exceeded those in plasma. Mean ulifloxacin concentrations measured in samples collected from the 6 o'clock central/transitional zone of the prostate were higher in patients who received prulifloxacin for 3 days than in those who received a single dose. Mean prostatic tissue/plasma ulifloxacin concentration ratios after single and repeated prulifloxacin administration ranged from 3.8 to 7.1 and from 3.9 to 9.5, respectively. The highest mean ratio was found in the 6 o'clock central/transitional zone after repeated dosing. Prostatic levels of ulifloxacin were above the minimum inhibitory concentrations for the most

  20. Oral Medication

    Science.gov (United States)

    ... Size: A A A Listen En Español Oral Medication The first treatment for type 2 diabetes blood ... new — even over-the-counter items. Explore: Oral Medication How Much Do Oral Medications Cost? Save money ...

  1. Oral myiasis

    OpenAIRE

    Thalaimalai Saravanan; Mathan A Mohan; Meera Thinakaran; Saneem Ahammed

    2015-01-01

    Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability ...

  2. Toxicity of adipic acid.

    Science.gov (United States)

    Kennedy, Gerald L

    2002-05-01

    Adipic acid has very low acute toxicity in rats with an LD50 > 5000 mg/kg. Adipic acid produced mild to no skin irritation on intact guinea pig skin as a 50% concentration in propylene glycol; it was not a skin sensitizer. Adipic acid caused mild conjunctival irritation in washed rabbit eyes; in unwashed rabbit eyes, there was mild conjunctival irritation, minimal iritis, but no corneal effects. Adipic acid dust may irritate the mucous membranes of the lungs and nose. In a 2-year feeding study, rats fed adipic acid at concentrations up to 5% in the diet exhibited only weight loss. Adipic acid is not genetically active in a wide variety of assay systems. Adipic acid caused no developmental toxicity in mice, rats, rabbits, or hamsters when administered orally. Adipic acid is partially metabolized in humans; the balance is eliminated unchanged in the urine. Adipic acid is slightly to moderately toxic to fish, daphnia, and algae in acute tests.

  3. Short-term oral toxicity of butyl ether, ethyl hexyl ether, methyl heptyl ether and 1,6-dimethoxyhexane in male rats and the role of 2-methoxyacetic acid.

    Science.gov (United States)

    Poon, Raymond; Wade, Michael; Valli, Victor E; Chu, Ih

    2005-10-15

    A 4-week oral study was conducted in male rats to characterize and compare the toxicity of four aliphatic ethers (butyl ether, BE; ethyl hexyl ether, EHxE; methyl heptyl ether, MHpE; and 1,6-dimethoxyhexane, DMH) which have been proposed as high-cetane diesel additives. Male Sprague-Dawley rats (280+/-20 g) were divided into groups of seven animals each and were administered by gavage low (2mg/kg body weight), medium (20mg/kg) or high (200mg/kg) doses of BE, EHxE, or MHpE, 5 days per week for 4 weeks. Another group of animals was administered DMH at 200mg/kg while the control group received the vehicle (corn oil at 1 ml/100g bw) only. At the end of the treatment period, relative testis weights and thymus weights were significantly decreased in the DMH group but not in animals receiving BE, EHxE, or MHpE. Microscopic examination revealed degeneration of the seminiferous tubules and reduction of sperm density in the epididymides in the DMH treatment group. Urinary creatine/creatinine ratio, a sensitive indicator of testicular damage, was markedly elevated in the DMH treated animals but not in those treated with BE, EHxE, or MHpE. In the bone marrow, DMH caused mild dyserythropoiesis and dysthrombopoiesis, while BE, EHxE, and MHpE produced mild increases in granulocytes and myelocyte/erythrocyte ratio. All four ethers at 200mg/kg caused mild histological changes in the thyroid but no significant modulation in the circulating thyroxin (T4) or triiodothyronine (T3) levels. All four ethers produced hepatic effects at 200mg/kg consisting of mild, adaptive histological changes, increased urinary ascorbic acid output, and elevation in the activities of one or more xenobiotic metabolizing enzymes (benzyloxyresorufin-O-dealkylase, UDP-glucuronosyltransferase, glutathione-S-transferases). The level of 2-methoxyacetic acid (MAA), a known testicular and developmental toxin, was significantly increased in the urine and plasma of animals treated with DMH but not in those

  4. Acute toxicity, haematological and histopathological assessment of ...

    African Journals Online (AJOL)

    Lorke's method was used for the acute oral toxicity testing. ... differential blood cell counts were determined using automated haematology analyzer. Histological examination of major organs was done using John D Bancroft manual method.

  5. Toxic Elements

    DEFF Research Database (Denmark)

    Hajeb, Parvaneh; Shakibazadeh, Shahram; Sloth, Jens Jørgen

    2016-01-01

    Food is considered the main source of toxic element (arsenic, cadmium, lead, and mercury) exposure to humans, and they can cause major public health effects. In this chapter, we discuss the most important sources for toxic element in food and the foodstuffs which are significant contributors...... to human exposure. The occurrence of each element in food classes from different regions is presented. Some of the current toxicological risk assessments on toxic elements, the human health effect of each toxic element, and their contents in the food legislations are presented. An overview of analytical...... techniques and challenges for determination of toxic elements in food is also given....

  6. The acute toxicity of Najanajaatra venom (NNAV) by oral and intravenous administration%中华眼镜蛇毒口服和静脉注射单次给药对小鼠毒性作用的比较

    Institute of Scientific and Technical Information of China (English)

    张甜; 薛洁; 王响英; 朱路佳; 孙志红; 秦正红

    2016-01-01

    目的:比较中华眼镜蛇毒(NNAV)经口灌服、静脉注射两种染毒途径的半数致死量(LD50),观察两种染毒途径小鼠的急性中毒症状,寻找可能发生毒性作用的靶器官。方法:小鼠经口灌服、静脉注射NNAV后,测定半数致死量(LD50)。观察14 d内小鼠的活动、体征及死亡情况,并对死亡小鼠和存活14 d小鼠的主要脏器进行病理组织学检查。结果:小鼠经口灌服、静脉注射NNAV的LD50分别为102.3、0.624 mg/kg ,95% CI 84.9~123、0.572~0.680 mg/kg。NNAV经口灌服小鼠中毒症状出现快,喘息、强直性抽搐、呼吸抑制、心衰很快死亡;急性中毒受损器官主要为肺毛细血管充血,局部肺泡间隔增宽伴少量炎性细胞浸润;肝血管充血。NNAV静脉注射小鼠中毒症状为瘫卧、呼吸功能麻痹,心肺功能衰竭而死亡。急性中毒受损器官主要为肺泡腔内及细支气管内有红细胞,血管壁周围有水肿;肝细胞弥漫性肿大,致肝小叶结构不清,肝细胞肿胀,基质稀疏,有的呈气球样变,肝血窦受压变狭或消失。结论:NNAV口服染毒的毒性剂量明显低于静脉注射,二种染毒途径动物急性中毒器官的受损程度也有所不同;NNAV两种染毒途径存活14 d的小鼠其组织病理改变均可恢复。%Objective:To compare the lethal dose 50 (LD50 ) of Najanajaatra venom (NNAV) with two routes of drug administration and to explore the target organs of acute toxicity of NNAV ,and to observe the acute poisoning symptoms of the mice and organ lesions with oral and intravenous administration of NNAV . Methods: Two different modes of drug administration (oral administration and intravenous injection) were used to determine the LD50 .Within 14 of survival time period ,the activities ,signs and death of the mice were observed .Then ,pathology analysis was applied to the main organs of the dead and survival

  7. Oral cadmium chloride intoxication in mice

    DEFF Research Database (Denmark)

    Andersen, O; Nielsen, J B; Svendsen, P

    1988-01-01

    Diethyldithiocarbamate (DDC) is known to alleviate acute toxicity due to injection of cadmium salts. However, when cadmium chloride was administered by the oral route, DDC enhanced rather than alleviated the acute toxicity; both oral and intraperitoneal (i.p.) administration of DDC had this effect....... Thus, orally administered DDC enhanced cadmium-induced duodenal and ileal tissue damage and inhibition of peristalsis, as indicated by an increased intestinal transit time. At low cadmium doses, the whole-body retention of cadmium was increased by oral DDC administration. Intraperitoneally administered...

  8. Oral myiasis

    Directory of Open Access Journals (Sweden)

    Thalaimalai Saravanan

    2015-01-01

    Full Text Available Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy.

  9. Some Toxic Effects of Dieldrin in Rats

    Science.gov (United States)

    Barnes, J. M.; Heath, D. F.

    1964-01-01

    The oral toxicity of dieldrin in rats depends upon its concentration in the vehicle (arachis oil). It is increased by a previous restriction of diet, leading to a loss of weight. Two equal doses given within three weeks of each other are more toxic than the sum of the two given as a single dose. PMID:14249896

  10. Acute Oral Toxicity of Nitroguanidine in Mice

    Science.gov (United States)

    1988-04-01

    microscopic examination. These areas did not respond t o special bacterial stains and may have been due to mouse hepa t i tis virus . Mic r oscopic...Observation Study i Animal Receipt Dosinq Teri od Termination J 4 84C00440 22 24 Dead 84C00445 20 2 b Dead 84C00446 22 28...iiisfil ’iy noin«’ Iwp.ititio virus . An mal ID*! 84C003<»7 P.it.holooy Af-ci’ssion »•■ 30)17. Slide 19A! Eye

  11. 崖柏精油的急性经口毒性、皮肤刺激性和致敏性实验%Experimental Studies on Acute Oral Toxicity, Skin Irritation and Skin Allergy of Thuja Essential Oil

    Institute of Scientific and Technical Information of China (English)

    彭锦; 唐璐; 肖艳; 陈洋; 鲍美华

    2016-01-01

    目的:评价崖柏精油的急性经口毒性、皮肤刺激性和致敏性,为其临床安全用药提供依据。方法:急性经口毒性采用霍恩(Horn’s)法测定。选用昆明种小鼠40只随机分为4组,给予不同剂量崖柏精油(21.50,10.00,4.64,2.15 g· kg-1),观察14 d。记录死亡数,查表求得LD50,并记录死亡时间及中毒表现等。皮肤刺激性采用健康成年的白色家兔9只随机分为3组,分别给予崖柏精油100%浓度、50%浓度、25%浓度。采用食用植物油作为阴性对照。观察药物贴敷后1,24,48,72 h受试部位皮肤红斑、水肿的反应并评分。采用迟发型致敏反应最大剂量法进行崖柏精油致敏性测定。取健康白色豚鼠30只,随机平均分为3组:给药组,空白对照组(给予植物油基质)、阳性对照组(1%的2,4-二硝基氯苯)。经皮内诱导、局部诱导阶段后,观察崖柏精油激发24 h及48 h的皮肤变态反应情况并进行评分。结果:崖柏精油21.50 g· kg-1可使小鼠全部死亡,10.00,4.64 g· kg-1组可使动物部分死亡,2.15 g· kg-1组动物无死亡,查表求得崖柏精油对雌雄性小鼠的 LD50分别为7.94,9.26 g· kg-1。皮肤刺激性结果显示,崖柏精油(100%浓度)贴敷后1 h有强刺激性,而稀释后的药物刺激性逐渐减弱,25%浓度崖柏精油无明显刺激性。致敏性结果显示,阳性对照组可使豚鼠皮肤出现中度或重度融合性红斑及水肿,具有明显致敏性。而崖柏精油组未见明显红斑和水肿,显示无致敏性。结论:崖柏精油具有明显皮肤刺激性,急性经口毒性属实际无毒,未见致敏性。%Objective:To evaluate the acute oral toxicity , skin irritation and skin allergy of Thuja essential oil ( TEO) , and pro-vide experimental basis for the clinical use of TEO .Methods:The acute oral toxicity was measured by

  12. Oral Thrush

    Science.gov (United States)

    ... feeding mothers In addition to the distinctive white mouth lesions, infants may have trouble feeding or be fussy ... candidiasis (yeast infection) patient information. American Academy of Oral & Maxillofacial Pathology. http://www.aaomp.org/public/oral-candidiasis.php. ...

  13. Oral Dysfunction

    OpenAIRE

    鈴木, 規子; スズキ, ノリコ; Noriko, SUZUKI

    2004-01-01

    The major oral functions can be categorized as mastication, swallowing, speech and respiratory functions. Dysfunction of these results in dysphagia, speech disorders and abnormal respiration (such as Sleep Apnea). These functions relate to dentistry in the occurrence of : (1) oral preparatory and oral phases, (2) articulation disorders and velopharyngeal incompetence (VPI), and (3) mouth breathing, respiratory and blowing disorders. These disorders are related to oral and maxillofacial diseas...

  14. Tungsten toxicity.

    Science.gov (United States)

    Witten, Mark L; Sheppard, Paul R; Witten, Brandon L

    2012-04-05

    There is emerging evidence that tungsten has toxic health effects. We summarize the recent tungsten toxicity research in this short review. Tungsten is widely used in many commercial and military applications because it has the second highest melting temperature of any element. Consequently, it is important to elucidate the potential health effects of tungsten.

  15. Study on General Reproductive Toxicity of Oral Administration of Pineapple Leaves Extract in Mice%新药用资源菠萝叶小鼠一般生殖毒性的研究

    Institute of Scientific and Technical Information of China (English)

    袁梽漪; 邢东明; 杜力军; 卢希; 雷帆; 柴玉爽; 冯天师; 姜敬非; 赵爽; 王欣佩; 李慧玉

    2014-01-01

    目的:对菠萝叶小鼠的一般生殖毒性进行研究,有助于更好的评价该植物的药用价值。方法:分别灌胃给予成年雄性和雌性小鼠菠萝叶,然后合笼进行交配。对于交配成功的雌鼠继续饲养。分别对孕鼠的妊娠、胎鼠的发育及生产的子代小鼠的情况进行实验观察。结果:菠萝叶除了大剂量(4 g·kg-1)对亲本雄性鼠体重有一定降低外,对其它各项指标均无明显影响。对孕鼠及其子代小鼠均未见有明显影响。结论:提示菠萝叶对小鼠一般生殖功能无明显毒性。%This article was aimed to study the general reproductive toxicity in mice in order to give a better evalua-tion of the medicinal plant of pineapple leaves (A nanas comasus L). Adult male and female mice were orally admin-istered with pineapple leaves. And then, each of the male and female mice was put together in one cage for mating. The mating success females were fed continuously. The experimental observation was conducted in pregnancy, fetal development, as well as the offspring of mice. The results showed that in addition to a large dose of pineapple leaves (4 g·kg-1) of the parental male rats having a lower body weight, pineapple leaves did not significantly affect on other parameters. There were no significant effects on pregnant mice and their offspring of mice. It was concluded that the pineapple leaves did not influence the general reproductive function of mice apparently.

  16. Study on alternative methods for the acute oral toxicity in detection of chemicals%急性经口毒性替代方法在化学品检验中的应用研究

    Institute of Scientific and Technical Information of China (English)

    谭剑斌; 赵敏; 杨杏芬; 周轶琳; 陈壁锋; 陈瑞仪; 黄建康

    2011-01-01

    ,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 ).Conclusions High 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.

  17. Oral histoplasmosis

    Directory of Open Access Journals (Sweden)

    Patil Karthikeya

    2009-01-01

    Full Text Available Histoplasmosis is a systemic fungal disease that takes various clinical forms, among which oral lesions are rare. The disseminated form of the disease that usually occurs in association with Human Immunodeficiency Virus (HIV is one of the AIDS-defining diseases. Isolated oral histoplasmosis, without systemic involvement, with underlying immunosuppression due to AIDS is very rare. We report one such case of isolated oral histoplasmosis in a HIV-infected patient.

  18. 京尼平苷四种不同给药途径的肝毒性初步研究%Preliminary Studies on Liver Toxicity of Gardenoside with Four Different Pathways of Administration

    Institute of Scientific and Technical Information of China (English)

    王智勇; 张海燕; 杨明; 高龙潭; 芦乾; 宋伟; 刘昊; 汪建民

    2013-01-01

    Objective: To study the liver toxicity of gardenoside with four different pathways of administration in rats, to provide more information for the further research and clinical application. Methods: The SD rats,were used and randomly divided into five groups, including blank group, oral group(ig), intravenous injection group(iv), muscles injection group(im), nasal group(ns). Gardenoside solution was repeated doses for one month. Then the rats were died, and we studied the liver toxicity of gardenoside with liver index, alanine aminotransferase and aspartate aminotransferase for index. Results: According to the liver index, the liver toxicity of gardenoside was ig>iv>ns≈ im>blank group (Pig>im>ns>blank group (P<0.01). Conclusion: Among the four pathways of administration of gardnoside, nasal (ns) was the best route, which has fewer liver toxicity than others.%目的:依据临床的几种常规的给药方式,对比研究京尼平苷不同给药途径对肝脏的毒性作用,为其进一步研究开发及临床应用提供依据.方法:应用SD大鼠,采用口服(ig)、静注(iv)、肌注(im)、鼻腔(ns)四种给药途径给予京尼平苷溶液一个月.以肝脏指数、丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)为指标,考察不同给药途径下京尼平苷的肝脏毒性作用.结果:由肝脏指数得出:口服(ig)>静注(iv)>鼻腔(ns)≈肌注(im)>空白(P<0.05);由血清丙氨酸氨基转移酶(ALT)及天冬氨酸氨基转移酶(AST)的活性得出:静注(iv)>口服(ig)>肌注(im)>鼻腔(ns)>空白(P<0.01).结论:综合上述指标分析,口服(ig)、静注(iv)、肌注(im)、鼻腔(ns)四种给药途径中,鼻腔(ns)给药方式的京尼平苷对肝脏的毒性作用较小.

  19. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    . The first section of this chapter outlines the complete cause-effect pathway, from emissions of toxic substances to intake by the population up to damages in terms of human health effects. Section 2 outlines the framework for assessing human toxicity in LCIA. Section 3 discusses the contributing substances......This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... – demonstrates the importance to account for both outdoor and indoor exposure, including consumer products. Analysing the variations in intake fraction (the fraction of the emitted or applied chemical that is taken in by the consumer and the general population), effect factor and characterisation factor across...

  20. 转FBP7-iaaM基因棉籽对大鼠的亚慢性毒性研究%Subchronic oral toxicity of genetically modified cottonseed with FBP7-iaaM gene in rats

    Institute of Scientific and Technical Information of China (English)

    马运明; 王静; 姜文玲; 张力; 王晓军; 刘英华; 张静

    2012-01-01

    目的 观察转FBP7-iaaM基因棉籽对大鼠的亚慢性毒性.方法 将Wistar大鼠按体重随机分为7组,即FBP7-iaaM基因棉籽3个剂量(1.25%,2.5%,5%)组,非FB P7-iaaM基因棉籽3个剂量(1.25%,2.5%,5%)组和1个常规基础饲料对照组.分别喂饲相应饲料90 d,自由进食饮水,观察大鼠体重、进食量、血液学、血生化、脏器系数及脏器组织病理学检查.结果 各实验组动物的体重增长正常,血液学和血生化个别指标虽有统计学差异,但并无生物学意义.转基因棉籽组及亲本组脏器系数与对照组比较,差异均无统计学意义(P>0.05),主要脏器病理学检查未发现明显异常.结论 现有实验结果不能证实该FBP7-iaaM基因棉籽对大鼠有亚慢性毒性作用.%Objective To study the subchronic oral toxic effects of genetically modified(GM) cottonseed with FBP7-iaaM gene in rats. Methods The rats were fed with diets containing GM cottonseed with FBP7-iaaM gene or containing non-GM cottonseed at a dose of 5%, 2.5%, 1.25% and 0%(control group) respectively for three consecutive months, the general behavior, body weight, food consumption, food efficiency, etc, were observed. At the mid and end of experiment, the blood and serum samples were collected for routine and biochemical assays; the internal organs were also taken for calculating the viscera coefficients and doing histopathological examinations. Results The rats exhibited free movements and shining coats without any abnormal symptoms and abnormal secretions in their noses, eyes or mouths. There were no adverse effects on body weight in GM cottonseed groups and non-GM cottonseed groups, no biological differences in hematological and biochemical indices were observed; no significant differences(P>0.05) in viscera coefficient were detected between experimental groups and control group. No histopathological changes were observed. Conclusion In the present study, no adverse effects of GM cottonseed with

  1. Toxic myopathies.

    Science.gov (United States)

    Pasnoor, Mamatha; Barohn, Richard J; Dimachkie, Mazen M

    2014-08-01

    Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, because they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features, and possible underlying cellular mechanisms.

  2. Repeated dose of ketamine effect to the rat hippocampus tissue

    Directory of Open Access Journals (Sweden)

    Mehtap Okyay Karaca

    2015-01-01

    Full Text Available Aim: We aimed to determine the neurotoxic effect of repeated ketamine administration on brain tissue and if neurotoxic effect was present, whether this effect continued 16 days later using histological stereological method, a quantitative and objective method. Materials and Methods: Female rats were divided into three groups, each containing five rats. Rats in Group I were given 0.9% saline solution 4 times a day for 5 days. The rats in Groups II and III were given ketamine as intraperitoneal injections. Rats in Groups I and II were sacrificed on 5 th day while the ones in Group III on 21 st day. Cornu ammonis (CA and gyrus dentatus (GD regions in hippocampus tissue of rats were studied using optic fractionation method. Findings: There were significantly less number of cells in hippocampal CA and GD regions of rats from Groups II and III compared to the ones from Group I. Difference in cell number was also significantly higher in Group III than in Group II, but this difference was not as pronounced as the one between Groups III and I. Conclusion: Repeated ketamine doses caused neurotoxicity in rat hippocampus.

  3. Antithrombotic effect of repeated doses of the ethanolic extract of ...

    African Journals Online (AJOL)

    2013-05-22

    May 22, 2013 ... botic drugs for the prevention and treatment of arterial and venous ... 7), antidiabetic (8, 9) and anticancer effects (10, 11), and also to possesses .... Another possible explanation for non-adherence of the thrombi to the vessel ...

  4. Pharmacokinetics of rectal paracetamol after repeated dosing in children

    DEFF Research Database (Denmark)

    Hahn, T W; Henneberg, S W; Holm-Knudsen, R J

    2000-01-01

    Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P

  5. Pharmacokinetics of rectal paracetamol after repeated dosing in children

    DEFF Research Database (Denmark)

    Hahn, T W; Henneberg, S W; Holm-Knudsen, R J

    2000-01-01

    Twenty-three children (aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mg kg-1 every 6 h (maximum 5 days) after major surgery and serum and saliva concentrations were measured. There was a good correlation (r = 0.91, P

  6. Oral iron chelators.

    Science.gov (United States)

    Kwiatkowski, Janet L

    2010-02-01

    Effective chelation therapy can prevent or reverse organ toxicity related to iron overload, yet cardiac complications and premature death continue to occur, largely related to difficulties with compliance in patients who receive parenteral therapy. The use of oral chelators may be able to overcome these difficulties and improve patient outcomes. A chelator's efficacy at cardiac and liver iron removal and side-effect profile should be considered when tailoring individual chelation regimens. Broader options for chelation therapy, including possible combination therapy, should improve clinical efficacy and enhance patient care.

  7. [Accidental oral mercurochrome poisoning].

    Science.gov (United States)

    Ayala Curiel J; Nieto Conde C; Santana Rodríguez C; Urbón Artero A; Gracia Remiro R

    2000-11-01

    Neonatal mercury poisoning, especially that due to merbromin ingestion, is uncommon. We describe the case of a 10 day old newborn infant who was given mercurochrome orally for 7 days due to misunderstanding of medical instructions. Initial symptoms included loss of appetite and low weight increase. Elevated blood mercury concentrations were found. Chelating therapy with dimercaprol was initiated and the patient's evolution was good. We discuss the potential toxicity of mercury and emphasise the importance of the transmission of information by physicians, especially to the immigrant population.

  8. Toxic synovitis

    Science.gov (United States)

    ... Names Synovitis - toxic; Transient synovitis References Horowitz R. Pediatric orthopedic emergencies. In: Adams JG, ed. Emergency Medicine: Clinical ... JW III, Schor NF, eds. Nelson Textbook of Pediatrics . 20th ed. Philadelphia, PA: Elsevier; 2016:chap ... Shoulder Service, UCSF Department of Orthopaedic Surgery, San Francisco, CA. Also reviewed by David ...

  9. Management of Patients with Oral Candidiasis

    DEFF Research Database (Denmark)

    Kragelund, Camilla; Reibel, Jesper; Pedersen, Anne Marie Lynge

    2016-01-01

    Oral candidal infections are medically treated with antifungal agents. In the fungal cell membrane, steroid ergosterol is the target of the antifungals on the market, but similarity with the human cell membrane may cause host toxicity and unintended reactions. Management of oral candidiasis depends...... in particular in patients with recurrent oral candidiasis. This risk can be reduced if different types of antifungal drugs are used over time or are combined. This chapter focuses on antifungal treatment of the medically compromised patient with oral candidiasis by highlighting the advantages and disadvantages...

  10. Oral Histoplasmosis.

    Science.gov (United States)

    Folk, Gillian A; Nelson, Brenda L

    2017-02-20

    A 44-year-old female presented to her general dentist with the chief complaint of a painful mouth sore of 2 weeks duration. Clinical examination revealed an irregularly shaped ulcer of the buccal and lingual attached gingiva of the anterior mandible. A biopsy was performed and microscopic evaluation revealed histoplasmosis. Histoplasmosis, caused by Histoplasma capsulate, is the most common fungal infection in the United States. Oral lesions of histoplasmosis are generally associated with the disseminated form of histoplasmosis and may present as a fungating or ulcerative lesion of the oral mucosa. The histologic findings and differential diagnosis for oral histoplasmosis are discussed.

  11. Oral leukoplakia

    DEFF Research Database (Denmark)

    Holmstrup, Palle; Dabelsteen, Erik

    2016-01-01

    The idea of identifying oral lesions with a precancerous nature, i.e. in the sense of pertaining to a pathologic process with an increased risk for future malignant development, of course is to prevent frank malignancy to occur in the affected area. The most common oral lesion with a precancerous...... nature is oral leukoplakia, and for decades it has been discussed how to treat these lesions. Various treatment modalities, such as systemic therapies and surgical removal, have been suggested. The systemic therapies tested so far include retinoids, extracts of green tea, inhibitors of cyclooxygenase-2...

  12. Oral pathology.

    Science.gov (United States)

    Niemiec, Brook A

    2008-05-01

    Oral disease is exceedingly common in small animal patients. In addition, there is a very wide variety of pathologies that are encountered within the oral cavity. These conditions often cause significant pain and/or localized and systemic infection; however, the majority of these conditions have little to no obvious clinical signs. Therefore, diagnosis is not typically made until late in the disease course. Knowledge of these diseases will better equip the practitioner to effectively treat them. This article covers the more common forms of oral pathology in the dog and cat, excluding periodontal disease, which is covered in its own chapter. The various pathologies are presented in graphic form, and the etiology, clinical signs, recommended diagnostic tests, and treatment options are discussed. Pathologies that are covered include: persistent deciduous teeth, fractured teeth, intrinsically stained teeth, feline tooth resorption, caries, oral neoplasia, eosinophilic granuloma complex, lymphoplasmacytic gingivostomatitis, enamel hypoplasia, and "missing" teeth.

  13. Herpes - oral

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000606.htm Herpes - oral To use the sharing features on this page, ... 374. Read More Atopic dermatitis Cancer Fever Genital herpes Mouth ulcers Vesicles Review Date 8/14/2015 Updated ...

  14. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... on characterisation factors means that results should by default be reported and interpreted in log scales when comparing scenarios or substance contribution! We conclude by outlining future trends in human toxicity modelling for LCIA, with promising developments for (a) better estimates of degradation halflives, (b......) the inclusion of ionization of chemicals in human exposure including bioaccumulation, (c) metal speciation, (d) spatialised models to differentiate the variability associated with spatialisation from the uncertainty, and (e) the assessment of chemical exposure via consumer products and occupational settings...

  15. Disparities in Oral Health

    Science.gov (United States)

    ... 2020: Oral Health Objectives Site Map Disparities in Oral Health Recommend on Facebook Tweet Share Compartir Oral health ... to get and keep dental insurance. Disparities in Oral Health Some of the oral health disparities that exist ...

  16. Thermal Stress and Toxicity

    Science.gov (United States)

    Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at subthermoneutral te...

  17. Oral candidiasis.

    Science.gov (United States)

    Millsop, Jillian W; Fazel, Nasim

    2016-01-01

    Oral candidiasis (OC) is a common fungal disease encountered in dermatology, most commonly caused by an overgrowth of Candida albicans in the mouth. Although thrush is a well-recognized presentation of OC, it behooves clinicians to be aware of the many other presentations of this disease and how to accurately diagnose and manage these cases. The clinical presentations of OC can be broadly classified as white or erythematous candidiasis, with various subtypes in each category. The treatments include appropriate oral hygiene, topical agents, and systemic medications. This review focuses on the various clinical presentations of OC and treatment options.

  18. Oral myiasis

    Directory of Open Access Journals (Sweden)

    Treville Pereira

    2010-01-01

    Full Text Available Myiasis is a relatively rare condition arising from the invasion of body tissues or cavities of living animals or humans by maggots or larvae of certain species of flies. It is an uncommon clinical condition, being more frequent in underdeveloped countries and hot climate regions, and is associated with poor hygiene, suppurative oral lesions; alcoholism and senility. Its diagnosis is made basically by the presence of larvae. The present article reports a case of oral myiasis involving 20 larvae in a patient with neurological deficiency.

  19. Oral calcitonin

    Directory of Open Access Journals (Sweden)

    Hamdy RC

    2012-09-01

    Full Text Available Ronald C Hamdy,1,2 Dane N Daley11Osteoporosis Center, College of Medicine, East Tennessee State University, 2Veterans Affairs Medical Center, Johnson City, TN, USAAbstract: Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl-amino-caprylic acid (5-CNAC (Emisphere Technologies, Cedar Knolls, NJ. Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis failed to

  20. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Topics > Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens during an oral cancer examination. Quick and painless, the exam can detect ...

  1. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Topics > Oral Cancer > Oral Cancer Exam Video Oral Cancer Exam Video This video shows what happens during an oral cancer examination. Quick and painless, the exam can detect ...

  2. Oral suspensions of morphine hydrochloride for controlled release: rheological properties and drug release.

    Science.gov (United States)

    Morales, M E; López, G; Gallardo, V; Ruiz, M A

    2011-04-04

    Recent developments in pharmaceutical technology have facilitated the design and production of modified release formulas for drugs whose physical, chemical or biological properties impede release and thus might compromise their efficacy or safety. One such drug is morphine, whose short half-life requires repeated doses at short intervals. The use of biocompatible polymers such as ethylcellulose has made it possible to develop microencapsulated formulations which facilitate liquid, sustained-release pharmaceutical formulas for oral administration. We developed a stable final formulation of morphine with an acceptable release profile by comparing the rheological properties and stability of formulations with different thickeners (xanthan gum, Carbopol, and carboxymethylcellulose with microcrystalline cellulose) at different concentrations from 0.25% to 1.0%. Release assays in a Franz-type cell were done to determine the most suitable release profile for the formulation.

  3. [Oral complications of chemotherapy of malignant neoplasms].

    Science.gov (United States)

    Obralić, N; Tahmiscija, H; Kobaslija, S; Beslija, S

    1999-01-01

    Function and integrity disorders of the oral cavity fall into the most frequent complication of the chemotherapy of leucemias, malignant lymphomas and solid tumors. Complications associated with cancer chemotherapy can be direct ones, resulting from the toxic action of antineoplastic agents on the proliferative lining of the mouth, or indirect, as a result of myelosuppression and immunosuppression. The most frequent oral complications associated with cancer chemotherapy are mucositis, infection and bleeding. The principles of prevention and management of oral complications during cancer chemotherapy are considered in this paper.

  4. Amphotericin B cochleates: a vehicle for oral delivery.

    Science.gov (United States)

    Perlin, David S

    2004-02-01

    Cochleates are a novel lipid-based delivery vehicle consisting of crystalline phospholipid-cation structures that form spiral lipid sheets. They represent a new technology platform for oral delivery of clinically important drugs that possess poor oral bioavailability. Orally administered cochleates containing amphotericin B (CAMB) showed broad-spectrum activity in murine infection models of candidiasis, aspergillosis and cryptococcosis. Initial biodistribution studies of CAMB administered orally in mice demonstrated that cochleates delivered significant levels of AMB to target organs. The lipid particulate nature of cochleates also imparted reduced toxicity that mimics other lipid-amphotericin B complexes. Cochleates are a promising new vehicle for oral delivery of amphotericin B at therapeutic levels.

  5. Oral dirofilariasis

    Directory of Open Access Journals (Sweden)

    R S Desai

    2015-01-01

    Full Text Available Dirofilaria is parasitic nematodes of domestic and wild animals that can infect humans accidentally via vectors. Its occurrence in the oral cavity is extremely rare. The most frequent presentation of human dirofilariasis is a single submucosal nodule without signs of inflammation. We hereby, report a case of human dirofilariasis affecting the buccal mucosa in a 32-year-old farmer caused by D. repens.

  6. Oral leiomyomas.

    Science.gov (United States)

    Damm, D D; Neville, B W

    1979-04-01

    Oral leiomyomas are considered to be rare neoplasms, but they may be encountered more frequently than generally believed. Three types of leiomyomas are commonly described: solid leiomyomas, angiomyomas, and epithelioid leiomyomas. Three cases of solid leiomyoma are presented, all of which occurred in the anterior mandibular mucobuccal fold. Leiomyomas can be easily confused with other spindle-cell tumors. The necessity of using special stains, especially Mallory's phosphotungstic acid hematoxylin, is discussed.

  7. Iodine toxicity and its amelioration.

    Science.gov (United States)

    Baker, David H

    2004-06-01

    Iodine (I) toxicity is rare in animals and humans, but nuclear explosions that give off radioactive I and excessive stable I ingestion in parts of the world where seaweed is consumed represent specialized I toxicity concerns. Chronic overconsumption of I reduces organic binding of I by the thyroid gland, which results in hypothyroidism and goiter. Bromine can replace I on position 5 of both T(3) and T(4) with no loss of thyroid hormone activity. Avian work has also demonstrated that oral bromide salts can reverse the malaise and growth depressions caused by high doses of I (as KI) added as supplements to the diet. Newborn infants by virtue of having immature thyroid glands are most susceptible to I toxicity, whether of stable or radioactive origin. For the latter, the 1986 Chernobyl nuclear accident in Belarus has provided evidence that KI blockage therapy for exposed individuals 18 years of age and younger is effective in minimizing the development of thyroid cancer. Whether bromide therapy has a place in I toxicity situations remains to be determined.

  8. Toxic Amblyopia (Nutritional Amblyopia)

    Science.gov (United States)

    ... Finds Additional Content Medical News Toxic Amblyopia (Nutritional Amblyopia) By James Garrity, MD, Whitney and Betty MacMillan ... Neuropathies) Ischemic Optic Neuropathy Optic Neuritis Papilledema Toxic Amblyopia Toxic amblyopia is damage to the optic nerve ...

  9. Distributed Structure Searchable Toxicity

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Distributed Structure Searchable Toxicity (DSSTox) online resource provides high quality chemical structures and annotations in association with toxicity data....

  10. Oral contraceptives.

    Science.gov (United States)

    Maclennan, A H

    1987-12-01

    Over 60 million women use highly efficient and safe modern combined oral contraceptives (OCs) every day. A women who takes the oral contraceptive for 5 years before the age of 30 will actually live 12 days longer, although a woman taking the pill for the 1st time for 5 years after the age of 30 will have her life span reduced on the average by 80 days. OC related morbidity and mortality mostly occur in women over 35 who smoke. Combined low dose OCs are safe for women who do not smoke, at least to 45 years of age and probably to the menopause. The prescription of OCs is also safe to the young adolescent. The pill does not interfere with maturation of the hypothalamic-pituitary ovarian axis and does not increase the incidence of amenorrhoea, oligomenorrhoea or infertility in later life. Patients with contraindications to estrogen therapy are excluded from OC use (history of thromboembolism, major heart disease, liver disease, breast cancer). Low-dose (30-35 mcg estrogen-containing monophasic or triphasic) pills are recommended. Combined oral contraceptives contain either ethinyl estradiol (1.7 to 2 times more potent) or mestranol. After absorption the progestagens, norethisterone acetate, ethynodiol diacetate and lynoestrenol are all metabolized to norethisterone. The progestagen-only pill has about a 2% failure rate and poorer cycle control than the combined pill, but it lacks estrogenic, progestagenic and androgenic side effects. This pill is suitable for the lactating mother, for smokers over 35, for hypertensive patients, and for those with a history of thrombosis. The efficacy of the progestagen-only pill is restored in 3 days of pill taking. Postcoital contraception is an alternative: treatment can be given for at least 72 hours after intercourse. The Yuzpe method calls for the patient to take 2 combined oral contraceptive tablets containing levonorgestrel and ethinyl estradiol (Eugynon or Ovral) followed by a further 2 tablets 12 hours later. This regimen

  11. Toxicity of hyperoside after long-term oral administration in Wistar rats%金丝桃苷对Wistar大鼠重复灌胃给药的毒性研究

    Institute of Scientific and Technical Information of China (English)

    艾国; 黄正明; 王德文; 张海艇

    2012-01-01

    目的:观察金丝桃苷对大鼠的长期毒性反应,评价金丝桃苷的安全性,为临床剂量的拟定提供依据.方法:健康Wistar大鼠160只,雌雄各半.按体重随机分为对照组和低、中、高(30,175,1 000 mg· kg-1·d-1)剂量组,每周给药6d,连续给药6个月.停药后留取部分动物继续观察1个月.分阶段考察大鼠的一般症状、体重、耗料量、血液学指标、血清生化学指标,动物剖检,对主要脏器进行称重、计算脏器系数,进行组织病理学检查.结果:长期毒性实验中与同期对照组比较,金丝桃苷低、中、高3个剂量组动物行为活动、体重增长、耗料量等均未见明显异常,血液学指标、血液生化指标、脏器系数及病理组织学检查发现肾脏是可能的毒性靶器官,但肾脏损害是可逆的,停药后可以恢复正常.结论:金丝桃苷具有较好的安全性,肾脏是可能的毒性靶器官,但损害是可逆的,建议临床使用时定期进行血液学和肾功能指标监测.%Objective: To investigate the chronic toxicity of hyperoside in rats for evaluating its safety and providing a recommendation in defining its clinical dose.Methods: Wistar rats (n = 160) were randomly divided into four groups of 40 animals each (20 per sex).They were administered with hyperoside 30, 175 and 1 000 mg·kg·d-1 by gavage for 6 months followed by subsequent 1 month recovery period; 1 % aqueous carboxymethyl-cellulose was used as the control.Mortality, clinical signs, body weight changes, food consumption, hematological and biochemical parameters, gross findings, organ weights and histological markers were monitored during the dosing and recovery periods.Results: Compared with normal control group, no significant differences were observed in rats' behaviors, food-intake, weight gain and related examination indexes among the treatment groups.Hematolo-gy index, blood biochemical index, viscera coefficient and histological examination indicated

  12. [Toxicity of sulpiride].

    Science.gov (United States)

    Ciszowski, Krzysztof; Szpak, Dorota; Wilimowska, Jolanta

    2010-01-01

    Sulpiride is a benzamide neuroleptic used in the treatment of some psychiatric and gastroenterological disorders. Its antipsychotic, antiautistic, activizing and antidepressive properties result from antagonistic action to dopaminergic D2, D3 and D4 receptors in the central nervous system (CNS). The oral bioavailability of sulpiride is poor and it does not appear to have an extensive first-pass metabolism, nor is it extensively protein-bound. Elimination of sulpiride appears to depend primarily on the kidneys. The acute sulpiride poisoning includes mainly neuropsychiatric (i.e., agitation, hallucinations, and CNS depression) as well as cardiac effects (i.e., hypotension, dysrhythmias, and sinus tachycardia). The life-threatening conditions with sometimes fatal outcome after sulpiride poisoning are prolongation of QTc interval with consequent torsade de pointes (TdP) and neuroleptic malignant syndrome (NMS). The quantitative methods for the measurement of sulpiride blood concentration are not routinely available and the toxic blood concentration is probably higher than 2 mg/L. Treatment of acute sulpiride poisoning includes standard protocols of gastrointestinal decontamination and further symptomatic and supportive measures, among them TdP (magnesium sulphate, isoproterenol, electrotherapy) and NMS treatment (benzodiazepines, bromocriptine, dantrolene, physical cooling).

  13. A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing - t4 report*.

    Science.gov (United States)

    Basketter, David A; Clewell, Harvey; Kimber, Ian; Rossi, Annamaria; Blaauboer, Bas; Burrier, Robert; Daneshian, Mardas; Eskes, Chantra; Goldberg, Alan; Hasiwa, Nina; Hoffmann, Sebastian; Jaworska, Joanna; Knudsen, Thomas B; Landsiedel, Robert; Leist, Marcel; Locke, Paul; Maxwell, Gavin; McKim, James; McVey, Emily A; Ouédraogo, Gladys; Patlewicz, Grace; Pelkonen, Olavi; Roggen, Erwin; Rovida, Costanza; Ruhdel, Irmela; Schwarz, Michael; Schepky, Andreas; Schoeters, Greet; Skinner, Nigel; Trentz, Kerstin; Turner, Marian; Vanparys, Philippe; Yager, James; Zurlo, Joanne; Hartung, Thomas

    2012-01-01

    Systemic toxicity testing forms the cornerstone for the safety evaluation of substances. Pressures to move from traditional animal models to novel technologies arise from various concerns, including: the need to evaluate large numbers of previously untested chemicals and new products (such as nanoparticles or cell therapies), the limited predictivity of traditional tests for human health effects, duration and costs of current approaches, and animal welfare considerations. The latter holds especially true in the context of the scheduled 2013 marketing ban on cosmetic ingredients tested for systemic toxicity. Based on a major analysis of the status of alternative methods (Adler et al., 2011) and its independent review (Hartung et al., 2011), the present report proposes a roadmap for how to overcome the acknowledged scientific gaps for the full replacement of systemic toxicity testing using animals. Five whitepapers were commissioned addressing toxicokinetics, skin sensitization, repeated-dose toxicity, carcinogenicity, and reproductive toxicity testing. An expert workshop of 35 participants from Europe and the US discussed and refined these whitepapers, which were subsequently compiled to form the present report. By prioritizing the many options to move the field forward, the expert group hopes to advance regulatory science.

  14. Acute toxic neuropathy mimicking guillain barre syndrome

    Directory of Open Access Journals (Sweden)

    Muhammed Jasim Abdul Jalal

    2015-01-01

    Full Text Available Case: A 30 year old male presented with numbness of palms and soles followed by weakness of upper limbs and lower limbs of 5 days duration, which was ascending and progressive. Three months back he was treated for oral and genital ulcers with oral steroids. His ulcers improved and shifted to indigenous medication. His clinical examination showed polyneuropathy. CSF study did not show albuminocytological dissociation. Nerve conduction study showed demyelinating polyneuropathy. His blood samples and the ayurvedic drug samples were sent for toxicological analysis. Inference: Acute toxic neuropathy - Arsenic

  15. Toxic material advisory report - 2-mercaptoethanol

    Energy Technology Data Exchange (ETDEWEB)

    Bernholc, N. M.; White, O. Jr.; Baloyi, R. S.; Silverstein, B. D.

    1983-03-01

    A review of the animal toxicity data for 2-ME is presented. The results revealed that chronic inhalation exposures at a concentration of 6 mg/m/sup 3/ produced decreased oxygen consumption, lymphopenia, and neutrophilia. Comparison of acute toxicity data for 2-ME with data of structurally similar compounds suggests that 2-ME may be 2.3 times more toxic than butanethiol (TLV = 0.5 ppM), 6.5 times more toxic than ethanethiol, and 6 times more toxic than propanethiol (TLV = 0.5 ppM) via oral administration but may be comparable to propanethiol and less toxic than butanethiol and ethanethiol by the inhalation route of exposure. The TLVs for ethanethiol, methanethiol, and butanethiol were based on discomfort to human volunteers rather than toxicity. Since 2-ME has many effects similar to those of the thiols discussed and its odor threshold falls in the range of other thiols, by analogy the exposure limit for 2-ME should be comparable to the TLVs for butanethiol and ethanethiol. An interim exposure limit (IEL) of 0.5 ppM for a time-weighted average concentration during an 8-hour work shift is recommended. As with other thiols, a nuisance problem due to 2-ME odors and complaints of odor may serve as a primary reason for controlling workplace concentrations.

  16. Oral dirofilariasis

    Directory of Open Access Journals (Sweden)

    Mahija Janardhanan

    2014-01-01

    Full Text Available Filariasis affecting animals can rarely cause infections in human beings through the accidental bite of potential vectors. The resulting infection in man, known as zoonotic filariasis occur worldwide. Human dirofilariasis, the most common zoonotic filariasis, is caused by the filarial worm belonging to the genus Dirofilaria. Dirofilarial worms, which are recognized as pathogenic in man can cause nodular lesions in the lung, subcutaneous tissue, peritoneal cavity or eyes. Oral dirofilariasis is extremely rare and only a few cases have been documented. We report an interesting case of dirofilariasis due to Dirofilaria repens involving buccal mucosa in a patient who presented with a facial swelling. The clinical features, diagnostic issues and treatment aspects are discussed. This paper stresses the importance of considering dirofilariasis as differential diagnosis for subcutaneous swelling of the face, especially in areas where it is endemic.

  17. Oral sex, oral health and orogenital infections

    Directory of Open Access Journals (Sweden)

    Saini Rajiv

    2010-01-01

    Full Text Available Oral sex is commonly practiced by sexually active male-female and same-gender couples of various ages, including adolescents. The various type of oral sex practices are fellatio, cunnilingus and analingus. Oral sex is infrequently examined in research on adolescents; oral sex can transmit oral, respiratory, and genital pathogens. Oral health has a direct impact on the transmission of infection; a cut in your mouth, bleeding gums, lip sores or broken skin increases chances of infection. Although oral sex is considered a low risk activity, it is important to use protection and safer sex precautions. There are various methods of preventing infection during oral sex such as physical barriers, health and medical issues, ethical issues and oral hygiene and dental issues. The lesions or unhealthy periodontal status of oral cavity accelerates the phenomenon of transmission of infections into the circulation. Thus consequences of unhealthy or painful oral cavity are significant and oral health should be given paramount importance for the practice of oral sex.

  18. Oral amyloidosis

    Directory of Open Access Journals (Sweden)

    Isabella Lima Arrais Ribeiro

    Full Text Available A amiloidose é uma doença complexa rara de difícil diagnóstico que ocorre devido à deposição de substância amilóide no meio extracelular. Ao ser diagnosticado na cavidade bucal, deve-se monitorar o paciente a fim de avaliar possíveis complicações sistêmicas da doença. Diante disso, o objetivo do presente estudo é relatar um caso de amiloidose oral em uma paciente do gênero feminino de 72 anos de idade. Baseado nos sinais clínicos observados, a hipótese diagnóstica foi de fibroma traumático. Após realização de biópsia e exame histopatológico, o diagnóstico foi de amiloidose oral, o que foi confirmado com a coloração do espécime com o reagente vermelho congo. Depósitos de amilóide foram encontrados no tecido conjuntivo, na avaliação através da luz polarizada, que apresentou birrefringência. Tal achado foi preocupante, já que a amiloidose geralmente acomete diversos tecidos levando a comprometimentos sistêmicos. Por essa razão a paciente foi encaminhada a procurar atendimento médico. No entanto, houve abandono do tratamento e a mesma veio a óbito 6 meses após o diagnóstico da doença. Lesões orais aparentemente simples podem revelar doenças raras e de difícil tratamento. O diagnóstico preciso e acompanhamentos médicos são fundamentais na sobrevida do paciente.

  19. Bioaccumulation and Subchronic Toxicity of 14 nm Gold Nanoparticles in Rats

    Directory of Open Access Journals (Sweden)

    Clinton Rambanapasi

    2016-06-01

    Full Text Available Colloidal suspensions of 14 nm gold nanoparticles (AuNPs were repeatedly administered intravenously at three dose levels (0.9, 9 and 90 µg to male Sprague Dawley rats weekly for 7 weeks, followed by a 14-day washout period. After sacrificing, the amount of gold was quantified in the liver, lungs, spleen, skeleton and carcass using neutron activation analysis (NAA. During the study, pre- and post (24 h administration blood samples were collected from both the test and control groups, the latter which received an equal injection volume of normal saline. General health indicators were monitored together with markers of kidney and liver damage for acute and subchronic toxicity assessment. Histopathological assessments were done on the heart, kidneys, liver, lungs and spleen to assess any morphological changes as a result of the exposure to AuNPs. The mass measurements of all the groups showed a steady increase with no signs of overt toxicity. The liver had the highest amount of gold (µg per gram of tissue after 56 days followed by the spleen, lungs, skeleton and carcass. Markers of kidney and liver damage showed similar trends between the pre and post samples within each group and across groups. The histopathological examination also showed no hepatotoxicity and nephrotoxicity. There was accumulation of Au in tissues after repeated dosing, albeit with no observable overt toxicity, kidney or liver damage.

  20. Insights on in vitro models for safety and toxicity assessment of cosmetic ingredients.

    Science.gov (United States)

    Almeida, Andreia; Sarmento, Bruno; Rodrigues, Francisca

    2017-03-15

    According to the current European legislation, the safety assessment of each individual cosmetic ingredient of any formulation is the basis for the safety evaluation of a cosmetic product. Also, animal testing in the European Union is prohibited for cosmetic ingredients and products since 2004 and 2009, respectively. Additionally, the commercialization of any cosmetic products containing ingredients tested on animal models was forbidden in 2009. In consequence of these boundaries, the European Centre for the Validation of Alternative Methods (ECVAM) proposes a list of validated cell-based in vitro models for predicting the safety and toxicity of cosmetic ingredients. These models have been demonstrated as valuable and effective tools to overcome the limitations of animal in vivo studies. Although the use of in vitro cell-based models for the evaluation of absorption and permeability of cosmetic ingredients is widespread, a detailed study on the properties of these platforms and the in vitro-in vivo correlation compared with human data are required. Moreover, additional efforts must be taken to develop in vitro models to predict carcinogenicity, repeat dose toxicity and reproductive toxicity, for which no alternative in vitro methods are currently available. This review paper summarizes and characterizes the most relevant in vitro models validated by ECVAM employed to predict the safety and toxicology of cosmetic ingredients. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Local and systemic toxicity of intraoral submucosal injections of phentolamine mesylate (OraVerse).

    Science.gov (United States)

    Rutherford, Bruce; Zeller, Jillynne R; Thake, Daryl

    2009-01-01

    OraVerse, an injectable formulation of phentolamine mesylate (PM), was recently approved by the U.S. Food and Drug Administration (FDA) for reversal of anesthesia of the lip and tongue and associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. Because PM had not been approved previously for submucosal administration, 2 Good Laboratory Practices (GLP) studies in dogs designed to investigate systemic toxicity and the local effects of single and repeated dosing of OraVerse on the inferior alveolar nerve and branches of the superior alveolar nerve and adjacent soft tissues after local administration were conducted. Systemic toxicity was measured by preinjection and postinjection clinical examinations, clinical chemistry, and gross and microscopic examinations of major organs after necropsy. No evidence of systemic toxicity was detected. Local nerve and adjacent tissue damage was assessed by conventional histopathology. Nerve degeneration was evident in 1 animal. Mild perineural inflammation adjacent to the inferior alveolar nerve and inflammatory exudates were observed in submucosal tissues in several animals. No changes were observed in the nerves at injection sites of dogs from any dose group that were considered directly related to the test articles. These data reveal that single and repeated intraoral administrations of OraVerse are well tolerated in beagle dogs.

  2. Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate toxicity in rat testis.

    Science.gov (United States)

    Sawada, Stefanie; Oberemm, Axel; Buhrke, Thorsten; Meckert, Christine; Rozycki, Christel; Braeuning, Albert; Lampen, Alfonso

    2015-09-01

    Thermal treatment of foodstuff containing fats and salt promotes the formation of 3-chloropropane-1,2-diol (3-MCPD) and its fatty acid esters. 3-MCPD-exposed rats develop testicular lesions and Leydig cell tumors. 3-MCPD and 3-MCPD ester toxicity is thought to be caused by 3-MCPD and its metabolites, since 3-MCPD esters are hydrolyzed in the gut. Inhibition of glycolysis is one of the few known molecular mechanisms of 3-MCPD toxicity. To obtain deeper insight into this process, a comparative proteomic approach was chosen, based on a 28-days repeated-dose feeding study with male Wistar rats. Animals received equimolar doses of 3-MCPD or 3-MCPD dipalmitate. A lower dose of 3-MCPD dipalmitate was also administered. Absence of histopathological changes supported an analysis of early cellular disturbance. Testes were analyzed by two-dimensional gel electrophoresis followed by mass-spectrometric protein identification. Data provide a comprehensive overview of proteomic changes induced by 3-MCPD and 3-MCPD dipalmitate in rat testis in an early phase of organ impairment. Results are compatible with known 3-MCPD effects on reproductive function, substantially extend our knowledge about cellular responses to 3-MCPD and support the hypothesis that toxicity of 3-MCPD and 3-MCPD esters is mediated via common effectors. DJ-1 was identified as a candidate marker for 3-MCPD exposure.

  3. Oral Cancer Exam

    Medline Plus

    Full Text Available ... for signs of oral cancer. For Patients and the Public Oral Cancer Pamphlet that describes the risk factors, signs and symptoms of oral cancer, and the importance of detecting the disease in its early ...

  4. Oral Cancer Exam

    Medline Plus

    Full Text Available ... Programs Careers in Dental Research See All Continuing Education Practical Oral Care for People With Developmental Disabilities – ... detection and treatment of oral cancers. Note: For materials specific to African American men, please see: Oral ...

  5. Oral Lichen Planus

    Science.gov (United States)

    Oral lichen planus Overview By Mayo Clinic Staff Oral lichen planus (LIE-kun PLAY-nus) is an ongoing (chronic) ... that affects mucous membranes inside your mouth. Oral lichen planus may appear as white, lacy patches; red, ...

  6. Oral Health Glossary

    Science.gov (United States)

    ... About | Contact InfoBites Quick Reference Learn more Children's Oral Health Mouth Breathing Can Cause Major Health Problems Over ... news feeds delivered directly to your desktop! more... Oral Health Glossary Article Chapters Oral Health Glossary print full ...

  7. Oral Cancer Exam

    Medline Plus

    Full Text Available ... for signs of oral cancer. For Patients and the Public Oral Cancer Pamphlet that describes the risk factors, signs and symptoms of oral cancer, and the importance of detecting the disease in its early ...

  8. Probiotics in oral health--a review.

    Science.gov (United States)

    Rao, Yadav; Lingamneni, Benhur; Reddy, Deepika

    2012-01-01

    Probiotics are dietary supplements containing potentially beneficial bacteria or yeasts. Probiotics are live microorganisms thought to be beneficial to the host organism and, when administered in adequate amounts, confer a health benefit on the host. Lactic acid bacteria and bifidobacteria are the most common types of microbes used as probiotics. Probiotics strengthen the immune system to combat allergies, stress, exposure to toxic substances and other diseases. There are reports of beneficial use in HIV infections and cancers.These products help in stimulating oral health promoting flora, and suppress the pathologic colonization and disease spread. Probiotics can be bacteria, molds and yeast, but most probiotics are bacteria. In recent years, there has been a lot of interest in the use of probiotics in maintaining good oral health and treating oral infections. Their use in premalignant and malignant oral disorders is yet to be probed.

  9. 泽漆乙酸乙酯萃取物对小鼠经口急性毒性%Acute Oral Toxicity of Euphorbia helioscopia’ Ethylacetate Extract in Mice

    Institute of Scientific and Technical Information of China (English)

    孙雪; 李明会; 张庆; 粟杨静

    2015-01-01

    With Kunming mouse as test animal , we studied Euphorib a helioscopia’ s toxicity and appraised the GHS class of E. heil oscopia’ s extract by onet-ime intragastric administration .The intragastric administration ’ s LD50 of Epu horbia heliosco-pia’ s ethylacetate extract .Ethylacetate extract of Euphorbia helioscopia was GHS Lever 3, and had good mouse killing ac-tive.All extracts effected moise ’ s physical signs , and created obviously different poison symptoms .The intragastric admin-istration’s LD50 of Euphorbia helioscopia’s ethylacetate extract was 314.80 mg・ kg-1.The 95%confidence interval was (314.80±38.29)mg・ kg-1.The lowest killed does estimated value was LD 10 of 220.53 mg・ kg-1, and at 95%confidence interval it was (220.53±35.61)mg・ kg-1.Ethylacetate extract made significant changes on many physiological indexes of mouse, and injured heart, liver, spleen, lung, kidney in varying degrees .%研究了泽漆( Euphorib a helioscopia)乙酸乙酯萃取物的灭鼠毒性,评价了其灌胃GHS毒性类别,并以点斜法测定其灌胃LD50和LD10。结果表明:泽漆乙酸乙酯萃取物属于GHS 3类,有较好的杀鼠活性,其灌胃LD50为314.80 mg・ kg-1,95%置信区间是(314.80±38.29)mg・ kg-1,最低致死剂量估计值LD10为220.53 mg・ kg-1,LD10的95%置信区间是(220.53±35.61)mg・ kg-1。萃取物对灌胃的KM小鼠造成了多项生理指标的显著变化,对KM小鼠心脏、肝脏、脾脏、肺脏、肾脏均造成了不同程度的损伤,并表现出多种明显的中毒症状。

  10. Methods of acute biological assays in guinea-pigs for the study of toxicity and innocuity of drugs and chemicals

    OpenAIRE

    2010-01-01

    In this study, 602 samples were tested by the following assays performed at the animal facilities (Cedeme) of the Federal University of São Paulo (UNIFESP): 385 for dermal irritability, 90 for ocular irritability (discontinued in 1995), 31 for systemic toxicity by injection, 26 for oral acute toxicity, 15 for toxicity by intracutaneous injection, 15 for skin sensitization, 15 for toxicity of serum and vaccines for human use, 14 for toxicity by intramuscular implantation, 7 for pyrogens, 2 for...

  11. Release and toxicity of dental resin composite

    OpenAIRE

    Saurabh K Gupta; Saxena, Payal; Pant, Vandana A.; Pant, Aditya B.

    2012-01-01

    Dental resin composite that are tooth-colored materials have been considered as possible substitutes to mercury-containing silver amalgam filling. Despite the fact that dental resin composites have improved their physico-chemical properties, the concern for its intrinsic toxicity remains high. Some components of restorative composite resins are released in the oral environment initially during polymerization reaction and later due to degradation of the material. In vitro and in vivo studies h...

  12. Information Search of Toxic-Free Ammunition

    Science.gov (United States)

    1994-04-01

    exposure has been with bismuth compounds used in medical procedures, such as the treatment of ulcers and other gastro-intestinal disorders. There is...necessitate frequent cleaning in order to ensure that toxic effluents do not runoff into ground water . The second option is to design service and/or...bone, and liver. (Ballou 1960). Kays (1968) who orally administered amonium tun•state and sodium tungstata in 3•OH to rats reported the concentration

  13. Ricin Toxicity: Clinical and Molecular Aspects

    Science.gov (United States)

    Moshiri, Mohammad; Hamid, Fatemeh; Etemad, Leila

    2016-01-01

    Seeds of the castor bean plant Ricinuscommunis L (CB) contain ricin toxin (RT), one of the most poisonous naturally-occurring substances known. Ricin toxin, a water-soluble glycoprotein that does not partition into the oil extract, is a ribosome-inactivating toxin composed of two chains, labeled A and B. Severity of the toxicity varies depending on the route of exposure to the toxin. Inhalational is the most toxic route, followed by oral ingestion. Orally-ingested RT accumulates in the liver and spleen but other cells are also affected. The main clinical manifestations are also related to the administration route. Oral ingestion of CB or RT results in abdominal pain, vomiting, diarrhea, and various types of gastrointestinal bleeding that leading to volume depletion, hypovolemic shock, and renal failure. Inhalation of the toxin presents with non-cardiogenic pulmonary edema, diffuse necrotizing pneumonia, interstitial and alveolar inflammation, and edema. Local injection of RT induces indurations at the injection site, swelling of regional lymph nodes, hypotension, and death. An enzyme-linked immunosorbent assay (ELISA) has been developed to detect RT in animal tissues and fluids. Ricinine, an alkaloid of CB, can be detected in rat urine within 48 h of RT exposure. Supportive care is the basic treatment and standard biowarfare decontamination protocols are used for RT intoxication. Dexamethasone and difluoromethylornithine might be effective treatments. This review examines the clinical and molecular aspects of ricin toxicity. PMID:27536698

  14. Oxime silanes: structure/toxicity relationships.

    Science.gov (United States)

    Derelanko, Michael J; Rusch, George M

    2008-01-01

    Acute and repeated oral and dermal rat toxicology studies of standard designs were conducted on four methyl ethyl ketoxime (MEKO) silanes and four methyl isobutyl ketoxime (MIBKO) silanes. Each compound contained either MEKO or MIBKO groups (but not both) and either a single methyl, vinyl, or phenyl group (trifunctional oxime silane), two methyl groups or a methyl and vinyl group (difunctional oxime silane), or no nonoxime group (tetrafunctional oxime silane) attached to the central silicon atom. All compounds caused transient narcosis and anemia, with oral exposure associated with the hydrolyzed oxime groups. Difunctional oxime silanes, containing both a methyl and a vinyl group, caused degeneration of the seminiferous tubules of the testes following oral administration. Serial testicular histopathology indicated the effect originated at the level of the spermatocyte, resulting in a wave of cellular depletion of later maturation stages of spermatogenesis. Spermatogenesis gradually recovered but function was not evaluated. Tetrafunctional oxime silanes, trifunctional oxime silanes, including those containing a single methyl or vinyl group, or difunctional oxime silane containing two methyl groups did not affect the testes, indicating that both a methyl and vinyl group needs to be present on the oxime silane molecule for testicular toxicity. The testicular toxicity appears to be associated with the methyl/vinyl silane portion and not the oxime portion of the oxime silane molecule. With the exception of the methyl/vinyl difunctional oxime silanes, the silane portion of oxime silanes does not appear to contribute any significant toxicity to these compounds.

  15. Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers.

    Science.gov (United States)

    Skerjanec, Andrej; Wang, Jixian; Maren, Kelly; Rojkjaer, Lisa

    2010-02-01

    Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, C(max)), suggesting a modest induction of CYP3A4/5 by deferasirox. Def erasirox caused increases in repaglinide plasma C(max) and AUC of 1.5-fold to over 2-fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.

  16. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Ana M. C. Faria

    2006-01-01

    Full Text Available Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10 and Th3 (TGF-β regulatory T cells (Tregs plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB, Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE, uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral, formulation, mucosal adjuvants, combination therapy and early therapy.

  17. Oral pathology in inflammatory bowel disease

    Science.gov (United States)

    Muhvić-Urek, Miranda; Tomac-Stojmenović, Marija; Mijandrušić-Sinčić, Brankica

    2016-01-01

    The incidence of inflammatory bowel diseases (IBD) - Crohn’s disease (CD) and ulcerative colitis (UC) - has been increasing on a global scale, and progressively, more gastroenterologists will be included in the diagnosis and treatment of IBD. Although IBD primarily affects the intestinal tract, extraintestinal manifestations of the disease are often apparent, including in the oral cavity, especially in CD. Specific oral manifestations in patients with CD are as follows: indurate mucosal tags, cobblestoning and mucogingivitis, deep linear ulcerations and lip swelling with vertical fissures. The most common non-specific manifestations, such as aphthous stomatitis and angular cheilitis, occur in both diseases, while pyostomatitis vegetans is more pronounced in patients with UC. Non-specific lesions in the oral cavity can also be the result of malnutrition and drugs. Malnutrition, followed by anemia and mineral and vitamin deficiency, affects the oral cavity and teeth. Furthermore, all of the drug classes that are applied to the treatment of inflammatory bowel diseases can lead to alterations in the oral cavity due to the direct toxic effects of the drugs on oral tissues, as well as indirect immunosuppressive effects with a risk of developing opportunistic infections or bone marrow suppression. There is a higher occurrence of malignant diseases in patients with IBD, which is related to the disease itself and to the IBD-related therapy with a possible oral pathology. Treatment of oral lesions includes treatment of the alterations in the oral cavity according to the etiology together with treatment of the primary intestinal disease, which requires adequate knowledge and a strong cooperation between gastroenterologists and specialists in oral medicine. PMID:27433081

  18. Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone.

    Science.gov (United States)

    Xiao, Yingying; Zhu, Yewei; Yu, Suhong; Yan, Cuicui; Ho, Rodney J Y; Liu, Jian; Li, Tao; Wang, Jie; Wan, Liyuan; Yang, Xingtian; Xu, Huo; Wang, Jichuang; Tu, Xiaohuang; Jia, Lee

    2016-01-01

    Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs. The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses. Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight. The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.

  19. A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development.

    Science.gov (United States)

    Robinson, Sally; Delongeas, Jean-Luc; Donald, Elizabeth; Dreher, David; Festag, Matthias; Kervyn, Sophie; Lampo, Ann; Nahas, Kamil; Nogues, Vicente; Ockert, Deborah; Quinn, Kirsty; Old, Sally; Pickersgill, Nigel; Somers, Kev; Stark, Claudia; Stei, Peter; Waterson, Lynne; Chapman, Kathryn

    2008-04-01

    Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose. A European initiative including 18 companies has undertaken an evidence-based review of acute toxicity studies and assessed the value of the data generated. Preclinical and clinical information was shared on 74 compounds. The analysis indicated acute toxicity data was not used to (i) terminate drugs from development (ii) support dose selection for repeat dose studies in animals or (iii) to set doses in the first clinical trials in humans. The conclusion of the working group is that acute toxicity studies are not needed prior to first clinical trials in humans. Instead, information can be obtained from other studies, which are performed at more relevant doses for humans and are already an integral part of drug development. The conclusions have been discussed and agreed with representatives of regulatory bodies from the US, Japan and Europe.

  20. Toxicity Studies on "840 Biologic Pesticide"

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    [Objective] "840 Biologic Pesticide" is a very effective biologic pesticide. It consists of Abamectin and celastrus angulatus. Toxicity study was aimed to provide scientific toxicological basis. [Methods] The acute toxicity test,Ames test,micronucleus test and testicle chromosome aberration test were done. [Results] The acute toxicity of single dose of "840 Biologic Pesticide" showed that acute oral LD50 for female and male rats are 4 300 and 4 280 mg/kg,and for female and male mice are 2 330 and 5 110 mg/kg,respectively. The dermal LD50 was >2 000 mg/kg for female and male rats. The mutagenesis studies indicated that Ames test,micronucleus test and testicle chromosome aberration test were negative. [Conclusion] Tested pesticidc belongs to low toticity grade.

  1. Release and toxicity of dental resin composite.

    Science.gov (United States)

    Gupta, Saurabh K; Saxena, Payal; Pant, Vandana A; Pant, Aditya B

    2012-09-01

    Dental resin composite that are tooth-colored materials have been considered as possible substitutes to mercury-containing silver amalgam filling. Despite the fact that dental resin composites have improved their physico-chemical properties, the concern for its intrinsic toxicity remains high. Some components of restorative composite resins are released in the oral environment initially during polymerization reaction and later due to degradation of the material. In vitro and in vivo studies have clearly identified that these components of restorative composite resins are toxic. But there is a large gap between the results published by research laboratories and clinical reports. The objective of this manuscript was to review the literature on release phenomenon as well as in vitro and in vivo toxicity of dental resin composite. Interpretation made from the recent data was also outlined.

  2. The effect of induced liver, kidney and lung lesions on the toxicity of levamisole and diazinon in calves.

    Science.gov (United States)

    Abdelsalam, E B; Ford, E J

    1987-11-01

    Liver damage in calves, produced by the oral administration of the flukecide, carbon tetrachloride, increased the toxic effect of diazinon but not of levamisole, whereas the presence of a renal tubular lesion caused by mercuric chloride enhanced the toxicity of both commonly used anthelmintic compounds. The toxicity of diazinon was increased in calves with a lung lesion caused by oral dosing with tryptophan, an agent implicated in 'fog fever' of cattle.

  3. Consensus report on the future of animal-free systemic toxicity testing.

    Science.gov (United States)

    Leist, Marcel; Hasiwa, Nina; Rovida, Costanza; Daneshian, Mardas; Basketter, David; Kimber, Ian; Clewell, Harvey; Gocht, Tilman; Goldberg, Alan; Busquet, Francois; Rossi, Anna-Maria; Schwarz, Michael; Stephens, Martin; Taalman, Rob; Knudsen, Thomas B; McKim, James; Harris, Georgina; Pamies, David; Hartung, Thomas

    2014-01-01

    Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council`s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was then further discussed and refined in two consensus meetings with over 200 stakeholders. The key recommendations include: focusing on improving existing methods rather than favoring de novo design; combining hazard testing with toxicokinetics predictions; developing integrated test strategies; incorporating new high content endpoints to classical assays; evolving test validation procedures; promoting collaboration and data-sharing of different industrial sectors; integrating new disciplines, such as systems biology and high throughput screening; and involving regulators early on in the test development process. A focus on data quality, combined with increased attention to the scientific background of a test method, will be important drivers. Information from each test system should be mapped along adverse outcome pathways. Finally, quantitative information on all factors and key events will be fed into systems biology models that allow a probabilistic risk assessment with flexible

  4. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2013 . S tatement on the safety of ' Cetyl Myristoleate Complex ' as an ingredient in food supplements

    DEFF Research Database (Denmark)

    Tetens, Inge

    Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to update its opinion on the safety of „Cetyl Myristoleate Complex‟ (CMC) as a novel food ingredient in the light of a new repeated dose 90-day oral toxicity study in mice. In its p...

  5. Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

    Science.gov (United States)

    Chen, Joey; Seabrook, Jamie; Fulford, Adrienne; Rajakumar, Irina

    2017-03-01

    Background Up to 70% of patients receiving hematopoietic stem cell transplant develop oral mucositis as a side effect of high-dose melphalan conditioning chemotherapy. Oral cryotherapy has been documented to be potentially effective in reducing oral mucositis. The aim of this study was to examine the effectiveness of the cryotherapy protocol implemented within the hematopoietic stem cell transplant program. Methods A retrospective chart review was conducted of adult multiple myeloma patients who received high-dose melphalan conditioning therapy for autologous hematopoietic stem cell transplant. Primary endpoints were incidence and severity of oral mucositis. Secondary endpoints included duration of oral mucositis, duration of hospital stay, parenteral narcotics use and total parenteral nutrition use. Results One hundred and forty patients were included in the study, 70 patients in both no cryotherapy and cryotherapy groups. Both oral mucositis incidence and severity were found to be significantly lower in the cryotherapy group. Fifty (71.4%) experienced mucositis post cryotherapy compared to 67 (95.7%) in the no cryotherapy group (p < 0.001). The median oral mucositis severity, assessed using the WHO oral toxicity scale from grade 0-4, experienced in the no group was 2.5 vs. 2 in the cryotherapy group (p = 0.03). Oral mucositis duration and use of parenteral narcotics were also significantly reduced. Duration of hospital stay and use of parenteral nutrition were similar between the two groups. Conclusion The cryotherapy protocol resulted in a significantly lower incidence and severity of oral mucositis. These results provide evidence for the continued use of oral cryotherapy, an inexpensive and generally well-tolerated practice.

  6. Pharmacokinetics of meloxicam in koalas (Phascolarctos cinereus) after intravenous, subcutaneous and oral administration.

    Science.gov (United States)

    Kimble, B; Black, L A; Li, K M; Valtchev, P; Gilchrist, S; Gillett, A; Higgins, D P; Krockenberger, M B; Govendir, M

    2013-10-01

    The pharmacokinetic profile of meloxicam in clinically healthy koalas (n = 15) was investigated. Single doses of meloxicam were administered intravenously (i.v.) (0.4 mg/kg; n = 5), subcutaneously (s.c.) (0.2 mg/kg; n = 1) or orally (0.2 mg/kg; n = 3), and multiple doses were administered to two groups of koalas via the oral or s.c. routes (n = 3 for both routes) with a loading dose of 0.2 mg/kg for day 1 followed by 0.1 mg/kg s.i.d for a further 3 days. Plasma meloxicam concentrations were quantified by high-performance liquid chromatography. Following i.v. administration, meloxicam exhibited a rapid clearance (CL) of 0.44 ± 0.20 (SD) L/h/kg, a volume of distribution at terminal phase (Vz ) of 0.72 ± 0.22 L/kg and a volume of distribution at steady state (Vss ) of 0.22 ± 0.12 L/kg. Median plasma terminal half-life (t(1/2)) was 1.19 h (range 0.71-1.62 h). Following oral administration either from single or repeated doses, only maximum peak plasma concentration (C(max) 0.013 ± 0.001 and 0.014 ± 0.001 μg/mL, respectively) was measurable [limit of quantitation (LOQ) >0.01 μg/mL] between 4-8 h. Oral bioavailability was negligible in koalas. Plasma protein binding of meloxicam was ~98%. Three meloxicam metabolites were detected in plasma with one identified as the 5-hydroxy methyl derivative. This study demonstrated that koalas exhibited rapid CL and extremely poor oral bioavailability compared with other eutherian species. Accordingly, the currently recommended dose regimen of meloxicam for this species appears inadequate.

  7. Drinking water toxicity study of the environmental contaminant--Bromate.

    Science.gov (United States)

    Dongmei, Liu; Zhiwei, Wang; Qi, Zhu; Fuyi, Cui; Yujuan, Shan; Xiaodong, Liu

    2015-12-01

    Bromate is a byproduct of water disinfection that is produced when waters contain bromide treated with ozone. To investigate the level of the toxicity of bromate and find the most sensitive indicators in a short time, a series of toxicological assessments were conducted including the acute toxicity, cumulative toxicity, genetic toxicity and subacute toxicity of bromate (using Potassium Bromate to represent bromate). The LD50 of orally administered Potassium Bromate was 215 mg/kg in Wistar rats and 464 mg/kg in ICR mice. The cumulative toxicity of Potassium Bromate was not obvious. The Ames test, mouse bone marrow cell micronucleus test and mouse sperm abnormality test did not indicate mutagenicity. The results of the subacute study did not exhibit significant differences in most of the parameters, except the white blood cell count, which was significantly decreased in male rats. In addition, Potassium Bromate influenced the albumin, creatinine, total cholesterol, triglycerides and glucose levels in male rats to various extents. A thorough analysis of the above tests clearly demonstrates that bromate has toxicity, not obvious cumulative toxicity and the white blood cell count can be used as an indicator to reflect the toxicity of bromate and investigate bromate's toxic mechanism.

  8. Oral complications of cancer therapies. Description and incidence of oral complications

    Energy Technology Data Exchange (ETDEWEB)

    Dreizen, S. (Univ. of Texas Dental Branch, Houston (USA))

    1990-01-01

    No part of the body reflects the complications of cancer chemotherapy as visibly and as vividly as the mouth. The infectious, hemorrhagic, cytotoxic, nutritional, and neurologic signs of drug toxicity are reflected in the mouth by changes in the color, character, comfort, and continuity of the mucosa. The stomatologic complications of radiotherapy for oral cancer are physical and physiological in nature, transient or lasting in duration, and reversible or irreversible in type. Some linger as permanent mementos long after the cancer has been destroyed. They stem from radiation injury to the salivary glands, oral mucosa, oral musculature, alveolar bone, and developing teeth. They are expressed clinically by xerostomia, trismus, radiation dermatitis, nutritional stomatitis, and dentofacial malformation. In both cancer chemotherapy and cancer radiotherapy, the oral complications vary in pattern, duration, intensity, and number, with not every patient developing every complication. 21 references.

  9. Subchronic toxicity of rebaudioside A.

    Science.gov (United States)

    Curry, Leslie L; Roberts, Ashley

    2008-07-01

    The safety of the stevia-derived sweetener, rebaudioside A (CAS No. 58543-16-1), was evaluated in two oral toxicity studies. In a 4-week study, Wistar rats were administered rebaudioside A at dietary concentrations of 0, 25,000, 50,000, 75,000 and 100,000ppm. The NOAEL, including an evaluation of testes histopathology, was determined to be 100,000 ppm. In the 13-week study, Wistar rats were administered rebaudioside A at dietary concentrations of 0, 12,500, 25,000 and 50,000ppm. Reductions in body weight gain attributable to initial taste aversion and lower caloric density of the diet were observed in high-dose male and females groups. Inconsistent reductions in serum bile acids and cholesterol were attributed to physiological changes in bile acid metabolism due to excretion of high levels of rebaudioside A via the liver. All other hepatic function test results and liver histopathology were within normal limits. Significant changes in other clinical pathology results, organ weights and functional observational battery test results were not observed. Macroscopic and microscopic examinations of all organs, including testes and kidneys, were unremarkable with respect to treatment-related findings. The NOAEL in the 13-week toxicity study was considered to be 50,000ppm or approximately 4161 and 4645mg/kg body weight/day in male and female rats, respectively.

  10. [Current management of toxic megacolon].

    Science.gov (United States)

    Leifeld, L; Kruis, W

    2012-03-01

    Toxic megacolon is a rare and life-threatening complication of severe colitis, defined as a dilatation of the colon > 6 cm in the absence of distal obstruction in combination with signs of systemic toxicity (major criteria: fever, tachycardia, leukocytosis, anaemia). Various triggers are known and the most common causes are underlying ulcerative colitis and Clostridium difficile. Diagnosis can easily be made by clinical examination, routine laboratory parameters and a plain X-ray of the abdomen. Much more difficult is to decide between non-surgical treatment including intensive care treatment or surgery (mostly subtotal colectomy with terminal ileostomy). Non-surgical therapy includes balancing of electrolytes and fluid volumes, broad-spectrum antibiotics including metronidazole, positioning of patients and probably careful intermittent decompression. In case of ulcerative colitis immunosuppression should be started with corticosteroids and potentially with calcineurin inhibitors. In pseudomembranous colitis vancomycin should be given orally and metronidazole should be given intravenously. As far as possible the patient should be treated in a centre with experience in the field.

  11. Pathogenesis and treatment of oral candidosis

    Directory of Open Access Journals (Sweden)

    David Williams

    2011-01-01

    Full Text Available Oral infections caused by yeast of the genus Candida and particularly Candida albicans (oral candidoses have been recognised throughout recorded history. However, since the 1980s a clear surge of interest and associated research into these infections have occurred. This has largely been due to an increased incidence of oral candidosis over this period, primarily because of the escalation in HIV-infection and the AIDS epidemic. In addition, changes in medical practice leading to a greater use of invasive clinical procedures and a more widespread use of immunosuppressive therapies have also contributed to the problem. Whilst oral candidosis has previously been considered to be a disease mainly of the elderly and very young, its occurrence throughout the general population is now recognised. Candida are true ‘opportunistic pathogens’ and only instigate oral infection when there is an underlying predisposing condition in the host. Treatment of these infections has continued (and in some regards continues to be problematic because of the potential toxicity of traditional antifungal agents against host cells. The problem has been compounded by the emergence of Candida species other than C. albicans that have inherent resistance against traditional antifungals. The aim of this review is to give the reader a contemporary overview of oral candidosis, the organisms involved, and the management strategies that are currently employed or could be utilised in the future.

  12. Pharmacokinetic Alteration of Baclofen by Multiple Oral Administration of Herbal Medicines in Rats

    Directory of Open Access Journals (Sweden)

    Tae Hwan Kim

    2014-01-01

    Full Text Available The potential pharmacokinetic (PK interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY and Achyranthes bidentata radix (AB extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW, OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42–4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (Cmax and longer time to reach Cmax (Tmax were observed in OY pretreated rats without changes in the area under the curve (AUC and the fraction excreted into urine (Furine. The absorption rate (Ka of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

  13. Predicting the future: opportunities and challenges for the chemical industry to apply 21st-century toxicity testing.

    Science.gov (United States)

    Settivari, Raja S; Ball, Nicholas; Murphy, Lynea; Rasoulpour, Reza; Boverhof, Darrell R; Carney, Edward W

    2015-03-01

    Interest in applying 21st-century toxicity testing tools for safety assessment of industrial chemicals is growing. Whereas conventional toxicology uses mainly animal-based, descriptive methods, a paradigm shift is emerging in which computational approaches, systems biology, high-throughput in vitro toxicity assays, and high-throughput exposure assessments are beginning to be applied to mechanism-based risk assessments in a time- and resource-efficient fashion. Here we describe recent advances in predictive safety assessment, with a focus on their strategic application to meet the changing demands of the chemical industry and its stakeholders. The opportunities to apply these new approaches is extensive and include screening of new chemicals, informing the design of safer and more sustainable chemical alternatives, filling information gaps on data-poor chemicals already in commerce, strengthening read-across methodology for categories of chemicals sharing similar modes of action, and optimizing the design of reduced-risk product formulations. Finally, we discuss how these predictive approaches dovetail with in vivo integrated testing strategies within repeated-dose regulatory toxicity studies, which are in line with 3Rs principles to refine, reduce, and replace animal testing. Strategic application of these tools is the foundation for informed and efficient safety assessment testing strategies that can be applied at all stages of the product-development process.

  14. Oral Cancer Exam

    Medline Plus

    Full Text Available ... and Deadlines Grant Application Forms Application Receipt Dates Electronic Submission of Applications Grants 101 (How to Write ... detection and treatment of oral cancers. Note: For materials specific to African American men, please see: Oral ...

  15. Oral Appliances Therapy

    Science.gov (United States)

    ... your sleep doctor may schedule you for a sleep study to verify treatment success. Follow-Up Visits Follow-up visits with your dentist will be needed to ensure the optimal fit of the oral appliance. Effective oral appliances ...

  16. Oral Cancer Exam

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    Full Text Available ... See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities Diabetes Heart Disease HIV/AIDS See ... this brochure includes information on symptoms, diagnosis, and treatment of oral cancer, along with definitions of selected ...

  17. Oral Cancer Exam

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    Full Text Available ... the exam can detect oral cancer early—when it can be treated more successfully. Publications​ For Health ... and the importance of detecting the disease in its early stages. The Oral Cancer Exam Step-by- ...

  18. Oral Cancer Exam

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    Full Text Available ... Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities Diabetes Heart Disease HIV/AIDS See All Order ... Education Practical Oral Care for People With Developmental Disabilities – This booklet presents an overview of physical, mental, ...

  19. Oral Cancer Exam

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    Full Text Available ... signs of oral cancer. For Patients and the Public Oral Cancer Pamphlet that describes the risk factors, ... not collect any actual information. External Web Site Policy This graphic notice ( ) means that you are leaving ...

  20. Oral Cancer Exam

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    Full Text Available ... diagnosis, and treatment of oral cancer, along with definitions of selected medical terms and resource information. Oral ... of Dental and Craniofacial Research National Institutes of Health Bethesda, MD 20892-2190 301-496-4261 NIH… ...

  1. Oral Cancer Exam

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    Full Text Available ... See All Oral Complications of Systemic Diseases Cancer Treatment Developmental Disabilities Diabetes Heart Disease HIV/AIDS See ... this brochure includes information on symptoms, diagnosis, and treatment of oral cancer, along with definitions of selected ...

  2. Oral Cancer Exam

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    Full Text Available ... and College Students Recent College Graduates Dental and Medical Students See All Careers & Training Opportunities Job Openings ... of oral cancer, along with definitions of selected medical terms and resource information. Oral Cancer A fact ...

  3. Oral Cancer Exam

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    Full Text Available ... signs of oral cancer. For Patients and the Public Oral Cancer Pamphlet that ... any actual information. External Web Site Policy This graphic notice ( ) means that you are leaving ...

  4. Oral Cancer Exam

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    Full Text Available ... the exam can detect oral cancer early—when it can be treated more successfully. Publications​ For Health ... and the importance of detecting the disease in its early stages. The Oral Cancer Exam Step-by- ...

  5. Ethyl t-butyl ether: review of reproductive and developmental toxicity.

    Science.gov (United States)

    de Peyster, Ann

    2010-06-01

    Ethyl t-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. Knowledge of developmental and reproductive toxicity potential of ETBE is critical for making informed decisions about acceptance and regulations. This review discusses toxicology studies providing information about effects on reproduction and the conceptus. Seven GLP-compliant studies following widely accepted protocols have focused specifically on developmental and reproductive toxicity (DART) in rats and rabbits exposed to ETBE by gavage with doses up to 1,000 mg/kg body weight/day, the limit specified in standardized test guidelines. Other repeat-dose general toxicology studies have administered ETBE to rodents for up to 180 days, and included reproductive organ weights, histology, or other indications of reproductive system structure or function. DART potential of the main ETBE metabolite t-butyl alcohol and class-related MTBE has also been studied. More GLP-compliant studies exist for evaluating ETBE using well-established, currently recommended protocols than are available for many other chemicals used today. The database for determining ETBE DART potential is adequate, although not all study details are currently easily accessible for peer-review. ETBE does not appear to be selectively toxic to reproduction or embryofetal development in the absence of other manifestations of general toxicity. Studies using recommend