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Sample records for repeated-dose toxicity studies

  1. Biokinetics in repeated-dosing in vitro drug toxicity studies.

    PubMed

    Kramer, Nynke I; Di Consiglio, Emma; Blaauboer, Bas J; Testai, Emanuela

    2015-12-25

    The aim of the EU FP7 Predict-IV project was to improve the predictivity of in vitro assays for unwanted effects of drugs after repeated dosing. The project assessed the added benefit of integrating long-lived in vitro organotypic cell systems with 'omics' technologies and in silico modelling, including systems biology and pharmacokinetic assessments. RPTEC/TERT1 kidney cells, primary rat and human hepatocytes, HepaRG liver cells and 2D and 3D primary brain cultures were dosed daily or every other day for 14 days to a selection of drugs varying in their mechanism of pharmacological action. Since concentration-effect relationships not only depend on the activity of the drug or the sensitivity of the target, but also on the distribution of compounds in the in vitro system, the concentration of a selection of drugs in cells, microtitre plate plastic and medium was measured over time. Results, reviewed in this paper, indicate that lipophilic drugs bind significantly to plastic labware. A few drugs, including less lipophilic drugs, bind to cell-attachment matrices. Chemicals that reach high concentrations in cells, including cyclosporin A and amiodarone, significantly accumulate over time after repeated dosing, partly explaining their increased toxicity after repeated dosing, compared to a single dose. PMID:26362508

  2. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 33 2013-07-01 2013-07-01 false TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) IDENTIFICATION OF SPECIFIC CHEMICAL SUBSTANCE AND MIXTURE TESTING REQUIREMENTS Health...

  3. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 33 2013-07-01 2013-07-01 false TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) IDENTIFICATION OF SPECIFIC CHEMICAL...

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

    PubMed

    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. PMID:25754724

  5. Immunotoxicity of silver nanoparticles in an intravenous 28-day repeated-dose toxicity study in rats

    PubMed Central

    2014-01-01

    Background Nanosilver is used in a variety of medical and consumer products because of its antibacterial activity. This wide application results in an increased human exposure. Knowledge on the systemic toxicity of nanosilver is, however, relatively scarce. In a previous study, the systemic toxicity of 20 nm silver nanoparticles (Ag-NP) was studied in a 28-day repeated-dose toxicity study in rats. Ag-NP were intravenously administered with a maximum dose of 6 mg/kg body weight (bw)/day. Several immune parameters were affected: reduced thymus weight, increased spleen weight and spleen cell number, a strongly reduced NK cell activity, and reduced IFN-γ production were observed. Methods Prompted by these affected immune parameters, we wished to assess exposure effects on the functional immune system. Therefore, in the present study the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) was measured in a similar 28-day intravenous repeated-dose toxicity study. In addition, a range of immunological parameters was measured. Data obtained using the benchmark dose (BMD) approach were analyzed by fitting dose-response models to the parameters measured. Results A reduction in KLH-specific IgG was seen, with a lowest 5% lower confidence bound of the BMD (BMDL) of 0.40 mg/kg bw/day. This suggests that Ag-NP induce suppression of the functional immune system. Other parameters sensitive to Ag-NP exposure were in line with our previous study: a reduced thymus weight with a BMDL of 0.76 mg/kg bw/day, and an increased spleen weight, spleen cell number, and spleen cell subsets, with BMDLs between 0.36 and 1.11 mg/kg bw/day. Because the effects on the spleen are not reflected by increased KLH-specific IgG, they, however, do not suggest immune stimulation. Conclusions Intravenous Ag-NP administration in a 28-day repeated-dose toxicity study induces suppression of the functional immune system. This finding underscores the importance to study the TDAR to

  6. Inclusion of Safety Pharmacology Endpoints in Repeat-Dose Toxicity Studies.

    PubMed

    Redfern, Will S

    2015-01-01

    Whereas pharmacological responses tend to be fairly rapid in onset and are therefore detectable after a single dose, some diminish on repeated dosing, and others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies. Safety pharmacology measurements can be incorporated into repeat-dose toxicity studies, either routinely or on an ad hoc basis. Drivers for this are both scientific (see above) and regulatory (e.g. ICH S6, S7, S9). There are inherent challenges in achieving this: the availability of suitable technical and scientific expertise in the test facility, unsuitable laboratory conditions, use of simultaneous (as opposed to staggered) dosing, requirement for toxicokinetic sampling, unsuitability of certain techniques (e.g. use of anaesthesia, surgical implantation, food restriction), equipment availability at close proximity and sensitivity of the methods to detect small, clinically relevant, changes. Nonetheless, 'fit-for-purpose' data can still be acquired without requiring additional animals. Examples include assessment of behaviour, sensorimotor, visual and autonomic functions, ambulatory ECG and blood pressure, echocardiography, respiratory, gastrointestinal, renal and hepatic function. This is entirely achievable if the safety pharmacology measurements are relatively unobtrusive, both with respect to the animals and to the toxicology study itself. Careful pharmacological validation of any methods used, and establishing their detection sensitivity, is vital to ensure the credibility of generated data. PMID:26091647

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

    PubMed

    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

  8. Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats

    PubMed Central

    Akagi, Jun-ichi; Toyoda, Takeshi; Cho, Young-Man; Mizuta, Yasuko; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2015-01-01

    Transgenic rodents carrying reporter genes to detect organ-specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co-operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. Here, we provide evidence to support equivalence of gpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, N-nitrosodiethylamine (DEN), and a non-genotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP). gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague–Dawley (SD) rats. DEN-treated gpt delta rats showed equivalent increases in the number and area of precancerous GST-P-positive foci in the liver compared to WT rats. The livers of DEN-treated gpt delta rats also showed increased frequencies of gpt and Spi− mutations; such changes were not observed in DEHP-treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) showed comparable DEHP-induced toxicity and DEN-induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by the canonical 4-week administration protocol. Therefore, this assay using gpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals. PMID:25683344

  9. Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats.

    PubMed

    Akagi, Jun-Ichi; Toyoda, Takeshi; Cho, Young-Man; Mizuta, Yasuko; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2015-05-01

    Transgenic rodents carrying reporter genes to detect organ-specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co-operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. Here, we provide evidence to support equivalence of gpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, N-nitrosodiethylamine (DEN), and a non-genotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP). gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague-Dawley (SD) rats. DEN-treated gpt delta rats showed equivalent increases in the number and area of precancerous GST-P-positive foci in the liver compared to WT rats. The livers of DEN-treated gpt delta rats also showed increased frequencies of gpt and Spi(-) mutations; such changes were not observed in DEHP-treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) showed comparable DEHP-induced toxicity and DEN-induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by the canonical 4-week administration protocol. Therefore, this assay using gpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals. PMID:25683344

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

    PubMed Central

    Freire Rocha Caldas, Germana; Araújo, Alice Valença; Albuquerque, Giwellington Silva; Silva-Neto, Jacinto da Costa; Costa-Silva, João Henrique; de Menezes, Irwin Rose Alencar; Leite, Ana Cristina Lima; da Costa, José Galberto Martins; Wanderley, Almir Gonçalves

    2013-01-01

    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. PMID:24151521

  11. Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

    PubMed Central

    2012-01-01

    Background Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. Methods Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. Conclusion Acute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects

  12. Repeated dose 28-day oral toxicity study of moniliformin in rats.

    PubMed

    Jonsson, Martina; Atosuo, Janne; Jestoi, Marika; Nathanail, Alexis V; Kokkonen, Ulla-Maija; Anttila, Marjukka; Koivisto, Pertti; Lilius, Esa-Matti; Peltonen, Kimmo

    2015-02-17

    Moniliformin is a Fusarium mycotoxin mainly produced by several species infecting grains in different climatic conditions. According to our previous studies, it is acutely toxic to rats, with an LD50 cut-off value of 25mg/kg b.w. To further assess the possible health risks of low dose exposure to moniliformin, a subacute oral toxicity study was conducted in Sprague-Dawley rats, adapting OECD guideline 407. Five dose groups and two satellite groups, each consisting of five male rats, were daily exposed to moniliformin by gavage. Two rats in the highest dose group, showed decreased activity followed by acute heart failure and death. The rats of the lower doses (<9mg/kg b.w.) showed no signs of toxicity. The daily intake of moniliformin strongly reduced the phagocytic activity of neutrophils in all dose groups. The decrease continued in the satellite group during the follow-up period, indicating a severe impact on the immune system and a LOAEL value of 3mg/kg b.w. for moniliformin. Moniliformin was rapidly excreted into urine, ranging between 20.2 and 31.5% daily and showed no signs of accumulation. The concentration of moniliformin in faeces was less than 2%, which suggests efficient absorption from the gastrointestinal tract. PMID:25482064

  13. Acute and repeated doses (28 days) oral toxicity study of glycosides based standardized fenugreek seed extract in laboratory mice.

    PubMed

    Kandhare, Amit D; Bodhankar, Subhash L; Mohan, V; Thakurdesai, Prasad A

    2015-07-01

    The objective of the present work was to study acute and subacute (28-days repeated dose) oral toxicity effect of glycosides based standardized fenugreek seed extract (SFSE-G) in vivo. SFSE-G was prepared by resin-based chromatography and standardized to glycosides namely trigoneoside Ib (76%) and vicenin 1 (15%). The acute oral toxicity (AOT) and subacute toxicity studies were performed in Swiss albino mice (5 mice/sex/group) as per OECD 425 (up-and-down procedure) and OCED 407 guidelines respectively. Acute oral administration of 5000mg/kg of SFSE-G showed 40% mortality with no mortality in lower dosages. The subacute oral administration of SFSE-G did not show observational or toxicological effects on the body or organ weights, food consumption, ophthalmic effects, locomotor activity, hematology, blood biochemistry, urinalysis, or histopathology at dose 250mg/kg. However, SFSE-G (1000mg/kg) showed mortality and minor alterations to body weight, relative liver weights, hematology and blood chemistry parameters related to treatment but it was within normal laboratory ranges. In conclusion, SFSE-G showed median lethal dose (LD50) more than 4350mg/kg and no-observed adverse effect levels (NOAEL) of 250mg/kg for both sexes during AOT and sub-acute toxicity study, respectively. PMID:25979642

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

    NASA Astrophysics Data System (ADS)

    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 < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and 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

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

    PubMed

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

    2014-01-01

    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 < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and 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

  16. A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration

    PubMed Central

    Shibui, Yusuke; Miwa, Tadashi; Yamashita, Mayumi; Chin, Keigi; Kodama, Terutaka

    2013-01-01

    In order to examine the toxicity profile of glycine, an authorized food additive, a solution of glycine in water for injection was administered orally (via gavage) to male SD rats (Crl:CD(SD)) once daily for 4 weeks at doses of 500, 1000 and 2000 mg/kg/day in a volume of 10 mL/kg. Control animals received vehicle only. No animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination or histopathological examination. In urinalysis, daily urinary volume and urinary Cl excretion were significantly higher in the 2000 mg/kg/day dose group, and urine pH and urinary protein showed lower trends in the glycine-treated groups. However, these changes were considered to be of little toxicological significance, because there were no histopathological changes in the kidneys or urinary bladder and no changes in other urinary parameters. As regards blood chemistry, phospholipids were significantly higher in the 2000 mg/kg/day dose group. However, the increase was small and was not considered to be toxicologically significant. In conclusion, none of the animals in any of the glycine-treated groups showed changes that were considered toxicologically significant. Therefore, the no-observed-adverse-effect level of glycine was estimated to be at least 2000 mg/kg/day under the conditions of this study. PMID:24526813

  17. A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration.

    PubMed

    Shibui, Yusuke; Miwa, Tadashi; Yamashita, Mayumi; Chin, Keigi; Kodama, Terutaka

    2013-12-01

    In order to examine the toxicity profile of glycine, an authorized food additive, a solution of glycine in water for injection was administered orally (via gavage) to male SD rats (Crl:CD(SD)) once daily for 4 weeks at doses of 500, 1000 and 2000 mg/kg/day in a volume of 10 mL/kg. Control animals received vehicle only. No animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination or histopathological examination. In urinalysis, daily urinary volume and urinary Cl excretion were significantly higher in the 2000 mg/kg/day dose group, and urine pH and urinary protein showed lower trends in the glycine-treated groups. However, these changes were considered to be of little toxicological significance, because there were no histopathological changes in the kidneys or urinary bladder and no changes in other urinary parameters. As regards blood chemistry, phospholipids were significantly higher in the 2000 mg/kg/day dose group. However, the increase was small and was not considered to be toxicologically significant. In conclusion, none of the animals in any of the glycine-treated groups showed changes that were considered toxicologically significant. Therefore, the no-observed-adverse-effect level of glycine was estimated to be at least 2000 mg/kg/day under the conditions of this study. PMID:24526813

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

    PubMed

    Ryu, Hwa Jung; Seo, Mu Yeb; Jung, Sung Kyu; Maeng, Eun Ho; Lee, Seung-Young; Jang, Dong-Hyouk; Lee, Taek-Jin; Jo, Ki-Yeon; Kim, Yu-Ri; Cho, Kyu-Bong; Kim, Meyoung-Kon; Lee, Beom Jun; Son, Sang Wook

    2014-01-01

    Zinc oxide (ZnO) works as a long-lasting, broad-spectrum physical sunblock, and can prevent skin cancer, sunburn, and photoaging. Nanosized ZnO particles are used often in sunscreens due to consumer preference over larger sizes, which appear opaque when dermally applied. Although the US Food and Drug Administration approved the use of nanoparticles (NPs) in sunscreens in 1999, there are ongoing safety concerns. The aim of this study was to evaluate the subchronic toxicity of ZnO NPs after dermal application according to the Organization for Economic Cooperation and Development Test Guidelines 411 using Good Laboratory Practice. Sprague Dawley rats were randomly divided into eight (one control, one vehicle control, three experimental, and three recovery) groups. Different concentrations of ZnO NPs were dermally applied to the rats in the experimental groups for 90 days. Clinical observations as well as weight and food consumption were measured and recorded daily. Hematology and biochemistry parameters were determined. Gross pathologic and histopathologic examinations were performed on selected tissues from all animals. Analyses of tissue were undertaken to determine target organ tissue distribution. There was no increased mortality in the experimental group. Although there 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. PMID:25565832

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

    PubMed Central

    Ryu, Hwa Jung; Seo, Mu Yeb; Jung, Sung Kyu; Maeng, Eun Ho; Lee, Seung-Young; Jang, Dong-Hyouk; Lee, Taek-Jin; Jo, Ki-Yeon; Kim, Yu-Ri; Cho, Kyu-Bong; Kim, Meyoung-Kon; Lee, Beom Jun; Son, Sang Wook

    2014-01-01

    Zinc oxide (ZnO) works as a long-lasting, broad-spectrum physical sunblock, and can prevent skin cancer, sunburn, and photoaging. Nanosized ZnO particles are used often in sunscreens due to consumer preference over larger sizes, which appear opaque when dermally applied. Although the US Food and Drug Administration approved the use of nanoparticles (NPs) in sunscreens in 1999, there are ongoing safety concerns. The aim of this study was to evaluate the subchronic toxicity of ZnO NPs after dermal application according to the Organization for Economic Cooperation and Development Test Guidelines 411 using Good Laboratory Practice. Sprague Dawley rats were randomly divided into eight (one control, one vehicle control, three experimental, and three recovery) groups. Different concentrations of ZnO NPs were dermally applied to the rats in the experimental groups for 90 days. Clinical observations as well as weight and food consumption were measured and recorded daily. Hematology and biochemistry parameters were determined. Gross pathologic and histopathologic examinations were performed on selected tissues from all animals. Analyses of tissue were undertaken to determine target organ tissue distribution. There was no increased mortality in the experimental group. Although there 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. PMID:25565832

  20. 13-week repeated dose toxicity study of l-tyrosine in rats by daily oral administration.

    PubMed

    Shibui, Yusuke; Manabe, Yasuhiro; Kodama, Terutaka; Gonsho, Akinori

    2016-01-01

    To evaluate the potential toxicity of l-tyrosine, 4 groups of Crl:CD(SD) rats of both sexes were administered l-tyrosine in water suspension by gavage once daily for 13 weeks at doses of 0 (vehicle), 200, 600 or 2000 mg/kg bw/day. Findings related to l-tyrosine administration were as follows. Edema of the cornified layer at the limiting ridge or forestomach was seen in 600 mg/kg bw/day female group and in both sexes of 2000 mg/kg bw/day group. In the liver, increased weight and hypertrophy of centrilobular hepatocytes were seen in both sexes at 2000 mg/kg bw/day, associated with slight increases in ALT and AST. Regarding the kidney morphology and function, increased hyaline droplets in the proximal tubules and increased urinary protein were seen in the 2000 mg/kg bw/day male group. In addition, increased kidney weight was also observed in both sexes of the 2000 mg/kg bw/day group, although the histological changes attributable to the weight increase remained unclear. As for blood chemistry, increases in triglycerides, total cholesterol, phospholipids, potassium ion, calcium, total protein, and α1 globulin were also seen in both sexes at 2000 mg/kg bw/day. Thus, in this study the no-observed-adverse-effect level (NOAEL) of l-tyrosine was considered to be 600 mg/kg bw/day for males and 200 mg/kg bw/day for females. PMID:26646752

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

    PubMed

    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 <1% of harmful compounds were misclassified as non-toxic. Since repeated dose toxicity studies can be performed in vivo until 2013, the proposed approach could have an immediate impact for the testing of cosmetic ingredients. PMID:18977273

  2. ACUTE, 14-DAY REPEATED DOSING, AND 90-DAY SUBCHRONIC TOXICITY STUDIES OF POTASSIUM PICLORAM (JOURNAL VERSION)

    EPA Science Inventory

    Potassium picloram was administered either by gavage (acute studies) or in drinking water to male and female Sprague-Dawley derived rats (14-day and 90-day studies). The acute oral LD50 was 950 mg/kg (812-1120) for males and 686 mg/kg (599-786) for females. Depression, prostratio...

  3. Collaborative work on evaluation of ovarian toxicity. 6) Two- or four-week repeated-dose studies and fertility study of cisplatin in female rats.

    PubMed

    Nozaki, Yusuke; Furubo, Eiko; Matsuno, Takayuki; Fukui, Rie; Kizawa, Kazuo; Kozaki, Tsukasa; Sanzen, Takahiro

    2009-01-01

    The main aim of the present study is to determine the optimal administration period of cisplatin with regards to its toxic effects on ovarian morphology in the repeated-dose toxicity study. Cisplatin was administered to female SD rats intraperitoneally once daily at dose levels of 0.25, 0.5, 1.0 and 2.0 mg/kg for 2 weeks, or at dose levels of 0.125, 0.25 and 0.5 mg/kg for 4 weeks in the repeated-dose toxicity study. In the female fertility study, 0.25, 0.5 and 1.0 mg/kg of cisplatin were administered in the same manner from 14 days prior to mating to Day 7 of gestation. In the repeated-dose toxicity study, a decrease in large follicle, an increase in atresia of medium and large follicles, and/or a decrease in currently formed corpus luteum were observed in animals receiving 1.0 and 2.0 mg/kg for 2 weeks, and decreases in small and/or large follicles and an increase in atresia of large follicle were observed in animals receiving 0.25 and 0.5 mg/kg for 4 weeks on the histopathological examination of the ovaries. In the female fertility study, the copulation and fertility indices in the animals receiving 1.0 mg/kg tended to be lower than those in the control animals. In conclusion, histopathological changes in the ovary that were attributable to cisplatin dosing were detected by detailed observation of the ovary in the 2-week study; and therefore, a 2-week administration period is sufficient to evaluate the ovarian toxicity of cisplatin. PMID:19265292

  4. A 4-week Repeated dose Oral Toxicity Study of Mecasin in Sprague-Dawley Rats to Determine the Appropriate Doses for a 13-week, Repeated Toxicity Test

    PubMed Central

    Cha, Eunhye; Lee, Jongchul; Lee, Seongjin; Park, Manyong; Song, Inja; Son, Ilhong; Song, Bong-Keun; Kim, Dongwoung; Lee, Jongdeok

    2015-01-01

    Objectives: In this study, we investigated the 4-week repeated-dose oral toxicity of gami-jakyak gamcho buja decoction (Mecasin) to develop safe treatments. Methods: In order to investigate the 4-week oral toxicity of Mecasin, we administered Mecasin orally to rats. Sprague-Dawley (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 Mecasin of 500, 1,000, and 2,000 mg/kg of body weight were administered to the experimental groups, and a dose of normal saline solution of 10 mL/kg was administered to the control group. We examined the survival rate, weight, clinical signs, and gross findings for four weeks. This study was conducted under the approval of the Institutional Animal Ethics Committee. Results: No deaths occurred in any of the four groups. No significant changes in weights or food consumption between the control group and the experimental groups were observed. Serum biochemistry revealed that some groups showed significant decrease in inorganic phosphorus (IP) (P < 0.05). During necropsy on the rats, one abnormal macroscopic feature, a slight loss of fur, was observed in the mid dosage (1,000 mg/ kg) male group. No abnormalities were observed in any other rats. In histopathological findings, the tubular basophilia and cast of the kidney and extramedullary hematopoiesis of the spleen were found. However, those changes were minimal and had occurred naturally or sporadically. No other organ abnormalities were observed. Conclusion: During this 4-week, repeated, oral toxicity test of Mecasin in SD rats, no toxicity changes due to Mecasin were observed in any of the male or the female rats in the high dosage group. Thus, we suggest that the doses in a 13-week, repeated test should be 0, 500, 1,000, and 2,000 mg/kg respectively. PMID:26998389

  5. 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.

    PubMed

    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. PMID:25892620

  6. Screening study for repeated dose and reproductive/developmental toxicity of rubber accelerator, N,N-dicyclohexyl-2-benzothiazolesulfenamide, in rats.

    PubMed

    Ema, Makoto; Ito, Yoshihiko; Matsumoto, Mariko; Hirose, Akihiko; Kamata, Eiichi

    2007-01-01

    A screening study for a vulcanization accelerator N,N-dicyclohexyl-2-benzothiazole-sulfenamide (DCBS) was performed in rats. Rats were given DCBS by gavage daily at 0, 6, 25, 100, or 400 mg/kg. Males were dosed for a total of 44 days beginning 14 days before mating. Females were dosed for a total of 40-51 days beginning 14 days before mating to day 3 of lactation. Toxicologic changes were significantly noted only at 400 mg/kg. Three females died. An increased incidence of females showing decreased locomotor activity, soil of the lower abdominal fur, and reddish tears was observed. A lowered body weight was found in males and females. Increased urinary ketones and serum inorganic phosphorus and decreased serum glutamate pyruvate transaminase in males were found. Increased absolute and relative weights of the kidneys in males and decreased absolute weight of the thymus in both sexes were noted. Significant fatty degeneration of the renal tubular epithelia, vacuolation of the adrenocortical cells, and atrophy of the spleen were observed in females. Significant decreases in the gestation index, numbers of corpura lutea, implantations, pups born and pups born alive, live birth index, and viability index were detected. It is concluded that the No Observed Adverse Effect Levels (NOAELs) for repeat dose and reproductive/developmental toxicity are 100 mg kg-1 day-1 in this screening study. PMID:17613004

  7. Proposal of an in silico profiler for categorisation of repeat dose toxicity data of hair dyes.

    PubMed

    Nelms, M D; Ates, G; Madden, J C; Vinken, M; Cronin, M T D; Rogiers, V; Enoch, S J

    2015-05-01

    This study outlines the analysis of 94 chemicals with repeat dose toxicity data taken from Scientific Committee on Consumer Safety opinions for commonly used hair dyes in the European Union. Structural similarity was applied to group these chemicals into categories. Subsequent mechanistic analysis suggested that toxicity to mitochondria is potentially a key driver of repeat dose toxicity for chemicals within each of the categories. The mechanistic hypothesis allowed for an in silico profiler consisting of four mechanism-based structural alerts to be proposed. These structural alerts related to a number of important chemical classes such as quinones, anthraquinones, substituted nitrobenzenes and aromatic azos. This in silico profiler is intended for grouping chemicals into mechanism-based categories within the adverse outcome pathway paradigm. PMID:24888375

  8. Repeated dose and reproductive/developmental toxicity of perfluorododecanoic acid in rats.

    PubMed

    Kato, Hina; Fujii, Sakiko; Takahashi, Mika; Matsumoto, Mariko; Hirata-Koizumi, Mutsuko; Ono, Atsushi; Hirose, Akihiko

    2015-11-01

    Perfluoroalkyl carboxylic acids (PFCAs) are a series of environmental contaminants that have received attention because of their possible adverse effects on wildlife and human health. Although many toxicological studies have been performed on perfluorooctanoic acid with carbon chain length C8, available toxicity data on PFCAs with longer chains are still insufficient to evaluate their hazard. A combined repeated dose and reproductive/developmental toxicity screening study for perfluorododecanoic acid (PFDoA; C12) was conducted in accordance with OECD guideline 422 to fill these toxicity data gaps. PFDoA was administered by gavage to male and female rats at 0.1, 0.5, or 2.5 mg/kg/day. The administration of PFDoA at 0.5 and 2.5 mg/kg/day for 42-47 days mainly affected the liver, in which hypertrophy, necrosis, and inflammatory cholestasis were noted. Body weight gain was markedly inhibited in the 2.5 mg/kg/day group, and a decrease in hematopoiesis in the bone marrow and atrophic changes in the spleen, thymus, and adrenal gland were also observed. Regarding reproductive/developmental toxicity, various histopathological changes, including decreased spermatid and spermatozoa counts, were observed in the male reproductive organs, while continuous diestrous was observed in the females of the 2.5 mg/kg/day group. Seven of twelve females receiving 2.5 mg/kg/day died during late pregnancy while four other females in this group did not deliver live pups. No reproductive or developmental parameters changed at 0.1 or 0.5 mg/kg/day. Based on these results, the NOAELs of PFDoA were concluded to be 0.1 mg/kg/day for repeated dose toxicity and 0.5 mg/kg/day for reproductive/developmental toxicity. PMID:24753098

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

    PubMed

    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. PMID:22422434

  10. Collaborative work on evaluation of ovarian toxicity. 4) Two- or four-week repeated dose study of 4-vinylcyclohexene diepoxide in female rats.

    PubMed

    Ito, Atsushi; Mafune, Naomi; Kimura, Takashi

    2009-01-01

    To determine the optimal administration period for evaluation of ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD), VCD was intraperitoneally administered to female Sprague-Dawley rats at 0 (Control), 5, 20 and 80 mg/kg once a day for 2 or 4 weeks (2- or 4-week study). To identify small follicles, serial sections of the ovaries were stained with routine hematoxylin and eosin (HE) and proliferating cell nuclear antigen (PCNA) immunohistochemistry. In the 4-week study, decrease in small follicles was observed in the ovaries at 20 and 80 mg/kg. In the 2-week study, the same change was also observed at 80 mg/kg. Identification of small follicles using PCNA-stained slides was easier than that using HE-stained slides. In conclusion, histopathological findings in the ovaries are important for evaluation of female reproductive toxicity of VCD, and ovarian toxicity of VCD can be detected by administration for 2 weeks at an appropriate dose level. Furthermore, PCNA immunohistochemistry is effective for evaluation of small follicle destruction in chemical-induced ovarian toxicity. PMID:19265289

  11. Repeated dose toxicity of alfa-cypermethrin in rats.

    PubMed

    Manna, S; Bhattacharyya, D; Mandal, T K; Das, S

    2004-09-01

    The present study was performed to investigate the subacute effect of alpha-cypermethrin (alpha-CP) in rats. Alfacypermethrin a synthetic pyrethroid insecticide, dissolved in dimethyl sulfoxide (DMSO) and oral LD50 was investigated after administering orally different doses in rats and was determined as 145 mg/kg. Other groups of rats were given repeated daily oral dose (1/10 LD50) of alpha-CP for 30 days. The animals were sacrificed on 31st day. Activities of various enzymes, cytochrome P450 and b5 contents in liver, hepatic antioxidant status, tissue residue concentration, haemogram and pathological changes were studied. It increased the serum aminotransaminases (AST, ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) activities and blood glucose level significantly. alpha-CP decreased RBC count, PCV and Hb level significantly. It significantly decreased cytochrome P450 in liver. Residues were present in different tissues. It increased malondialdehyde (MDA) level, while decreased the activities of catalase (CAT), superoxide dismutase (SOD) and glycogen level in liver significantly. Mild to moderate histological alterations were observed in lungs, liver, stomach, kidneys, testes and cerebellum. So repeated daily oral doses of alpha-CP at 1/10LD50 altered the biochemical parameters, decreased cytochrome P450 content, antioxidant status, which correlated with histopathological changes of tissues. PMID:15365239

  12. Single- and repeated-dose toxicities of aloe fermentation products in rats

    PubMed Central

    Kim, Hyun-Kyoung; Baik, Soon-Ok; Choi, Soo-Young; Lee, Jae-Young

    2011-01-01

    In this study, aloe fermentation products were derived from mycelia from 3 mushrooms: Ganoderma lucidum (AG), Hericium erinaceum (AH), and Phellinus linteus (AP). Levels of aloin A and B increased with fermentation time. The highest levels were measured on the fifth day of fermentation. β-Glucan levels decreased with fermentation time. The safety of aloe fermentation products were examined in male and female Sprague-Dawley rats. Rats were orally administered the three aloe fermentation products at dose levels of 1, 2 or 5 g/kg for single-dose toxicity test and 0.5, 1, or 2 g/kg for repeated-dose toxicity test. There were no significant differences in body weight gain between vehicle control and AG-, AH- or AP-treated rats. Also, significant changes in daily feed intake and water consumption were not observed. In hematological analysis, none of the parameters were affected by aloe fermentation products with mushroom mycelia. This suggests that there are no negative effects on homeostasis and immunity. In blood biochemistry analysis, none of the markers were affected by feeding rats with AG, AH or AP. Similarly, there were no significant effects on markers for liver, kidney, skeletal and heart muscle functions. No remarkable lesions were observed in these organs at histopathology. Since there were no adverse effects of AG, AH and AP in single- or repeated-dose toxicity tests, even at higher doses than normal, we conclude that the aloe fermentation products with mushroom mycelia possess long-term safety and could be candidates as multifunctional nutrients for the improvement of intestinal function and immunity. PMID:21998613

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

    PubMed

    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. PMID:23439429

  14. Toxicity from repeated doses of acetaminophen in children: Assessment of causality and dose in reported cases

    PubMed Central

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

    2012-01-01

    Background Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study is to identify and validate reports of liver injury or death in children younger than 6 years of age following repeated therapeutic doses of acetaminophen. Methods We reviewed United States (US) Poison Center data, peer-reviewed literature, US FDA Adverse event reports and US Manufacturer safety reports describing adverse effects following acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death following administration to children younger than 6 years of age 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 supra-therapeutic. Results 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. Conclusions While we identified numerous examples of liver injury and death following repeated doses of acetaminophen, all of the deaths and all but 6 cases of hepatic abnormalities involved doses greater than 75 mg/kg/day. This study suggests that the doses of less than 75 mg/kg/day of acetaminophen are safe for children younger than 6 years of age. PMID:22407198

  15. 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.

    PubMed

    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. PMID:24179028

  16. Integration of Mutation and Chromosomal Damage Endpoints into 28-Day Repeat Dose Toxicology Studies

    PubMed Central

    Dertinger, Stephen D.; Phonethepswath, Souk; Franklin, Dean; Weller, Pamela; Torous, Dorothea K.; Bryce, Steven M.; Avlasevich, Svetlana; Bemis, Jeffrey C.; Hyrien, Ollivier; Palis, James; MacGregor, James T.

    2010-01-01

    Two endpoints of genetic toxicity, mutation at the X-linked Pig-a gene and chromosomal damage in the form of micronucleated reticulocytes (MN-RETs), were evaluated in blood samples obtained from 28-day repeat-dosing studies typical of those employed in toxicity evaluations. Male Wistar Han rats were treated at 24-h intervals on days 1 through 28 with one of five prototypical genotoxicants: N-ethyl-N-nitrosourea, 7,12-dimethyl-12-benz[a]anthracene, 4-nitroquinoline-1-oxide (4NQO), benzo(a)pyrene, and N-methyl-N-nitrosourea. Flow cytometric scoring of CD59-negative erythrocytes (indicative of glycosylphosphatidylinositol anchor deficiency and hence Pig-a mutation) was performed using blood specimens obtained on days −1, 15, 29, and 56. Blood specimens collected on days 4 and 29 were evaluated for MN-RET frequency using flow cytometry–based MicroFlow Kits. With the exception of 4NQO, each chemical induced significant increases in the frequency of MN-RETs on days 4 and 29. All five agents increased the frequency of mutant phenotype (CD59 negative) reticulocytes (RETs) and erythrocytes. Mutation responses in RETs occurred earlier than in erythrocytes and tended to peak, or nearly peak, at day 29. In contrast, the mutant phenotype erythrocyte responses were modest on day 29 and required additional time to reach their maximal value. The observed kinetics were expected based on the known turnover of RETs and erythrocytes. The data show that RETs can serve as an appropriate indicator cell population for 28-day studies. Collectively, these data suggest that blood-based genotoxicity endpoints can be effectively incorporated into routine toxicology studies, a strategy that would reduce animal usage while providing valuable genetic toxicity information within the context of other toxicological endpoints. PMID:20202993

  17. Acute and repeated dose (28 days) oral safety studies of ALIBIRD in rats.

    PubMed

    Anadón, Arturo; Martínez, María A; Ares, Irma; Castellano, Victor; Martínez-Larrañaga, Maria R; Corzo, Nieves; Olano, Agustin; Montilla, Antonia; Recio, Isidra; Martínez-Maqueda, Daniel; Miralles, Beatriz; Fornari, Tiziana; García-Risco, Mónica R; Gonzalez, Monserrat; Reglero, Guillermo

    2013-07-01

    ALIBIRD, a test substance composed of oligosaccharides derived from lactulose, a hydrolysate of a whey protein concentrate, and a supercritical extract of rosemary (1:0.5:0.05), was prepared in the laboratory and evaluated for its safety as a multifunctional food additive. In oral toxicity studies (acute and 28 days repeated dose) using Wistar rats, ALIBIRD was administered in a single oral gavage dose of 2,000 mg/kg of body weight and resulted in no adverse events or mortality; a daily dose of 2,000 mg/kg of body weight for 28 days by gavage also resulted in no adverse effects or mortality. No abnormal clinical signs, behavioral changes, body weight changes, or changes in food and water consumption occurred in either study. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. Based on test results, it is concluded that ALIBIRD is well tolerated in rats at an acute and subchronic (28 days) dose of 2,000 mg/kg of body weight. PMID:23834798

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

    PubMed

    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. PMID:24351872

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

    PubMed

    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. PMID:24179027

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

    PubMed

    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. PMID:27481023

  1. Combined repeated dose and reproductive/developmental toxicity screening test of 4-methoxy-2-nitroaniline in rats.

    PubMed

    Tsubokura, Yasuhiro; Aso, Sunao; Koga, Takayuki; Kikuchi, Junichi; Kobayashi, Toshio; Hoshuyama, Satsuki; Oshima, Yutaka; Miyata, Katsumi; Kusune, Yuji; Muroi, Takako; Yoshida, Tomohiko; Hasegawa, Ryuichi; Ajimi, Shozo; Furukawa, Kotaro

    2015-10-01

    4-Methoxy-2-nitroaniline (4M2NA) is widely used as an intermediate for the synthesis of dyes, pigments and other chemical compounds. Since 4M2NA has amino-group and nitro-group on the benzene ring, it was expected that it induced obvious hemolytic anemia. We conducted a combined repeated dose and reproductive/developmental toxicity screening test according to Organisation for Economic Co-operation and Development (OECD) Test Guideline No. 422 (OECD TG 422) to enrich the toxic information and ensure the safety of 4M2NA. 4M2NA was administered to Crl:CD(SD) male and female rats by gavage at 0, 12.5, 75 or 450 mg/kg/day for 42 to maximum of 54 days through pre-mating, mating, pregnancy and lactation periods. An extramedullary hematopoiesis and congestion in spleen, and higher reticulocyte ratio were noted in only females at 450 mg/kg/day without decreased anemic parameters in the hematological examination. Hypertrophy of centrilobular hepatocytes in both sexes was observed with increased relative liver weight at 450 mg/kg/day. Furthermore, the diffuse follicular cell hypertrophy of the thyroid was observed in females at 450 mg/kg/day. No abnormalities were detected in the reproductive indices of copulation, delivery or fetal viability. We concluded the no-observed-adverse-effect level (NOAEL) for repeated-dose toxicity was 75 mg/kg/day based on the trace evidences of hemolytic anemia, and the NOAEL for reproductive/developmental toxicity as 450 mg/kg/day based on no toxicological concerns for reproductive endpoints. The hemolytic anemia was much milder than expected. Thus, we discussed the reason of this much less hemolytic effect from the point of view of the structural characteristics of 4M2NA. PMID:25367778

  2. The added value of the 90-day repeated dose oral toxicity test for industrial chemicals with a low (sub)acute toxicity profile in a high quality dataset.

    PubMed

    Taylor, Katy; Andrew, David J; Rego, Laura

    2014-08-01

    A survey conducted on the EU Notification of New Substances (NONS) database suggested that for industrial chemicals with a profile of low toxicity in (sub)acute toxicity tests there is little added value to the conduct of the 90-day repeated dose study. Avoiding unnecessary animal testing is a central aim of the EU REACH chemicals legislation; therefore we sought to verify the profile using additional data. The OECD's eChemPortal was searched for substances that had both a 28-day and a 90-day study and their robust study summaries were then examined from the ECHA CHEM database. Out of 182 substances with high quality 28-day and 90-day study results, only 18 reported no toxicity of any kind in the (sub)acute tests. However, for 16 of these there were also no reported signs of toxicity at or close to the limit dose (1000mg/kgbw/d) in the 90-day study. Restricting the 'low (sub)acute toxicity in a high quality dataset' profile to general industrial chemicals of no known biological activity, whilst allowing irritant substances, increases the data set and improves the prediction to 95% (20 substances out of 21 substances). The low toxicity profile appears to be of low prevalence within industrial chemicals (10-15%), nevertheless, avoidance of the conduct of a redundant 90-day study for this proportion of the remaining REACH phase-in substances would avoid the use of nearly 50,000 animals and save industry 50million Euros, with no impact on the assessment of human health. PMID:24768988

  3. The repeated dose toxicity of a zinc oxide/hexachloroethane smoke.

    PubMed

    Marrs, T C; Colgrave, H F; Edginton, J A; Brown, R F; Cross, N L

    1988-01-01

    Mice, rats and guinea pigs were exposed to the smoke produced by ignition of a zinc oxide/hexachloroethane pyrotechnic composition, 1 h/day, 5 days/week, at three different dose levels, together with controls. The animals received 100 exposures except for the high dose guinea pigs, which underwent 15 exposures, because of high death rate during the first few days of exposure. The test material had very little effect on weight gain, but there was a high rate of early deaths in the top dose of mice. A variety of incidental findings was seen in both decedents and survivors, but organ specific toxicity was, with one exception, confined to the respiratory tract. The most important of these findings was a statistically significant increase in the frequency of alveologenic carcinoma in the high dose group mice (p less than 0.01) and a statistically significant trend in the prevalence of the same tumour over all dose groups and the controls. A variety of inflammatory changes was seen in the lungs of all species and some appeared to be treatment-related. Fatty change in the mouse liver was more common in the middle and high dose groups than the controls. The aetiology of the tumour incidence is discussed and it is pointed out that hexachloroethane and zinc, as well as carbon tetrachloride, which may be present in the smoke, may be animal carcinogens in appropriate circumstances. Carbon tetrachloride is a known human carcinogen. PMID:3196147

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

    PubMed

    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). PMID:25786522

  5. The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse

    PubMed Central

    Molyneux, Gemma; Gibson, Frances M; Gordon-Smith, Edward C; Pilling, Andrew M; Liu, Kai Chiu; Rizzo, Sian; Sulsh, Susan; Turton, John A

    2005-01-01

    Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose-related, bone marrow depression in man and laboratory animals; this change is generally reversible. However, there is evidence that MMC may also cause a late-stage or residual bone marrow injury. The present study in female CD-1 mice investigated the haematological and bone marrow changes induced by MMC in a repeat dose study lasting 50 days. Control and MMC-treated mice were dosed intraperitoneally on eight occasions over 18 days with vehicle, or MMC at 2.5 mg/kg, autopsied (n = 6–12) at 1, 7, 14, 28, 42 and 50 days after the final dose and haematological changes investigated. Femoral nucleated bone marrow cell counts and levels of apoptosis were also evaluated and clonogenic assays carried out; serum levels of FLT3 ligand (FL) were assessed. At day 1 post-dosing, MMC induced significant reductions in RBC, Hb and haematocrit (HCT) values, and there were decreases in reticulocyte, platelet, and femoral nucleated cell counts (FNCC); neutrophil, lymphocyte and monocyte values were also significantly reduced. On days 7 and 14 post-dosing, all haematological parameters showed evidence of a return towards normal values, but at these times, and at day 28, values for RBC and FNCC remained significantly reduced in comparison with controls. At days 42 and 50 post-dosing, many haematological parameters in MMC-treated mice had returned to control levels; however, there remained evidence of late-stage effects on RBC, Hb and HCT values, and FNCC also continued to be significantly decreased. Results for granulocyte-macrophage colony-forming units and erythroid colonies showed a profound decrease immediately post-dosing, but a return to normal values was evident at day 50. Serum FL concentrations demonstrated very significant increases in the immediate post-dosing period, but a return to normal was seen at day 50 post-dosing; a relatively similar pattern was seen in the number of apoptotic femoral

  6. 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.

    PubMed

    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. PMID:24574060

  7. Evaluation of repeated dose micronucleus assays of the liver and gastrointestinal tract using potassium bromate: a report of the collaborative study by CSGMT/JEMS.MMS.

    PubMed

    Okada, Emiko; Fujiishi, Yohei; Narumi, Kazunori; Kado, Shoichi; Wako, Yumi; Kawasako, Kazufumi; Kaneko, Kimiyuki; Ohyama, Wakako

    2015-03-01

    The food additive potassium bromate (KBrO3) is known as a renal carcinogen and causes chromosomal aberrations in vitro without metabolic activation and in vivo in hematopoietic and renal cells. As a part of a collaborative study by the Mammalian Mutagenicity Study group, which is a subgroup of the Japanese Environmental Mutagen Society, we administered KBrO3 to rats orally for 4, 14, and 28 days and examined the micronucleated (MNed) cell frequency in the liver, glandular stomach, colon, and bone marrow to confirm whether the genotoxic carcinogen targeting other than liver and gastrointestinal (GI) tract was detected by the repeated dose liver and GI tract micronucleus (MN) assays. In our study, animals treated with KBrO3 showed some signs of toxicity in the kidney and/or stomach. KBrO3 did not increase the frequency of MNed cells in the liver and colon in any of the repeated dose studies. However, KBrO3 increased the frequency of MNed cells in the glandular stomach and bone marrow. Additionally, the MNed cell frequency in the glandular stomach was not significantly affected by the difference in the length of the administration period. These results suggest that performing the MN assay using the glandular stomach, which is the first tissue to contact agents after oral ingestion, is useful for evaluating the genotoxic potential of chemicals and that the glandular stomach MN assay could be integrated into general toxicity studies. PMID:24637080

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

    PubMed Central

    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

    2008-01-01

    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. PMID:18336531

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

    PubMed

    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. PMID:27153797

  10. Repeated dose titration versus age-based method in electroconvulsive therapy: a pilot study.

    PubMed

    Aten, Jan Jaap; Oudega, Mardien; van Exel, Eric; Stek, Max L; van Waarde, Jeroen A

    2015-06-01

    In electroconvulsive therapy (ECT), a dose titration method (DTM) was suggested to be more individualized and therefore more accurate than formula-based dosing methods. A repeated DTM (every sixth session and dose adjustment accordingly) was compared to an age-based method (ABM) regarding treatment characteristics, clinical outcome, and cognitive functioning after ECT. Thirty-nine unipolar depressed patients dosed using repeated DTM and 40 matched patients treated with ABM were compared. Montgomery-Åsberg Depression Rating Scale (MADRS) and Mini-Mental State Examination (MMSE) were assessed at baseline and at the end of the index course, as well as the total number of ECT sessions. Both groups were similar regarding age, sex, psychotic features, mean baseline MADRS, and median baseline MMSE. At the end of the index course, the two methods showed equal outcome (mean end MADRS, 11.6 ± 8.3 in DTM and 9.5 ± 7.6 in ABM (P = 0.26); median end MMSE, 28 (25-29) and 28 (25-29.8), respectively (P = 0.81). However, the median number of all ECT sessions differed 16 (11-22) in DTM versus 12 (10-14.8) in ABM; P = 0.02]. Using regression analysis, dosing method and age were independently associated with the total number of ECT sessions, with less sessions needed in ABM (P = 0.02) and in older patients (P = 0.001). In this comparative cohort study, ABM and DTM showed equal outcome for depression and cognition. However, the median ECT course duration in repeated DTM appeared longer. Additionally, higher age was associated with shorter ECT courses regardless of the dosing method. Further prospective studies are needed to confirm these findings. PMID:25804765

  11. Collaborative study on fifteen compounds in the rat-liver Comet assay integrated into 2- and 4-week repeat-dose studies.

    PubMed

    Rothfuss, Andreas; O'Donovan, Mike; De Boeck, Marlies; Brault, Dominique; Czich, Andreas; Custer, Laura; Hamada, Shuichi; Plappert-Helbig, Ulla; Hayashi, Makoto; Howe, Jonathan; Kraynak, Andrew R; van der Leede, Bas-jan; Nakajima, Madoka; Priestley, Catherine; Thybaud, Veronique; Saigo, Kazuhiko; Sawant, Satin; Shi, Jing; Storer, Richard; Struwe, Melanie; Vock, Esther; Galloway, Sheila

    2010-09-30

    A collaborative trial was conducted to evaluate the possibility of integrating the rat-liver Comet assay into repeat-dose toxicity studies. Fourteen laboratories from Europe, Japan and the USA tested fifteen chemicals. Two chemicals had been previously shown to induce micronuclei in an acute protocol, but were found negative in a 4-week Micronucleus (MN) Assay (benzo[a]pyrene and 1,2-dimethylhydrazine; Hamada et al., 2001); four genotoxic rat-liver carcinogens that were negative in the MN assay in bone marrow or blood (2,6-dinitrotoluene, dimethylnitrosamine, 1,2-dibromomethane, and 2-amino-3-methylimidazo[4,5-f]quinoline); three compounds used in the ongoing JaCVAM (Japanese Center for the Validation of Alternative Methods) validation study of the acute liver Comet assay (2,4-diaminotoluene, 2,6-diaminotoluene and acrylamide); three pharmaceutical-like compounds (chlordiazepoxide, pyrimethamine and gemifloxacin), and three non-genotoxic rodent liver carcinogens (methapyrilene, clofibrate and phenobarbital). Male rats received oral administrations of the test compounds, daily for two or four weeks. The top dose was meant to be the highest dose producing clinical signs or histopathological effects without causing mortality, i.e. the 28-day maximum tolerated dose. The liver Comet assay was performed according to published recommendations and following the protocol for the ongoing JaCVAM validation trial. Laboratories provided liver Comet assay data obtained at the end of the long-term (2- or 4-week) studies together with an evaluation of liver histology. Most of the test compounds were also investigated in the liver Comet assay after short-term (1-3 daily) administration to compare the sensitivity of the two study designs. MN analyses were conducted in bone marrow or peripheral blood for most of the compounds to determine whether the liver Comet assay could complement the MN assay for the detection of genotoxins after long-term treatment. Most of the liver genotoxins

  12. Lactate is an ideal non-invasive marker for evaluating temporal alterations in cell stress and toxicity in repeat dose testing regimes.

    PubMed

    Limonciel, Alice; Aschauer, Lydia; Wilmes, Anja; Prajczer, Sinikka; Leonard, Martin O; Pfaller, Walter; Jennings, Paul

    2011-12-01

    Technological developments are driving in vitro methods towards integrated "omic" strategies. However, there is still an over reliance on classical viability assays for dose range finding. Such assays are not readily suited to the investigation of subtle alterations in cell function and most require termination of the experiment, which makes it difficult to monitor temporal alterations in repeat-dose long term exposure experiments. To this end, we investigated the use of lactate production as a marker of cell stress in long term repeat dose experiments. We conducted daily exposures to eight compounds at five concentrations for 14 days on human renal proximal tubular cells (RPTEC/TERT1), human hepatoma cells (HepaRG) and mouse fibroblasts (BALB-3T3) cells. Compounds were chosen from a training set used in the 7th EU Framework project Predict-IV and consisted of amiodarone, diclofenac, troglitazone, cadmium chloride, cephaloridine, cidofovir, cyclosporine A and buflomedil. At days 1, 3, 7 and 14, lactate was measured in the supernatant medium. At day 14, cells were assayed for resazurin reduction capability and subsequently lysed in methanol for ATP determination. Compound-induced loss of viability was comparable across all cell lines. For all cell types, when cell viability was compromised at day 14, lactate production was induced during the treatment period. In some situations, lactate also fell below control values, indicating cell death. Thus, temporal alterations in supernatant lactate provides information on the time and concentration of stress induction and the time and concentration where cell death becomes the dominant factor. Supernatant lactate production is a simple, cheap and non-invasive parameter. Since many molecular pathways converge on the glycolytic pathway, enhanced lactate production may be considered as a global marker of sub-lethal injury and thus an ideal marker for investigating temporal alterations in long term repeat dose testing in vitro

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

    PubMed

    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. PMID:25900579

  14. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The... concentration, erythrocyte count, total and differential leukocyte count, platelet count and a measure of blood clotting time/potential. (ii) Blood samples should be taken from a named site just prior to or as part...

  15. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The... concentration, erythrocyte count, total and differential leukocyte count, platelet count and a measure of blood clotting time/potential. (ii) Blood samples should be taken from a named site just prior to or as part...

  16. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The... aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, and...

  17. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The... aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, and...

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

    PubMed

    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. PMID:25892624

  19. [A relative bioavailability study of 2 oral formulations of omeprazole after their administration in repeated doses to healthy volunteers].

    PubMed

    Richards, J P; Gimeno, M; Moreland, T A; McEwen, J

    1999-04-01

    To determine the relative bioavailability of Ulceral (study formula) with respect to Losec (reference standard formula) and establish their bioequivalence daily doses of 20 mg of omeprazole were given during 5 consecutive days to 24 healthy volunteers. No significant differences were observed in the area under the curve (AUC0-t), a parameter directly related to the inhibition of acid secretion induced by omeprazole. The confidence interval of 90% for the difference between the two formulations for AUC0-t was within the interval of acceptance (0.80-1.25). The confidence interval for the difference between the two formulations for Cmax were also within the range of acceptance (0.70-1.43). In relation to the time for achieving (Cmax (tmax), the difference between the two formulations and the confidence interval of 95% for the tmax was 0.75 (-0.5-1.75) h indicating that no significant differences were observed between the two treatments. This study confirms the bioequivalence of Ulceral with the standard reference formulation as well as the tolerability of the two formulae. PMID:10349786

  20. Repeated-dose liver and gastrointestinal tract micronucleus assays for quinoline in rats.

    PubMed

    Uno, Fuyumi; Tanaka, Jin; Ueda, Maya; Nagai, Miho; Fukumuro, Masahito; Natsume, Masakatsu; Oba, Michiyo; Akahori, Ayaka; Masumori, Shoji; Takami, Shigeaki; Wako, Yumi; Kawasako, Kazufumi; Kougo, Yuriko; Ohyama, Wakako; Narumi, Kazunori; Fujiishi, Yohei; Okada, Emiko; Hayashi, Makoto

    2015-03-01

    Repeated-dose liver, bone marrow, and gastrointestinal tract micronucleus assays that use young adult rats were evaluated in a collaborative study that was organized by the Japanese Environmental Mutagen Society-Mammalian Mutagenicity Study Group. A genotoxic hepatocarcinogen quinoline was orally administered to independent groups of five Crl:CD (SD) male rats at doses of 30, 60 and 120mg/kg for 14 days and at doses of 15, 30 and 60mg/kg for 28 days. After treatment, the livers were harvested and hepatocytes were isolated by collagenase treatment. The frequency of micronucleated hepatocytes (MNHEPs) increased significantly in both the 14- and 28-day repeated dose studies. However, the frequency of micronucleated cells did not increase in the bone marrow, stomach or colon cells, which were not quinoline-induced carcinogenic target organs in the rats. These results indicate that a repeated-dose liver micronucleus (RDLMN) assay using young adult rats is capable of detecting the genotoxicity of quinoline at the target organ of carcinogenicity. The protocol may also permit the integration of the genotoxic endpoint into general repeated-dose toxicity studies. Furthermore, we elucidated that conducting the micronucleus assay in multiple organs could potentially assess organ specificity. PMID:25892622

  1. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The following... leucocyte count, platelet count and a measure of blood clotting time/potential. (ii) Blood samples should be... of dams prior to blood collection (if this option is preferred), dams and their offspring need...

  2. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The following... leucocyte count, platelet count and a measure of blood clotting time/potential. (ii) Blood samples should be... of dams prior to blood collection (if this option is preferred), dams and their offspring need...

  3. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The following... leucocyte count, platelet count and a measure of blood clotting time/potential. (ii) Blood samples should be... of dams prior to blood collection (if this option is preferred), dams and their offspring need...

  4. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The following... leucocyte count, platelet count and a measure of blood clotting time/potential. (ii) Blood samples should be... of dams prior to blood collection (if this option is preferred), dams and their offspring need...

  5. Toxicity Studies.

    PubMed

    2016-01-01

    Toxicity studies in the animal models are done to determine the dose level recommended for the treatment of disease as drug. This guideline enables the characterization of adverse effects following repeated daily inhalation exposure to a test. This chapter includes oral and dermal toxicity studies which are discussed as per OECD guidelines. Both acute and subacute toxicity studies are given special emphasis. PMID:26939270

  6. Safety evaluation of AB-LIFE(®) (Lactobacillus plantarum CECT 7527, 7528 and 7529): Antibiotic resistance and 90-day repeated-dose study in rats.

    PubMed

    Mukerji, Pushkor; Roper, Jason M; Stahl, Buffy; Smith, Amy B; Burns, Frank; Rae, Jessica Caverly; Yeung, Nicolas; Lyra, Anna; Svärd, Laura; Saarinen, Markku T; Alhoniemi, Esa; Ibarra, Alvin; Ouwehand, Arthur C

    2016-06-01

    AB-LIFE(®) is a probiotic product consisting of equal parts of three strains of Lactobacillus plantarum (CECT 7527, 7528, and 7529) blended with inert excipients. Whole genome sequencing was performed on each of the three strains. Antibiotic resistance was evaluated by genomic mining for resistance genes, and assessment for transferability. No risk of transfer potential was identified for any antibiotic resistance genes in the three strains. AB-LIFE(®) was evaluated for potential subchronic oral toxicity in rats, with dosages of 300 and 1000 mg/kg BW/day (equivalent to 5.55 × 10(10) and 1.85 × 10(11) CFU/kg BW/day). Survival of the three test strains through the gastrointestinal tract was supported by fecal analysis. No adverse effects were identified with respect to in-life parameters, clinical or anatomic pathology, translocation, or fecal chemical analyses. The no-observed-adverse-effect level (NOAEL) for AB-LIFE(®) in male and female rats was 1000 mg/kg BW/day (1.85 × 10(11) CFU of AB-LIFE(®)/kg BW/day), the highest dose level evaluated. These results, in conjunction with a previous acute toxicity study in rats, support the conclusion that AB-LIFE(®) is safe for human consumption. PMID:27016492

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

    PubMed

    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. PMID:24768639

  8. Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study

    PubMed Central

    Truman, Lucy A; Pekalski, Marcin L; Kareclas, Paula; Evangelou, Marina; Walker, Neil M; Howlett, James; Mander, Adrian P; Kennet, Jane; Wicker, Linda S; Bond, Simon; Todd, John A; Waldron-Lynch, Frank

    2015-01-01

    Introduction Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin-2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor-α chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self-tolerance and prevent further autoimmunity by enhancing the function of CD4+ T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D. Methods and analysis The Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4+ Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups. Ethics Ethical approval for DILfrequency was granted on 12 August 2014. Results The results of this study will be reported, through peer-reviewed journals, conference presentations and

  9. Ketoprofen versus paracetamol (acetaminophen) or ibuprofen in the management of fever: results of two randomized, double-blind, double-dummy, parallel-group, repeated-dose, multicentre, phase III studies in children.

    PubMed

    Kokki, Hannu; Kokki, Merja

    2010-01-01

    Fever is a common symptom in children and one of the major concerns of parents of younger and preschool-age children. To compare the efficacy and safety of ketoprofen with that of paracetamol (acetaminophen) and ibuprofen in the treatment of febrile conditions in children. Two prospective, randomized, double-blind, double-dummy, repeated-dose, multicentre, phase III studies with two parallel groups in each study were conducted in primary-care outpatient clinics. Children aged 6 months to 6 years presenting with a febrile condition and an oral body temperature of > or =38.8 degrees C or rectal temperature of > or =39 degrees C were eligible for inclusion. Patients were randomized to receive either ketoprofen syrup 0.5 mg/kg, ibuprofen suspension 5 mg/kg or paracetamol suspension 15 mg/kg every 6 hours by the oral route. The primary outcome measure was the change in temperature at 3 hours (H3), compared with baseline (H0). All three treatments provided similar mean maximum decreases of 1.4-1.5 degrees C in body temperature at H3 compared with H0. Use of ketoprofen was not associated with any increased risk of adverse events compared with the two reference compounds. Ketoprofen 0.5 mg/kg appeared to be equivalent to the standard antipyretic doses of the reference products ibuprofen 5 mg/kg and paracetamol 15 mg/kg. Ketoprofen at the 0.5 mg/kg dose should be an effective and safe option for symptomatic management of fever in children. PMID:20380479

  10. 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).

    PubMed

    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. PMID:25892619

  11. Elimination kinetics of disulfiram in alcoholics after single and repeated doses.

    PubMed

    Faiman, M D; Jensen, J C; Lacoursiere, R B

    1984-10-01

    Elimination kinetics of disulfiram were determined in 15 male alcoholics after 250 mg disulfiram taken by mouth as a single dose and again after 12 days of dosing. Apparent t 1/2s were calculated for disulfiram, diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), diethylamine (DEA), and carbon disulfide (CS2) and were found to be 7.3, 15.5, 22.1, 13.9, and 8.9 hr. Elimination t 1/2 for CS2 in breath was 13.3 hr. Average time to reach maximal plasma concentration after either single or repeated doses was 8 to 10 hr for disulfiram, DDTC, DDTC-Me, DEA, and CS2 in breath, while plasma CS2 concentration peaked 5 to 6 hr after disulfiram. In these studies, 22.4% and 31.3% of the disulfiram after single and repeated dosing was eliminated in the breath during one dosing interval. In urine, 1.7% and 8.3% of the disulfiram dose was eliminated as DDTC-glucuronide after single and repeated dosing, while DEA accounted for 1.6% and 5.7% of the dose. There was marked intersubject variability in plasma levels of disulfiram and its metabolites. This variability may be the result of the lipid solubility of disulfiram, differences in plasma protein binding, or the effect of enterohepatic cycling. PMID:6090051

  12. Oral Toxicity Study and Skin Sensitization Test of a Cricket.

    PubMed

    Ryu, Hyeon Yeol; Lee, Somin; Ahn, Kyu Sup; Kim, Hye Jin; Lee, Sang Sik; Ko, Hyuk Ju; Lee, Jin Kyu; Cho, Myung-Haing; Ahn, Mi Young; Kim, Eun Mi; Lim, Jeong Ho; Song, Kyung Seuk

    2016-04-01

    Crickets have been attracting considerable interest in the field of nutrition and toxicology due to the global exhaustion of food resulting from a growing population. The cricket is normally eaten in several countries after roasting, similar to the grasshopper; however, safety evaluation data on cricket powder is limited. Here, we performed general toxicity studies of cricket powder including a single, 2-week repeated dose range evaluation test, a 13-week repeated oral dose toxicity test in Sprague-Dawley rats, a single oral dose toxicity test in Beagle dogs, and a skin sensitization test in guinea pigs following the Organization for Economic Cooperation and Development test guidelines 406 and 408 in addition to Good Laboratory Practice. To investigate the NOAEL and target organs of cricket powder, Sprague-Dawley rats were allocated to 4 groups: vehicle control, 1,250 mg/kg, 2,500 mg/kg, 5,000 mg/kg dose test groups and cricket powder was administered over 13 weeks after single dose and dose range finding studies in rats based on the results of the single oral administration toxicity study in rats and Beagle dogs. The results of the study showed that the NOAEL of cricket powder was over 5,000 mg/kg for both sexes of rats without adverse effects in a 13-week repeated oral toxicity study and there was no skin hypersensitivity reaction. Therefore, our results reveal that crickets can be widely used as a new substitute food or nutrient resource. PMID:27123167

  13. Oral Toxicity Study and Skin Sensitization Test of a Cricket

    PubMed Central

    Ryu, Hyeon Yeol; Lee, Somin; Ahn, Kyu Sup; Kim, Hye Jin; Lee, Sang Sik; Ko, Hyuk Ju; Lee, Jin Kyu; Cho, Myung-Haing; Ahn, Mi Young; Kim, Eun Mi; Lim, Jeong Ho; Song, Kyung Seuk

    2016-01-01

    Crickets have been attracting considerable interest in the field of nutrition and toxicology due to the global exhaustion of food resulting from a growing population. The cricket is normally eaten in several countries after roasting, similar to the grasshopper; however, safety evaluation data on cricket powder is limited. Here, we performed general toxicity studies of cricket powder including a single, 2-week repeated dose range evaluation test, a 13-week repeated oral dose toxicity test in Sprague-Dawley rats, a single oral dose toxicity test in Beagle dogs, and a skin sensitization test in guinea pigs following the Organization for Economic Cooperation and Development test guidelines 406 and 408 in addition to Good Laboratory Practice. To investigate the NOAEL and target organs of cricket powder, Sprague-Dawley rats were allocated to 4 groups: vehicle control, 1,250 mg/kg, 2,500 mg/kg, 5,000 mg/kg dose test groups and cricket powder was administered over 13 weeks after single dose and dose range finding studies in rats based on the results of the single oral administration toxicity study in rats and Beagle dogs. The results of the study showed that the NOAEL of cricket powder was over 5,000 mg/kg for both sexes of rats without adverse effects in a 13-week repeated oral toxicity study and there was no skin hypersensitivity reaction. Therefore, our results reveal that crickets can be widely used as a new substitute food or nutrient resource. PMID:27123167

  14. Effects of repeated dosing with mechanistically distinct antinociceptive ligands in a rat model of neuropathic spinal cord injury pain

    PubMed Central

    Hama, Aldric T; Pearson, James P; Sagen, Jacqueline

    2014-01-01

    A lack of efficacy of some analgesic drugs has been previously described in rats with neuropathic spinal cord injury (SCI) pain. It has been suggested that repeated dosing in these animals over time may eventually lead to efficacy. However, it is also possible that efficacy may diminish over time with repeated dosing. This study evaluated the efficacy of various drugs upon repeated dosing over time in a rat model of SCI pain. Four weeks following an acute spinal cord compression at the mid-thoracic level, rats developed decreased hind paw withdrawal threshold, suggestive of below level neuropathic hypersensitivity. Either cannabinoid (CB) receptor agonist CP 55,940, the anticonvulsant carbamazepine or gabapentin, the antidepressant amitriptyline or vehicle was administered over a period of 7 days. Neither carbamazepine nor amitriptyline demonstrated efficacy either after a single or repeated dosing. Beginning with a 50% efficacious dose of gabapentin, the effect of gabapentin in SCI rats neither increased nor decreased over the treatment period. The antinociceptive effect of CP 55,940 was maintained for the entire treatment period, which was mediated by CB1 but not CB2 receptors. The current data suggest that sustained antinociception can be obtained with some drugs in rats with neuropathic SCI pain. Furthermore, the current data do not substantiate the notion that repeated treatment with initially ineffective drugs will eventually lead to efficacy; treatments that are not acutely effective are unlikely to demonstrate clinical efficacy. PMID:25505583

  15. Acute and environmental toxicity studies with hexazinone.

    PubMed

    Kennedy, G L

    1984-08-01

    The acute toxicity of hexazinone, a herbicide intended for general noncropland areas and selected crop uses (alfalfa and sugarcane), has been evaluated to establish proper handling guidelines and to measure its potential impact on the environment. The material is slightly to moderately toxic when given as a single oral dose; its LD50 in male rats is 1690 mg/kg, in male guinea pigs 860 mg/kg, and in male dogs greater than 3400 mg/kg although in the dog emesis prevented accurate quantitation. When the material is administered intraperitoneally, the LD50 in rats is 530 mg/kg. Repeated doses (five oral doses per week for 2 weeks) of 300 mg/kg to rats produced slight weight loss in one of two replicate experiments. In both studies, no gross or histologic alterations were apparent. Hexazinone is a moderate to severe eye irritant in the rabbit and produced only mild erythema in rabbit skin at 5278 mg/kg, a dose which did not produce lethality or other clinical signs. Subchronic dermal exposures (10 consecutive doses) to rabbits produced increases in serum alkaline phosphatase and glutamic-pyruvic transaminase at the highest levels tested (680 and 770 mg/kg in two separate experiments) with no effects seen at 150 mg/kg. There were no alterations in livers from treated rabbits examined by light microscopy. No dermal sensitization was produced when concentrations of up to 50% were tested in guinea pigs. One-hour inhalation exposure of up to 7.48 mg/liter did not produce mortality in rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6479506

  16. A 90-day subchronic toxicity study and reproductive toxicity studies on ACE-inhibiting lactotripeptide.

    PubMed

    Dent, M P; O'Hagan, S; Braun, W H; Schaetti, P; Marburger, A; Vogel, O

    2007-08-01

    In recent years there has been an increasing body of literature describing the antihypertensive effects of peptides produced from milk protein. The tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), isolated from hydrolysed casein have been shown to lower blood pressure by inhibiting angiotensin I-converting enzyme (ACE). This has led to the use of these tripeptides, collectively referred to as lactotripeptide (LTP) as ingredients of functional foods intended to help control blood pressure. A programme of studies including a 90-day repeat-dose oral gavage toxicity study in the rat and an embryo-fetal (pre-natal) development study in the rabbit was conducted to ensure the safety of this ACE-inhibiting ingredient. In addition, a non-standard pre- and post-natal development study in the rat was performed. This study included direct dosing of the neonates, and was designed specifically to investigate renal development and to ensure that the bioactive peptides were not associated with the same type of fetopathy exhibited by ACE inhibiting drugs. These studies showed that there were no adverse effects of treatment at the highest doses tested. PMID:17383063

  17. Differential effects of clozapine and pimozide on fixed-ratio responding during repeated dosing.

    PubMed

    Wiley, J L; Compton, A D; Porter, J H

    1994-05-01

    Previous research has shown that the differential development of tolerance to the disruption of operant responding produced by repeated dosing with pimozide (PMZ) or clozapine (CLZ) can distinguish these two drugs. In the present study, the effects of PMZ (1 mg/kg) and CLZ (10 mg/kg) on response rate and response duration in rats lever pressing for food reward under a fixed-ratio 30 (FR-30) operant schedule were examined. PMZ suppressed response rates across all 10 days of drug dosing; CLZ produced an initial response rate decrease, with partial recovery (50%) occurring within the 10 day period. Similarly, PMZ produced an increase in response duration that persisted into the postdrug vehicle-injection period, while CLZ did not significantly change response duration. The prolonged suppression of FR responding produced by PMZ is similar to the lack of tolerance to this drug in other types of operant schedules. In contrast, CLZ's effects on response rate are schedule dependent. These results suggest that changes in response duration with repeated dosing may more reliably differentiate typical and atypical neuroleptics than do changes in response rate under FR schedules. PMID:8029297

  18. Clinical experience and results of treatment with suprofen in pediatrics. 3rd communication: Antipyretic effect and tolerability of repeat doses of suprofen and paracetamol syrup in hospitalized children/A single-blind study.

    PubMed

    Weippl, G; Michos, N; Sundal, E J; Stocker, H

    1985-01-01

    Antipyretic effect and tolerability of alpha-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol), syrup and paracetamol (acetaminophen) were compared within the scope of the present randomized single-blind study; the test population included a total of 115 children ranging in age from 6 months to 12 years. All patients were admitted to the hospital with an average temperature of 39.3 degrees C, their disease being caused by bacterial or viral infections. The dose levels for treatment with syrup depended upon the children's age and body weight. Treatment was in most cases given for two days; a three-times-a-day schedule was used. The (rectal) temperature as well as pulse and respiratory rates were measured prior to treatment and 0.5, 1, 1.5, 2, 3, 4, 5, 6 h after first administration of the test preparations. The results showed that the antipyretic effect of suprofen was in both age groups at all rating times statistically significantly superior to that of paracetamol. Pulse and respiratory rates dropped in both age groups after treatment; the means were within the normal range at all rating times. Adverse drug reactions were seen in 5 patients on suprofen and in 3 cases on paracetamol. It is, however, questionable whether such reactions are drug-dependent. PMID:3911963

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

    PubMed

    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. PMID:25418605

  20. 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

    PubMed Central

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

    2012-01-01

    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, 50000 and 500000 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. PMID:22813907

  1. Toxicity profile of lisdexamfetamine dimesylate in three independent rat toxicology studies.

    PubMed

    Krishnan, Suma; Montcrief, Scott

    2007-10-01

    Lisdexamfetamine dimesylate (LDX) is a d-amphetamine prodrug developed for the treatment of attention-deficit/hyperactivity disorder. The toxicity profile of orally administered LDX has been evaluated in rats. In an acute study, LDX doses of 60 mg/kg and higher caused increased motor activity. At 1000 mg/kg, one rat died and another was euthanized. In a 7-day repeat-dose study, all rats dosed with LDX (14 per dose group for each sex) showed increased activity; 10 male rats and 11 female rats at 300 mg/kg/day and 3 female rats at 100 mg/kg/day were euthanized because of self-mutilation and 1 male rat at 300 mg/kg/day was found dead. In a 28-day study, only rats at 80 mg/kg showed signs of self-mutilation and thin body condition. In both the 7- and 28-day studies, LDX caused significant changes in some blood chemistry parameters (e.g. blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase) and organ weights (e.g. particularly heart, liver, brain, and spleen). Overall, no apparent treatment-related histopathologic changes were observed. Toxicokinetic assessments indicated that as the dose of LDX was increased, rats were exposed to increasing levels of LDX and d-amphetamine. The extent of exposure to LDX and d-amphetamine increased after repeated-dose in the 28-day study. The findings of the repeat-dose studies indicate that the toxicity profile in rats administered LDX orally is comparable to that for d-amphetamine; however, the apparent lethal dose of LDX in rats is more than five times higher than the LD(50) of orally administered d-amphetamine, supporting a putative protective effect of conjugating amphetamine with lysine. PMID:17845504

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

    PubMed Central

    Ríos, Victoria; Guzmán-Guillén, Remedios; Moreno, Isabel M.; Prieto, Ana I.; Puerto, María; Jos, Angeles; Cameán, Ana M.

    2014-01-01

    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. PMID:24632554

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

    PubMed

    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. PMID:24849678

  4. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes

    PubMed Central

    Crowther, Caroline A; McKinlay, Christopher JD; Middleton, Philippa; Harding, Jane E

    2014-01-01

    Background It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial. Objectives To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 March 2011), searched reference lists of retrieved studies and contacted authors for further data. Selection criteria Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth. Data collection and analysis We assessed trial quality and extracted data independently. Main results We included 10 trials (more than 4730 women and 5650 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNT 30, 95% CI 19 to 79). Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) −75.79 g, 95% CI −117.63 to −33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small-for-gestational age) did not differ between treatment groups. At early childhood follow-up no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or

  5. LITHIUM TOXICITY - A DESCRIPTIVE STUDY

    PubMed Central

    Kumar, Ratanendra; Deb, Jayant Kumar; Sinha, Baxi Neeraj Prasad; Sinha, Vinod Kumar

    2001-01-01

    Lithium is the treatment for acute mania and bipolar disorders. Ever since its introduction in the psychiatric arsenal, case reports of toxicity have been appearing in the literature at regular intervals. This study was thus carried out to study the presentation and associated features of lithium toxicity. In this retrospective study, case record files of all patients suspected to have developed lithium toxicity during a five year period were retrieved. It was found that toxicity presented most commonly with cerebellar symptoms and appeared at lower serum levels. Lithium could be restarted albeit at a lower dose and with a gradual titration in a number of cases. PMID:21407839

  6. MICROBIAL TOXICITY STUDIES

    EPA Science Inventory

    The chapter cites examples of the common methods used to determine the toxicity of chemicals to bacteria. It covers only the most common methods, particularly those that are easy to perform. Numerous literature citations have been included to help illustrate how a method is used ...

  7. Pharmacokinetics and tolerance of cefuroxime axetil in volunteers during repeated dosing.

    PubMed Central

    Sommers, D K; Van Wyk, M; Williams, P E; Harding, S M

    1984-01-01

    A total of 158 volunteers each received 21 repeated oral doses of 500 mg of cefuroxime axetil (CAE) during four comparative cross-over trials. Pharmacokinetics were studied in 8 volunteers (CAE versus ampicillin), relative bioavailability and tolerance were studied in 100 volunteers (CAE versus pivmecillinam and CAE versus pivampicillin), and tolerance alone was studied in 50 volunteers (CAE versus ampicillin). Overall, urinary recoveries of the active antibiotics ranked absorption of the drugs in the order least to greatest: pivmecillinam, ampicillin, CAE, and pivampicillin. The pharmacokinetics of CAE and ampicillin did not change after repeated dosing. Peak serum levels of cefuroxime were significantly higher than those of ampicillin after doses 1 and 21 but the urinary recoveries of both antibiotics were around 35% of the dose. CAE was as well tolerated as ampicillin but there were smaller numbers of episodes of fluid bowel motions on pivmecillinam and pivampicillin than on CAE, which may have been due to the smaller amounts of active antibiotic in the doses of the pivaloyloxymethyl esters. PMID:6721467

  8. Toxicity of nanosilver in intragastric studies: Biodistribution and metabolic effects.

    PubMed

    Hendrickson, Olga D; Klochkov, Sergey G; Novikova, Oksana V; Bravova, Irina M; Shevtsova, Elena F; Safenkova, Irina V; Zherdev, Anatoly V; Bachurin, Sergey O; Dzantiev, Boris B

    2016-01-22

    The unique physicochemical properties of silver nanoparticles explain their extensive application in consumer goods, food, and medicinal products. However, the biological effects of nanosilver after peroral exposure of mammals are still debatable. This study describes the biodistribution and biological action of 12nm non-coated silver nanoparticles intragastrically administered to male rats after acute (single exposure) and sub-acute (multiple exposures over 30 days) toxicity experiments. The daily doses were 2000 and 250mg/kg of body weight for single and multiple administrations, respectively. Silver tissue detection was conducted by elemental analysis with the help of atomic absorption spectroscopy. An estimation of the state of exposed animals was made and the dynamics of hematological and biochemical parameters of rats was studied. It was demonstrated that single and multiple administrations resulted in silver accumulation in the liver, kidneys, spleen, stomach, and small intestine. After both one- and repeated-dose exposures, the highest Ag contents were detected in the liver (0.87±0.37μg/g of organ) and kidneys (0.24±0.02μg/g of organ). The concentrations of silver detected in tissues were far smaller than the administered doses (<99%), indicating its efficient excretion from the organism. Acute and sub-acute exposures caused no animal mortality or signs of toxicity, manifested as changes in outward appearance or notable deviations in behavior or locomotor activity. Postmortem study revealed no visible pathomorphological abnormalities of internal organs. Hematological indices and biochemical parameters of the treated rats did not differ from those of the vehicle control animals. Overall, it can be concluded that nanosilver is able to be absorbed from the gastrointestinal tract into the bloodstream and accumulate in the secondary organs of rats. It showed no distinct toxicity under the experimental conditions of this study. PMID:26617184

  9. Repeated-dose liver and gastrointestinal tract micronucleus assays with CI Solvent Yellow 14 (Sudan I) using young adult rats.

    PubMed

    Matsumura, Shoji; Ikeda, Naohiro; Hamada, Shuichi; Ohyama, Wakako; Wako, Yumi; Kawasako, Kazufumi; Kasamatsu, Toshio; Nishiyama, Naohiro

    2015-03-01

    The in vivo genotoxicity of CI Solvent Yellow 14 (Sudan I) was examined using repeated-dose liver and gastrointestinal tract micronucleus (MN) assays in young adult rats. Sudan I is a mono-azo dye based on aniline and 1-amino-2-hydroxynaphthalene. This dye was demonstrated as a rat liver carcinogen in a National Toxicology Program (NTP) bioassay, and genotoxicity was noted in a rat bone marrow micronucleus (BMMN) assay. In the present study, Sudan I was administered orally to rats for 14-days, and the MN frequency in the liver, stomach, colon, and bone marrow were analyzed. The frequency of micronucleated hepatocytes (MNHEPs) was not significantly increased by the administration of the Sudan I. Gastrointestinal tract MNs were also not induced. However, in the BMMN assay, a significant increase in micronucleated immature erythrocytes (MNIMEs) was observed in a dose-dependent manner. While Sudan I has been reported to lack hepatic genotoxicity, it has also exhibited tumor-promoting activities. These results are consistent with the lack of induction of MN in the hepatocytes. The lack of MN induction in cells of the gastrointestinal tract was also logical because azo-compounds are reported to be unlikely to induce DNA damage in the rat gut. The repeated-dose rat liver and gastrointestinal tract MN assays have the potential to be used in the evaluation of the genotoxicity of a chemical in each organ in accordance with its mode of action. PMID:25892626

  10. Histamine2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing

    PubMed Central

    McRorie, Johnson W; Kirby, James A; Miner, Philip B

    2014-01-01

    Histamine2-receptor antagonists (H2RAs) are available over-the-counter (OTC) for the treatment and prevention of heartburn, but more than occasional, single-dose use can lead to rapid development of tachyphylaxis. The aim of this review is to assess the published evidence regarding the development of tachyphylaxis with repeat usage of H2RAs. PubMed and SCOPUS were searched across all years to identify clinical studies that examined the development of tachyphylaxis with repeated dosing of H2RAs. Although a single (first) dose of an H2RA can be effective for controlling gastric acid and preventing or relieving food-related heartburn, numerous studies confirm that tachyphylaxis, also known as tolerance, is consistently detected at the first time point assessed after the first dose, including the second day and/or second dose. Even if symptom relief is achieved with an H2RA, it may be due to desensitization of the esophagus to acid exposure, potentially providing symptom relief without significantly decreasing esophageal acid exposure. When recommending OTC drugs for treatment of frequent heartburn, clinicians should be aware of the potential for rapid development of tachyphylaxis in patients who use H2RAs for 2 or more consecutive days. Even if symptom relief is achieved, it may be due to desensitization of the esophagus to acid by the H2RA, potentially providing symptom relief without significantly decreasing esophageal acid exposure. Other strategies, such as an OTC proton pump inhibitor, may be needed to optimize management of frequent heartburn. PMID:24868486

  11. Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study.

    PubMed

    Nakayama, Koji; Kawano, Yukiko; Kawakami, Yuuki; Moriwaki, Norichika; Sekijima, Masaru; Otsuka, Masanori; Yakabe, Yoshikuni; Miyaura, Hideki; Saito, Koichi; Sumida, Kayo; Shirai, Tomoyuki

    2006-12-15

    Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as "carcinogenic", and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as "non-carcinogenic"; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as "carcinogenic", and 4-AAF, 2,6-DAT, and 1-NP as "non-carcinogenic". After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a "carcinogenic" branch. 2-NpP was in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity. PMID:17070881

  12. Baltimore Air Toxics Study (BATS)

    SciTech Connect

    Sullivan, D.A.

    1996-12-31

    The Baltimore Air Toxics Study is one of the three urban air toxics initiatives funded by EPA to support the development of the national air toxics strategy. As part of this project, the Air Quality Integrated Management System (AIMS) is under development. AIMS is designed to bring together the key components of urban air quality management into an integrated system, including emissions assessment, air quality modeling, and air quality monitoring. Urban area source emissions are computed for a wide range of pollutants and source categories, and are joined with existing point source emissions data. Measured air quality data are used to evaluate the adequacy of the emissions data and model treatments as a function of season, meteorological parameters, and daytime/nighttime conditions. Based on tested model performance, AIMS provides the potential to improve the ability to predict air quality benefits of alternative control options for criteria and toxic air pollutants. This paper describes the methods used to develop AIMS, and provides examples from its application in the Baltimore metropolitan area. The use of AIMS in the future to enhance environmental management of major industrial facilities also will be addressed in the paper.

  13. How toxic is coal ash? A laboratory toxicity case study.

    PubMed

    Sherrard, Rick M; Carriker, Neil E; Greeley, Mark S

    2015-01-01

    Under a consent agreement among the Environmental Protection Agency (EPA) and proponents both for and against stricter regulation, EPA is to issue a new coal ash disposal rule by the end of 2014. Laboratory toxicity investigations often yield conservative estimates of toxicity because many standard test species are more sensitive than resident species, thus could provide information useful to the rule-making. However, few laboratory studies of coal ash toxicity are available; most studies reported in the literature are based solely on field investigations. This brief communication describes a broad range of toxicity studies conducted for the Tennessee Valley Authority (TVA) Kingston ash spill, results of which help provide additional perspective on the toxicity of coal ash. PMID:25348557

  14. How toxic is coal ash? A laboratory toxicity case study

    DOE PAGESBeta

    Sherrard, Rick M.; Carriker, Neil; Greeley, Jr., Mark Stephen

    2014-12-08

    Under a consent agreement among the Environmental Protection Agency (EPA) and proponents both for and against stricter regulation, EPA is to issue a new coal ash disposal rule by the end of 2014. Laboratory toxicity investigations often yield conservative estimates of toxicity because many standard test species are more sensitive than resident species, thus could provide information useful to the rule-making. However, few laboratory studies of coal ash toxicity are available; most studies reported in the literature are based solely on field investigations. In this paper, we describe a broad range of toxicity studies conducted for the Tennessee Valley Authoritymore » (TVA) Kingston ash spill, results of which help provide additional perspective on the toxicity of coal ash.« less

  15. How toxic is coal ash? A laboratory toxicity case study

    SciTech Connect

    Sherrard, Rick M.; Carriker, Neil; Greeley, Jr., Mark Stephen

    2014-12-08

    Under a consent agreement among the Environmental Protection Agency (EPA) and proponents both for and against stricter regulation, EPA is to issue a new coal ash disposal rule by the end of 2014. Laboratory toxicity investigations often yield conservative estimates of toxicity because many standard test species are more sensitive than resident species, thus could provide information useful to the rule-making. However, few laboratory studies of coal ash toxicity are available; most studies reported in the literature are based solely on field investigations. In this paper, we describe a broad range of toxicity studies conducted for the Tennessee Valley Authority (TVA) Kingston ash spill, results of which help provide additional perspective on the toxicity of coal ash.

  16. Repeated dose liver and gastrointestinal tract micronucleus assays using N-methyl-N'-nitro-N-nitrosoguanidine in young adult rats.

    PubMed

    Takayanagi, Tomomi; Wako, Yumi; Kawasako, Kazufumi; Hori, Hisako; Fujii, Wataru; Ohyama, Wakako

    2015-03-01

    N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a direct-acting mutagen that induces tumors in the glandular stomach, but not in the liver or colon, of rats after oral administration. To evaluate the performance of repeated dose liver and gastrointestinal tract micronucleus (MN) assays in young adult rats, MNNG was administered by oral gavage to male CD (SD) rats aged 6 weeks at doses of 0 (vehicle; 2.5% DMSO aqueous solution), 3.125, 6.25, 12.5, and 25mg/kg/day once daily for 14 and 28 days, and the MN frequencies were examined in the hepatocytes, glandular stomach cells, and colonic cells. The MN induction in immature erythrocytes in the bone marrow of these animals was also simultaneously evaluated. The frequencies of micronucleated (MNed) glandular stomach cells were significantly increased in all MNNG treatment groups in a dose-dependent manner in both repeated dose studies. In contrast, the frequencies of MNed hepatocytes and colonic cells were not significantly increased compared to the vehicle control. In the bone marrow, a small but significant increase in the frequency of MNed immature erythrocytes was observed only at the highest dose in the 28-day study. Since a clear positive result in the glandular stomach agrees with the tissue specificity of tumor induction by this chemical, the MN assay with the glandular stomach, which is a direct contact site with high concentrations of test substances administered by oral gavage, may be useful for detecting genotoxic compounds that are short-lived in vivo, such as MNNG. PMID:25892628

  17. Identifying the cause of toxicity in an algal whole effluent toxicity study - an unanticipated toxicant.

    PubMed

    Naddy, Rami B; Tapp, Kelly; Rehner, Anita B; Pillard, David A; Schrage, Laura

    2011-10-01

    Toxicity was observed in whole effluent toxicity (WET) studies with the freshwater alga, Pseudokirchneriella subcapitata, in three consecutive monthly studies, (NOEC=50-75%). Toxicity was not observed to Ceriodaphnia dubia or the fathead minnow, Pimephales promelas in concurrent studies. Selected toxicity identification evaluation (TIE) tests were conducted in a tiered approach to eliminate possible toxicants and progressively identify the causative agent. Filtration following alkaline adjustment (pH 10 or 11) was effective in eliminating significant growth effects and also reduced phosphate concentration. The TIE studies confirmed that the observed effluent toxicity was caused by excess ortho-phosphate in the effluent not by overstimulation or related to unfavorable N:P ratios; but due to direct toxicity. The 96-h 25% inhibition concentration (IC25) of ortho-phosphate to P. subcapitata was 3.4 mg L⁻¹ while the maximum acceptable toxicant concentration was 4.8 mg L⁻¹. This study illustrates the value of multi-species testing and also provides an example of an effective TIE using algae identifying an unanticipated toxicant. PMID:21840029

  18. [Preclinical study of noopept toxicity].

    PubMed

    Kovalenko, L P; Smol'nikova, N M; Alekseeva, S V; Nemova, E P; Sorokina, A V; Miramedova, M G; Kurapova, S P; Sidorina, E I; Kulakova, A V; Daugel'-Dauge, N O

    2002-01-01

    Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice. PMID:12025790

  19. In vivo flow cytometric Pig-a and micronucleus assays: highly sensitive discrimination of the carcinogen/noncarcinogen pair benzo(a)pyrene and pyrene using acute and repeated-dose designs.

    PubMed

    Torous, Dorothea K; Phonethepswath, Souk; Avlasevich, Svetlana L; Mereness, Jared; Bryce, Steven M; Bemis, Jeffrey C; Weller, Pamela; Bell, Sara; Gleason, Carol; Custer, Laura L; MacGregor, James T; Dertinger, Stephen D

    2012-07-01

    Combining multiple genetic toxicology endpoints into a single in vivo study, and/or integrating one or more genotoxicity assays into general toxicology studies, is attractive because it reduces animal use and enables comprehensive comparative analysis using toxicity, metabolism, and pharmacokinetic information from the same animal. This laboratory has developed flow cytometric scoring techniques for monitoring two blood-based genotoxicity endpoints-micronucleated reticulocyte frequency and gene mutation at the Pig-a locus-thereby making combination and integration studies practical. The ability to effectively monitor these endpoints in short-term and repeated dosing schedules was investigated with the carcinogen/noncarcinogen pair benzo(a)pyrene (BP) and pyrene (Pyr). Male Sprague-Dawley rats were treated via oral gavage for 3 or 28 consecutive days with several dose levels of Pyr, including maximum tolerated doses. BP exposure was administered by the same route but at one dose level, 250 or 125 mg/kg/day for 3-day and 28-day studies, respectively. Serial blood samples were collected up to Day 45, and were analyzed for Pig-a mutation with a dual labeling method (SYTO 13 in combination with anti-CD59-PE) that facilitated mutant cell frequency measurements in both total erythrocytes and the reticulocyte subpopulation. A mutant cell enrichment step based on immunomagnetic column separation was used to increase the statistical power of the assay. BP induced robust mutant reticulocyte responses by Day 15, and elevated frequencies persisted until study termination. Mutant erythrocyte responses lagged mutant reticulocyte responses, with peak incidences observed on Day 30 of the 3-day study (43-fold increase) and on Day 42 of the 28-day study (171-fold increase). No mutagenic effects were apparent for Pyr. Blood samples collected on Day 4, and Day 29 for the 28-day study, were evaluated for micronucleated reticulocyte frequency. Significant increases in micronucleus

  20. Acute and subchronic toxicity studies of pyrroloquinoline quinone (PQQ) disodium salt (BioPQQ™) in rats.

    PubMed

    Nakano, Masahiko; Takahashi, Hisaaki; Koura, Seiko; Chung, Catherine; Tafazoli, Shahrzad; Roberts, Ashley

    2014-10-01

    The potential use of pyrroloquinoline quinone disodium salt (BioPQQ™), as a supplemental food ingredient, was evaluated in a range of oral toxicity studies in rats including an acute study, a 14-day preliminary and a 28-day repeated-dose study, and a 13-week subchronic study. The median lethal dose of BioPQQ™ was shown to be 1000-2000mg/kg body weight (bw) in male and 500-1000mg/kgbw in female rats. In the 14-day study, high doses of BioPQQ™ resulted in increases in relative kidney weights with associated histopathology in female rats only, while a follow-up 28-day study in female animals resulted in increases in urinary protein and crystals. These findings were reversible, and resolved during the recovery period. In the 13-week study, a number of clinical chemistry findings and histopathological changes were noted, which were deemed to be of no toxicological significance, as the levels were within the historical control range, were not dose-dependent, occurred at a similar frequency in control groups, or only occurred in the control group. Based on these findings, a no-observed-adverse-effect level of 100mg/kgbw/day was determined for BioPQQ™ in rats, the highest dose tested in the 13-week study. PMID:24995591

  1. LAKE MICHIGAN URBAN AIR TOXICS STUDY

    EPA Science Inventory

    During the summer of 1991, an air toxics monitoring program wa conducted in the lower Lake Michigan area. his study was designed to take advantage of the intensive meteorological and oxidant data base being generated concurrently by the Lake Michigan Ozone Study (LMOS stations). ...

  2. Clinical and Pathological Effects of Short-term Cyanide Repeated Dosing to Goats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this work is to determine and describe the effects of subacute cyanide toxicity to goats. Eight female goats were divided into two groups. The first group of five animals was treated with 8.0mg KCN kg-1 body weight day -1 for seven consecutive days. The second group of three animal...

  3. Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database

    EPA Science Inventory

    Multigeneration reproduction studies are used to characterize parental and offspring systemic toxicity, as well as reproductive toxicity of pesticides, industrial chemicals and pharmaceuticals. Results from 329 multigeneration studies on 316 chemicals have been digitized into sta...

  4. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.

    PubMed

    Suttle, A Benjamin; Grossmann, Kenneth F; Ouellet, Daniele; Richards-Peterson, Lauren E; Aktan, Gursel; Gordon, Michael S; LoRusso, Patricia M; Infante, Jeffrey R; Sharma, Sunil; Kendra, Kari; Patel, Manish; Pant, Shubham; Arkenau, Hendrik-Tobias; Middleton, Mark R; Blackman, Samuel C; Botbyl, Jeff; Carson, Stanley W

    2015-04-01

    The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib. PMID:25449654

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

    PubMed

    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

  6. Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine

    PubMed Central

    Zamuner, Stefano; Johnson, Brendan M; Pagliarusco, Sabrina; Fina, Paolo; Peroni, Michela; Fiore, Monica; Adams, Laurel M; Fernandes, Sofia A

    2010-01-01

    AIM To evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed. METHODS Three open-label studies were conducted in healthy subjects. In the first study subjects received single dose 50 or 100 mg oral casopitant, single dose 5 mg oral midazolam and single dose 10 mg oral debrisoquine. In the other two studies subjects received repeated doses of 10 mg (study 2), 30, or 120 mg oral casopitant and single doses of 5 mg oral midazolam (study 2) and single doses of 10 mg oral nifedipine (study 3). Plasma concentration–time data were analyzed using standard non-compartmental methods. The effect of casopitant on all probes was assessed using geometric means ratios and corresponding 90% confidence intervals (CIs). RESULTS The AUC(0,∞) of midazolam was increased 1.44-fold (90% CI 1.35, 1.54) and 1.52-fold (90% CI 1.41, 1.65) after co-administration with a single dose of 50 or 100 mg casopitant, respectively. Debrisoquine metabolism was unchanged. After 3 days of casopitant administration, midazolam AUC(0,∞) was increased 1.45- (90% CI 1.32, 1.59), 2.02- (90% CI 1.75, 2.32), and 2.67-fold (90% CI 2.18, 3.27) after co-administration with 10, 30 or 120 mg casopitant, respectively. After 14 days of casopitant administration, midazolam AUC(0,∞) was increased 1.51- (90% CI 1.40, 1.63) to 3.49-fold (90% CI 2.98, 4.08). After 3 days of casopitant administration, nifedipine AUC(0,∞) was increased 1.56- (90% CI 1.37, 1.78) and 1.77-fold (90% CI 1.54, 2.04) after co-administration with 30 or 120 mg casopitant, respectively. Similar increases in nifedipine exposure were observed after 14 days of casopitant administration. CONCLUSIONS Casopitant is a dose- and duration-dependent weak to moderate inhibitor of CYP3A. PMID:20840445

  7. TOXICANT IDENTIFICATION STUDIES ON A HARBOR SEDIMENT

    EPA Science Inventory

    Presentation summarizes the results of experiments on sediment toxicity identification evaluation (TIE) techniques that allow researchers to characterize and identify chemical causes of acute toxicity in sediments that can be applied using the 10-d solid-phase sediment toxicity t...

  8. Modeling Single and Repeated Dose Pharmacokinetics of PFOA in Mice (J)

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that serum concentrations indicate long half-lives despite which steady state appears to be achieved rapidly. In this study, serum and tissue concentration time-courses were obtained for male and female CD1 m...

  9. Acute and environmental toxicity studies with hexazinone

    SciTech Connect

    Kennedy, G.L. Jr.

    1984-08-01

    The acute toxicity of hexazinone, a herbicide intended for general noncropland areas and selected crop uses (alfalfa and sugarcane), has been evaluated to establish proper handling guidelines and to measure its potential impact on the environment. The material is slightly to moderately toxic when given as a single oral dose; its LD50 in male rats is 1690 mg/kg, in male guinea pigs 860 mg/kg, and in male dogs greater than 3400 mg/kg although in the dog emesis prevented accurate quantitation. When the material is administered intraperitoneally, the LD50 in rats is 530 mg/kg. In both studies, no gross or histologic alterations were apparent. Hexazinone is a moderate to severe eye irritant in the rabbit and produced only mild erythema in rabbit skin at 5278 mg/kg, a dose which did not produce lethality or other clinical signs. Subchronic dermal exposures (10 consecutive doses) to rabbits produced increases in serum alkaline phosphatase and glutamic-pyruvic transaminase at the highest levels tested (680 and 770 mg/kg in two separate experiments) with no effects seen at 150 mg/kg. One-hour inhalation exposure of up to 7.48 mg/liter did not produce mortality in rats.

  10. Chronic toxicity study of neosaxitoxin in rats.

    PubMed

    Zepeda, Ramiro J; Candiracci, Manila; Lobos, Nicolas; Lux, Sebastian; Miranda, Hugo F

    2014-09-01

    Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic. PMID:25257789

  11. Chronic Toxicity Study of Neosaxitoxin in Rats

    PubMed Central

    Zepeda, Ramiro J.; Candiracci, Manila; Lobos, Nicolas; Lux, Sebastian; Miranda, Hugo F.

    2014-01-01

    Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic. PMID:25257789

  12. Pharmacokinetics of repeated doses of intravenous cocaine across the menstrual cycle in rhesus monkeys.

    PubMed

    Evans, Suzette M; Foltin, Richard W

    2006-01-01

    Numerous studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Given that female rhesus monkeys have menstrual cycles that are remarkably similar to those of humans, they provide an ideal laboratory animal model for assessing the effects of cocaine across the menstrual cycle. The present study assessed the effects of 4 injections of intravenous (i.v.) cocaine (0.00, 0.25 or 0.50 mg/kg), spaced 15 min apart, in 4 female rhesus monkeys. Each monkey was tested with each dose during 4 phases of the menstrual cycle: menses, midfollicular, periovulatory and midluteal. Estradiol and progesterone levels were measured each session before cocaine administration to verify phase of the menstrual cycle. Cocaine and cocaine metabolite levels were measured 5 min after each cocaine dose and 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Similarly, levels of luteinizing hormone (LH) and prolactin levels were measured before, 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Cocaine and metabolite levels increased as a function of dose, but there were minimal differences across the menstrual cycle following repeated injections of cocaine. With a few exceptions, LH levels decreased as a function of time within the session, with no differences as a function of cocaine dose. Cocaine produced transient increases in LH levels during the luteal phase, with maximal levels occurring after the second cocaine injection. Lastly, cocaine substantially decreased prolactin levels across all menstrual cycle phases. Taken together, these data indicate that any behavioral differences observed either across the menstrual cycle or between males and females, are probably not related to alterations in the pharmacokinetics of cocaine across the menstrual cycle. PMID:16426669

  13. [Biological models in studying of staphylococci enterotoxin toxicity].

    PubMed

    Shepeliakovskaia, A O; Semushina, S G; Murashev, A N; Adameĭko, I I; Brovko, F A

    2014-01-01

    Enterotoxins--superantigens--are the main toxic agents of staphylococci. Currently, an important role of these proteins is estabished in both toxicity itself--toxic shock and in the development of autoimmune diseases. Enterotoxin studies are carried out in several directions including the search for novel molecular targets, studies in cell tests and establishment of toxicity in animal models. Methods of studying toxicity in animal models: monkeys, mice and rabbits are examined in the review. Methods of animal priming to achieve lethality, features of using various lines of mice during analysis of individual enterotoxins are discussed. Methods of studying enterotoxin-neutralizing compounds in animal models are discussed. PMID:25536781

  14. Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy

    PubMed Central

    Chavan, Swapnil; Friedman, Ran; Nicholls, Ian A.

    2015-01-01

    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. PMID:26006240

  15. Preclinical pharmacokinetic evaluation of resveratrol trimethyl ether in sprague-dawley rats: the impacts of aqueous solubility, dose escalation, food and repeated dosing on oral bioavailability.

    PubMed

    Lin, Hai-Shu; Ho, Paul C

    2011-10-01

    Resveratrol trimethyl ether (trans-3,5,4'-trimethoxystilbene, RTE) is a naturally occurring and pharmacologically active resveratrol derivative. To evaluate its suitability as a drug candidate, a pharmacokinetic study was carried out in Sprague-Dawley rats with the emphasis to identify the impact of aqueous solubility, dose escalation, food, and repeated dosing on its oral bioavailability. Upon single intravenous administration (5 mg/kg), RTE displayed moderate clearance (35.5 ± 5.3 mL/min/kg) and a fairly long terminal elimination half-life (511 ± 136 min); dose escalation (5-20 mg/kg) did not cause nonlinear pharmacokinetics. When given orally in suspension (60 mg/kg), RTE was poorly absorbed with negligible bioavailability (< 1.5%), fasting further decreased its bioavailability (<1%). However, when administered in a solution formulated with randomly methylated-β-cyclodextrin (15 mg/kg), RTE was rapidly absorbed with good bioavailability (46.5 ± 4.8%). Dose escalation resulted in increased bioavailability (64.6 ± 8.0%) at the dose of 60 mg/kg. Repeated RTE dosing (7 daily oral doses) did not alter the clearance, terminal elimination half-life and bioavailability. In summary, the aqueous solubility of RTE was a barrier to oral absorption; repeated RTE administrations did not alter its pharmacokinetic profiles; as RTE possessed appropriate pharmacokinetic profiles, further investigation on RTE as a drug candidate is warranted. PMID:21520090

  16. Meta-analysis of toxicity and teratogenicity of 133 chemicals from zebrafish developmental toxicity studies

    EPA Science Inventory

    Zebrafish developmental toxicity testing is an emerging field, which faces considerable challenges regarding data meta-analysis and the establishment of standardized test protocols. Here, we present an initial correlation study on toxicity of 133 chemicals based on data in the li...

  17. Corrosion-induced Whole Effluent Toxicity from a cooling tower: A toxicity reduction evaluation case study

    SciTech Connect

    Fort, D.J.; Stover, E.L.; Talley, J.M.; Copenhaver, M.B.

    1996-11-01

    As the result of Whole Effluent Toxicity (WET) test failures with Daphnia pulex, the US Environmental Protection Agency (EPA) required an industrial facility discharging approximately 5 million gallons per day (MGD) of recirculating cooling water obtained from a large freshwater river to conduct a Toxicity Reduction Evaluation (TRE) program. Under the terms of the National Pollutant Discharge Elimination System (NPDES) permit, the facility was required to conduct 48-hour acute toxicity tests with D. pulex and Pimephales promelas (fathead minnow). Although effluent toxicity to D. pulex was consistently observed, no toxicity was induced to the fathead minnow during the TRE program. The situation was further complicated by the fact that the recirculating cooling water was discharged back into the same river. The objectives of the TRE program were to investigate the causes of toxicity, locate potential sources of the suspected toxicant(s), and identify practicable toxicity reduction methodologies to be used. The TRE program approach and results from the associated studies are presented in this report, including a successful remedy for the WET problem.

  18. Toxicity Evaluation of Pũrṇa Cantirotaya Centũram, a Siddha Medicine in Wistar Rats

    PubMed Central

    Chitra, B.; Ramaswamy, R. S.; Suba, V.

    2015-01-01

    Pũrṇa Cantirotaya Centũram (PCC), a herbometallic formulation of Siddha medicine, consists of mercury, sulphur, and gold, processed with red cotton flower and plantain stem pith juices. To evaluate its safety, acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively. In acute study, PCC was administered orally at 5, 50, 300, and 2000 mg/kg body weight. Animals were observed for toxic signs for 14 days. Gross pathology was performed at the end of the study. In repeated dose toxicity study, PCC was administered at 2.5, 25, and 50 mg/kg body weight daily for 28 days. Satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of PCC. In acute toxicity study, no treatment related death or toxic signs were observed. It revealed that the LD50 cut-off value of PCC is between 2000 and 5000 mg/kg body weight. The repeated dose study did not show evidence of any treatment related changes in all observations up to the high dose level, when compared with the control. Histopathological examination revealed no abnormalities except mild hyperplasia of stomach in high dose group. This study provides scientific validation for the safety of PCC. PMID:27347522

  19. In vivo toxicity study of Lantana camara

    PubMed Central

    Pour, Badakhshan Mahdi; Sasidharan, Sreenivasan

    2011-01-01

    Objective To investigate the toxicity of methanol extract of various parts (Root, Stem, Leaf, Flower and Fruit) of Lantana camara (L. Camara) in Artemia salina. Methods The methanol extracts of L. camara were tested for in vivo brine shrimp lethality assay. Results All the tested extract exhibited very low toxicity on brine shrimp larva. The results showed that the root extract was the most toxic part of L. camara and may have potential as anticancer agent. Conclusions Methanolic extract of L. camara is relatively safe on short-term exposure. PMID:23569765

  20. [An acute toxicity study of bromantane].

    PubMed

    Bugaeva, L I; Verovskiĭ, V E; Iezhitsa, I N; Spasov, A A

    2000-01-01

    The toxicity of bromantan was evaluated by conventional acute tests (according to Belen'kiĭ) and by the behavioral activity data (according to Irvin). A method of integral graphical representation of the behavioral activity data is suggested, according to which the results are plotted as a "dose trajectory." Using the dose trajectory constructed for bromantan, the levels of therapeutic, toxic, and lethal doses were calculated. It was established that catecholaminergic effects account for the mechanism of therapeutic action of bromantan, while cholinergic effects determine the drug action in toxic doses. PMID:10763112

  1. Assessing the mammalian toxicity of high-boiling petroleum substances under the rubric of the HPV program.

    PubMed

    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. PMID:23247262

  2. A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity.

    PubMed

    Blackburn, Karen; Daston, George; Fisher, Joan; Lester, Cathy; Naciff, Jorge M; Rufer, Echoleah S; Stuard, Sharon B; Woeller, Kara

    2015-07-01

    Alternative methods for full replacement of in vivo tests for systemic endpoints are not yet available. Read across methods provide a means of maximizing utilization of existing data. A limitation for the use of read across methods is that they require analogs with test data. Repeat dose data are more frequently available than are developmental and/or reproductive toxicity (DART) studies. There is historical precedent for using repeat dose data in combination with a database uncertainty factor (UF) to account for missing DART data. We propose that use of the DART decision tree (Wu et al., 2013), in combination with a database UF, provides a path forward for DART data gap filling that better utilizes all of the data. Our hypothesis was that chemical structures identified by the DART tree as being related to structures with known DART toxicity would potentially have lower DART NOAELs compared to their respective repeat dose NOAELs than structures that lacked this association. Our analysis supports this hypothesis and as a result also supports that the DART decision tree can be used as part of weight of evidence in the selection of an appropriate DART database UF factor. PMID:25910676

  3. Toxicity studies of a polyurethane rigid foam

    NASA Technical Reports Server (NTRS)

    Hilado, C. J.; Schneider, J. E.

    1977-01-01

    Relative toxicity tests were performed on a polyurethane foam containing a trimethylopropane-based polyol and an organophosphate flame retardant. The routine screening procedure involved the exposure of four Swiss albino male mice in a 4.2 liter hemispherical chamber to the products generated by pyrolyzing a 1.00 g sample at a heating rate of 40 deg C/min from 200 to 800 C in the absence of air flow. In addition to the routine screening, experiments were performed with a very rapid rise to 800 C, with nominal 16 and 48 ml/sec air flow and with varying sample rates. No unusual toxicity was observed with either gradual or rapid pyrolysis to 800 C. Convulsions and seizures similar to those previously reported were observed when the materials were essentially flash pyrolyzed at 800 C in the presence of air flow, and the toxicity appeared unusual because of low sample weights required to produce death.

  4. Reproductive and developmental toxicity testing: Examination of the extended one-generation reproductive toxicity study guideline.

    PubMed

    Saghir, Shakil A; Dorato, Michael A

    2016-08-01

    An important aspect of safety assessment of chemicals (industrial and agricultural chemicals and pharmaceuticals) is determining their potential reproductive and developmental toxicity. A number of guidelines have outlined a series of separate reproductive and developmental toxicity studies from fertilization through adulthood and in some cases to second generation. The Extended One-Generation Reproductive Toxicity Study (EOGRTS) is the most recent and comprehensive guideline in this series. EOGRTS design makes toxicity testing progressive, comprehensive, and efficient by assessing key endpoints across multiple life-stages at relevant doses using a minimum number of animals, combining studies/evaluations and proposing tiered-testing approaches based on outcomes. EOGRTS determines toxicity during preconception, development of embryo/fetus and newborn, adolescence, and adults, with specific emphasis on the nervous, immunological, and endocrine systems, EOGRTS also assesses maternal and paternal toxicity. However, EOGRTS guideline is complex, criteria for selecting doses is unclear, and monitoring systemic dose during the course of the study for better interpretation and human relevance is not clear. This paper discusses potential simplification of EOGRTS, suggests procedures for relevant dose selection and monitors systemic dose at multiple life-stages for better interpretation of data and human relevance. PMID:27074386

  5. Skin temperature recording with phosphors: toxicity studies on animals.

    PubMed

    Derse, P H; Alt, L L

    1966-08-20

    In a previous communication in this journal, a method was described for converting invisible thermal patterns of the human skin into a detailed visible picture. At that time, the question of possible toxicity of the thermographic phosphor was raised. Toxicity studies conducted on laboratory animals indicate that the probability of toxic side reactions resulting from the use of zinc-cadmium sulfide phosphor spray is very low. PMID:5943198

  6. Toxicity studies of mild gasification products

    SciTech Connect

    Ong, T.M.; Whong, W.Z.; Ma, J.; Zhong, B.Z.; Bryant, D.

    1992-01-01

    The objectives of this project are: (1) to perform mutagenicity studies with the Ames Salmonella/microsomal assay system on coal liquids produced by mild gasification from different coals and/or processing conditions, (2) to determine whether coal liquids which are mutagenic to bacteria are also genotoxic to mammalian cells, (3) to establish correlations between mutagenicity, aromaticity, and boiling point range of coal liquids, and (4) to identify the chemical classes which are likely to be responsible for the mutagenic activity of gasification products. Four of the seven samples tested so far failed to demonstrate any mutagenic activity under any conditions tested. Those samples were SHELL[number sign]830331, MG-122IBP-420[degree]F, MG-122 420--720[degree]F, and MG-122 720[degree]F+. Table 1 summarizes the results from all samples tested in DMSO and Tween 80. When solvated in DMSO, MG-119 and MG-120 composite materials displayed slight, but ultimately insignificant, genotoxic activity on TA98 and TA1OO in the presence of S9. When Tween 80 was used as the solvent, MG-119 and MG-120 displayed slight, but significant, geno-toxic activity on TA98 with S9 (Figure 4). CTC[number sign]11 in DMSO displayed significant genotoxic activity on both TA98 and TA1OO with and without S9. The activity was higher on TA98 than TA100, and higher with S9 than without, primarily indicating the presence of indirect-acting frameshift mutagen. The results of the testing on CTC[number sign]11 were similar for both solvents, DMSO and Tween 80 (Table 2).

  7. Toxicity studies of mild gasification products

    SciTech Connect

    Ong, T.M.; Whong, W.Z.; Ma, J.; Zhong, B.Z.; Bryant, D.

    1992-11-01

    The objectives of this project are: (1) to perform mutagenicity studies with the Ames Salmonella/microsomal assay system on coal liquids produced by mild gasification from different coals and/or processing conditions, (2) to determine whether coal liquids which are mutagenic to bacteria are also genotoxic to mammalian cells, (3) to establish correlations between mutagenicity, aromaticity, and boiling point range of coal liquids, and (4) to identify the chemical classes which are likely to be responsible for the mutagenic activity of gasification products. Four of the seven samples tested so far failed to demonstrate any mutagenic activity under any conditions tested. Those samples were SHELL{number_sign}830331, MG-122IBP-420{degree}F, MG-122 420--720{degree}F, and MG-122 720{degree}F+. Table 1 summarizes the results from all samples tested in DMSO and Tween 80. When solvated in DMSO, MG-119 and MG-120 composite materials displayed slight, but ultimately insignificant, genotoxic activity on TA98 and TA1OO in the presence of S9. When Tween 80 was used as the solvent, MG-119 and MG-120 displayed slight, but significant, geno-toxic activity on TA98 with S9 (Figure 4). CTC{number_sign}11 in DMSO displayed significant genotoxic activity on both TA98 and TA1OO with and without S9. The activity was higher on TA98 than TA100, and higher with S9 than without, primarily indicating the presence of indirect-acting frameshift mutagen. The results of the testing on CTC{number_sign}11 were similar for both solvents, DMSO and Tween 80 (Table 2).

  8. [Study on the regulation of autophagy against anticancer drugs' toxicity].

    PubMed

    Lou, Xiao-e; Zhu, Yi; He, Qiao-jun

    2016-01-01

    Autophagy is a crucial biological process in eukaryotes, which is involved in cell growth, survival and energy metabolism. It has been confirmed that autophagy mediates toxicity of anticancer drugs, especially in heart, liver and neuron. It is important to understand the function and mechanism of autophagy in anticancer drugs-induced toxicity. Given that autophagy is a double-edged sword in the maintenance of the function of heart, liver and neuron, the autophagy-mediated toxicity are very complicated in the body. We provide a review on the concept of autophagy and current status about autophagy-mediated toxicity of anticancer drugs. The knowledge is crucial in the basic study of anticancer drugs-induced toxicity, and provides some strategies for the development of alleviating the toxicity of anticancer drugs. PMID:27405158

  9. Harmonization of animal clinical pathology testing in toxicity and safety studies. The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing.

    PubMed

    Weingand, K; Brown, G; Hall, R; Davies, D; Gossett, K; Neptun, D; Waner, T; Matsuzawa, T; Salemink, P; Froelke, W; Provost, J P; Dal Negro, G; Batchelor, J; Nomura, M; Groetsch, H; Boink, A; Kimball, J; Woodman, D; York, M; Fabianson-Johnson, E; Lupart, M; Melloni, E

    1996-02-01

    Ten scientific organizations formed a joint international committee to provide expert recommendations for clinical pathology testing of laboratory animal species used in regulated toxicity and safety studies. For repeated-dose studies in rodent species, clinical pathology testing is necessary at study termination. Interim study testing may not be necessary in long-duration studies provided that it has been done in short-duration studies using dose levels not substantially lower than those used in the long-duration studies. For repeated-dose studies in nonrodent species, clinical pathology testing is recommended at study termination and at least once at an earlier interval. For studies of 2 to 6 weeks in duration in nonrodent species, testing is also recommended within 7 days of initiation of dosing, unless it compromises the health of the animals. If a study contains recovery groups, clinical pathology testing at study termination is recommended. The core hematology tests recommended are total leukocyte (white blood cell) count, absolute differential leukocyte count, erythrocyte (red blood cell) count, evaluation of red blood cell morphology, platelet (thrombocyte) count, hemoglobin concentration, hematocrit (or packed cell volume), mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. In the absence of automated reticulocyte counting capabilities, blood smears from each animal should be prepared for reticulocyte counts. Bone marrow cytology slides should be prepared from each animal at termination. Prothrombin time and activated partial thromboplastin time (or appropriate alternatives) and platelet count are the minimum recommended laboratory tests of hemostasis. The core clinical chemistry tests recommended are glucose, urea nitrogen, creatinine, total protein, albumin, calculated globulin, calcium, sodium, potassium, total cholesterol, and appropriate hepatocellular and hepatobiliary tests. For hepatocellular

  10. SOURCE ASSESSMENT: TEXTILE PLANT WASTEWATER TOXICS STUDY, PHASE II

    EPA Science Inventory

    The report gives results of a study concerned with BATEA for the textile manufacturing industry. The level of removal of specific toxic pollutants and toxicity (measured by results of bioassays) attained by selected tertiary systems treating secondary effluents from textile plant...

  11. MOLECULAR CONNECTIVITY STUDY OF PHENOLS AND THEIR TOXICITY TO FISH

    EPA Science Inventory

    A set of 25 substituted phenols have been examined in a QSAR study of their toxicity to fathead minnows, Pimephales promelas. The acute toxicities were measured in a flow-through system over a 96 hr. period as lethal concentration to kill 50 percent of the population, LC50. The n...

  12. ACUTE AND CHRONIC TOXICITY STUDIES WITH MONOCHLOROBENZENE IN RAINBOW TROUT

    EPA Science Inventory

    The toxicity of monochlorobenzene (CB) was investigated in rainbow trout following acute intraperitoneal (i.p.) administration and chronic exposure via the water in a continuously flowing system for 15 or 30 days. In the acute study overt toxicity and hepatotoxicity was monitored...

  13. Distribution of radio-labeled N-Acetyl-L-Cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage.

    PubMed

    Arfsten, Darryl P; Johnson, Eric W; Wilfong, Erin R; Jung, Anne E; Bobb, Andrew J

    2007-01-01

    were measured in the skin and kidney in association with repeat administration of 1,200 mg/kg NAC. Glutathione peroxidase (GxP) activity was increased in the skin, kidney, and liver suggesting that oxidative stress was occurring in these tissues in response to repeat dosing with NAC. Overall, the results of this study present the possibility that NAC could provide some benefit in preventing or reducing toxicity related to exposure to chemical irritants (particularly sulfur mustard) in some tissues by increasing tissue NAC and/or cysteine levels, GSH concentrations, and GST activity. However, follow-on studies in animals are needed to confirm that oral administration of single and multiple doses of NAC can significantly reduce skin, eye, and lung toxicity associated with sulfur mustard exposure. The finding that GxP activity is elevated, albeit transiently, following repeat administration of NAC suggests that repeat administration of NAC may induce oxidative stress in some tissues and further studies are needed to confirm this finding. PMID:17612979

  14. Pulmonary Toxicity Studies of Lunar Dusts in Rodents

    NASA Technical Reports Server (NTRS)

    Lam, Chiu-wing; James, John T.; Taylor, Larry

    2008-01-01

    NASA will build an outpost on the lunar surface for long-duration human habitation and research. The surface of the Moon is covered by a layer of fine, reactive dust, and the living quarters in the lunar outpost are expected to be contaminated by lunar dust. NASA established the Lunar Airborne Dust Toxicity Advisory Group (LADTAG) to evaluate the risk of exposure to the dust and to establish safe exposure limits for astronauts working in the lunar habitat. Because the toxicity of lunar dust is not known, LADTAG has recommended investigating its toxicity in the lungs of laboratory animals. After receiving this recommendation, NASA directed the JSC Toxicology Laboratory to determine the pulmonary toxicity of lunar dust in exposed rodents. The rodent pulmonary toxicity studies proposed here are the same as those proposed by the LADTAG. Studies of the pulmonary toxicity of a dust are generally done first in rodents by intratracheal instillation (ITI). This toxicity screening test is then followed by an inhalation study, which requires much more of the test dust and is labor intensive. We succeeded in completing an ITI study on JSC-1 lunar dust simulant in mice (Lam et al., Inhalation Toxicology 14:901-916, 2002, and Inhalation Toxicology 14: 917-928, 2002), and have conducted a pilot ITI study to examine the acute toxicity of an Apollo lunar (highland) dust sample. Preliminary results obtained by examining lung lavage fluid from dust-treated mice show that lunar dust was somewhat toxic (more toxic than TiO2, but less than quartz dust). More extensive studies have been planned to further examine lung lavage fluid for biomarkers of toxicity and lung tissues for histopathological lesions in rodents exposed to aged and activated lunar dust samples. In these studies, reference dusts (TiO2 and quartz) of known toxicities and have industrial exposure limits will be studied in parallel so the relative toxicity of lunar dust can be determined. The ITI results will also be

  15. Studies on the mechanism of benzene toxicity.

    PubMed Central

    Snyder, R; Dimitriadis, E; Guy, R; Hu, P; Cooper, K; Bauer, H; Witz, G; Goldstein, B D

    1989-01-01

    Using the 59Fe uptake method of Lee et al. it was shown that erythropoiesis in female mice was inhibited following IP administration of benzene, hydroquinone, p-benzoquinone, and muconaldehyde. Toluene protected against the effects of benzene. Coadministration of phenol plus either hydroquinone or catechol resulted in greatly increased toxicity. The combination of metabolites most effective in reducing iron uptake was hydroquinone plus muconaldehyde. We have also shown that treating animals with benzene leads to the formation of adducts of bone marrow DNA as measured by the 32P-postlabeling technique. PMID:2792049

  16. Study on wastewater toxicity using ToxTrak™ method.

    PubMed

    Liwarska-Bizukojc, Ewa; Ślęzak, Radoslaw; Klink, Małgorzata

    2016-05-01

    ToxTrak™ method is an analytical tool for the measurement of toxicity of drinking water, wastewater and natural water. It is based upon the estimation of the inhibitive effect on bacterial respiration processes. The main aim of this work was to test the applicability of ToxTrak™ method in the assessment of wastewater toxicity in a full-scale WWTP in Poland. In order to achieve it, the study was divided into two parts. First, the validation of ToxTrak™ method was performed. Second, wastewater toxicity was monitored in the long- and short-term campaigns. Validation of ToxTrak™ method revealed that the indigenous biomass (mixed cultures of activated sludge microorganisms) was more sensitive than Escherichia coli for both materials (wastewater and phenol) tested. The values of degree of inhibition determined for phenol towards indigenous biomass and E. coli were close to each other, and no statistically significant difference between them was found. It confirmed the reliability of the results obtained with the help of ToxTrak™ test. The toxicity of the effluent was always lower than that of the influent and the linear correlation between them was found. Despite, the decrease of wastewater toxicity in the WWTP, the effluents were ranked as toxic or highly toxic according to the classification of wastewater based upon the acute toxicity. PMID:26832868

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

    PubMed

    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. PMID:11559561

  18. Pulmonary Toxicity Studies of Lunar Dusts in Rodents

    NASA Technical Reports Server (NTRS)

    Lam, Chiu-wing; James, John T.

    2009-01-01

    NASA will build an outpost on the lunar surface for long-duration human habitation and research. The surface of the Moon is covered by a layer of fine, reactive dust, and the living quarters in the lunar outpost are expected to be contaminated by lunar dust. Because the toxicity of lunar dust is not known, NASA has tasked its toxicology laboratory to evaluate the risk of exposure to the dust and to establish safe exposure limits for astronauts working in the lunar habitat. Studies of the pulmonary toxicity of a dust are generally done first in rodents by intratracheal/intrapharyngeal instillation. This toxicity screening test is then followed by an inhalation study, which requires much more of the test dust and is labor intensive. Preliminary results obtained by examining lung lavage fluid from dust-treated mice show that lunar dust was somewhat toxic (more toxic than TiO2, but less than quartz dust). More extensive studies are in progress to further examine lung lavage fluid for biomarkers of toxicity and lung tissues for histopathological lesions in rodents exposed to aged and activated (ground) lunar dust samples. In these studies, reference dusts (TiO2 and quartz) of known toxicities and have industrial exposure limits will be studied in parallel so the relative toxicity of lunar dust can be determined. The results from the instillation studies will be useful for choosing exposure concentrations for the animal inhalation study. The animal inhalation exposure will be conducted with lunar dust simulant prior to the study with the lunar dust. The experiment with the simulate will ensure that the study techniques used with actual lunar dust will be successful. The results of instillation and inhalation studies will reveal the toxicological risk of exposures and are essential for setting exposure limits on lunar dust for astronauts living in the lunar habitat.

  19. Acute and chronic toxicity studies with monochlorobenzene in rainbow trout

    USGS Publications Warehouse

    Dahlich, G.M.; Larson, R.E.; Gingerich, W.H.

    1982-01-01

    The toxicity of monochlorobenzene (CB) was investigated in rainbow trout following acute intraperitoneal (i.p.) administration and chronic exposure via the water in a continuously flowing system for 15 or 30 days. In the acute study overt toxicity and hepatotoxicity were monitored over a 96-h time period. Variables measured to assess toxicity included weight changes, liver weight to body weight ratios, behavioral changes, alanine aminotransferase activity (GPT), sulfobromophthalein (BSP) retention, total plasma protein concentration and liver histopathology. In the chronic study the same measures of toxicity were followed as well as food consumption and alkaline phosphatase (AP) activity. Upon acute i.p. exposure the toxicant (9.8 mmol/kg) caused behavioral changes in the fish which were consistent with the known anesthetic properties of CB in mammals. Elevations in BSP retention and GPT activity, and histopathology indicated that CB was hepatotoxic in fish. The LC50 of CB in trout exposed via the water for 96 h was 4.7 mg/l. Chronic exposure of trout to 2 or 3 mg/l CB resulted in similar behavioral changes as seen in the acute study. Liver toxicity was evident from elevations in GPT activity. BSP retention and AP activity appeared to be affected by the nutritional status of the trout as much as by the CB treatment. After 30 days of exposure to 3 mg/l CB, trout appeared to have developed some tolerance to the toxic effects.

  20. Sub-acute toxicity evaluation of an aqueous extract of Labisia pumila, a Malaysian herb.

    PubMed

    Singh, G D; Ganjoo, M; Youssouf, M S; Koul, A; Sharma, R; Singh, S; Sangwan, P L; Koul, S; Ahamad, D B; Johri, R K

    2009-10-01

    Labisia pumila (Myrsinaceae), is a popular herb among the women in Malaysia known locally as "Kacip Fatimah". Recently many nutraceutical products containing the powdered or extracted parts of the plant have become available for women's health care. However no evaluation of the effect of the repeated dosing of any herbal product of this plant had been undertaken prior to a 28-day sub-acute study presented in this report. The results showed that a dose of 50mg/kg of an aqueous extract of L. pumila corresponded to no-adverse-effect-level (NOAEL), whereas higher doses were associated with some toxicity concerns. PMID:19654032

  1. Toxic Hazards Research Unit annual report, 1990. Annual report No. 27 (Final), 1 Oct 89-15 Nov 90

    SciTech Connect

    Wall, H.G.; Vinegar, A.; Kinkead, E.R.

    1990-12-01

    This report presents a review of the activities of the Toxic Hazards Research Unit for the period of 1 October 1989 through 15 November 1990. Research activities focused on toxicity evaluations of aerospace and naval chemicals to include aircraft fuels and rocket fuels, hydraulic fluids, ground water contaminants, and chemical defense simulants. There was increased utilization of multidisciplinary efforts for quantitative toxicology studies and the development and validation of physiologically based pharmacokinetic models for predicting toxicity responses. The General Toxicology Laboratory conducted acute studies, toxicokinetic studies, repeated-dose studies, and subchronic inhalation studies to include a 90-day continuous inhalation study using the Thomas Domes. The development and characterization of a unique high pressure aerosol generator was a significant adjunct benefitting the study conducted in the Thomas Domes.

  2. LAKE MICHIGAN URBAN AIR TOXICS STUDY DESIGN AND OVERVIEW

    EPA Science Inventory

    During the summer of 1991, an air toxics monitoring program was conducted in the lower Lake Michigan area. his study was designed to take advantage of the extensive meteorological and oxidant database being generated concurrently by the Lake Michigan Ozone Study (LMOS). ntegrated...

  3. Historical control data on developmental toxicity studies in rodents.

    PubMed

    Ema, Makoto; Endoh, Katsumi; Fukushima, Ryou; Fujii, Sakiko; Hara, Hiroaki; Hirata-Koizumi, Mutsuko; Hirose, Akihiko; Hojo, Hitoshi; Horimoto, Masao; Hoshino, Nobuhito; Hosokawa, Yoshinori; Imai, Yukari; Inada, Hiroshi; Inawaka, Kunifumi; Itoh, Keiichi; Katsumata, Yoshihiro; Izumi, Hiroyuki; Kato, Hirohito; Maeda, Maki; Matsumoto, Kiyoshi; Matsuo, Seiki; Matsuoka, Toshiki; Matsuura, Ikuo; Mineshima, Hiroshi; Miwa, Yoji; Nakano, Nao; Naya, Masato; Noyori, Hiroko; Ohta, Takafumi; Oku, Harutaka; Ono, Atsushi; Shimizu, Tatsuya; Shimomura, Kazuhiro; Takakura, Ikuro; Tanaka, Ryota; Tateishi, Taishi; Tominaga, Yuko; Uesugi, Tohru; Urakawa, Chizuru; Yabe, Kaoru; Yamashita, Akihito; Yamauchi, Toshiaki; Yokoi, Ryohei

    2014-08-01

    Historical control data on rodent developmental toxicity studies, performed between 1994 and 2010, were obtained from 19 laboratories in Japan, including 10 pharmaceutical and chemical companies and nine contract research organizations. Rats, mice, and hamsters were used for developmental toxicity studies. Data included maternal reproductive findings at terminal cesarean sections and fetal findings including the spontaneous incidences of external, visceral, and skeletal anomalies. No noticeable differences were observed in maternal reproductive data between laboratories. Inter-laboratory variations in the incidences of fetuses with anomalies appeared to be due to differences in the selection of observation parameters, observation criteria, classification of the findings, and terminology of fetal alterations. Historical control data are useful for the appropriate interpretation of experimental results and evaluation of the effects of chemical on reproductive and developmental toxicities. PMID:24666250

  4. Analysis of public oral toxicity data from REACH registrations 2008-2014.

    PubMed

    Luechtefeld, Thomas; Maertens, Alexandra; Russo, Daniel P; Rovida, Costanza; Zhu, Hao; Hartung, Thomas

    2016-01-01

    The European Chemicals Agency, ECHA, made available a total of 13,832 oral toxicity studies for 8,568 substances up to December 2014. 75% of studies were from the retired OECD Test Guideline 401 (11% TG 420, 11% TG 423 and 1.5% TG 425). Concordance across guidelines, evaluated by comparing LD50 values ≥ 2000 or < 2000 mg/kg body weight from chemicals tested multiple times between different guidelines, was at least 75% and for their own repetition more than 90%. In 2009, Bulgheroni et al. created a simple model for predicting acute oral toxicity using no observed adverse effect levels (NOAEL) from 28-day repeated dose toxicity studies in rats. This was reproduced here for 1,625 substances. In 2014, Taylor et al. suggested no added value of the 90-day repeated dose oral toxicity test given the availability of a low 28-day study with some constraints. We confirm that the 28-day NOAEL is predictive (albeit imperfectly) of 90-day NOAELs, however, the suggested constraints did not affect predictivity. 1,059 substances with acute oral toxicity data (268 positives, 791 negatives, all Klimisch score 1) were used for modeling: The Chemical Development Kit was used to generate 27 molecular descriptors and a similarity-informed multilayer perceptron showing 71% sensitivity and 72% specificity. Additionally, the k-nearest neighbors (KNN) algorithm indicated that similarity-based approaches alone may be poor predictors of acute oral toxicity, but can be used to inform the multilayer perceptron model, where this was the feature with highest information value. PMID:26863198

  5. [Cadmium toxicity: summary of personal studies].

    PubMed

    Lauwerys, R; Buchet, J P; Roels, H; Bernard, A

    1982-01-01

    Occupational and environmental exposure to cadmium leads to a progressive and almost irreversible accumulation of the metal in the body. The epidemiological and experimental studies carried out by the authors allow them to draw the following conclusions: 1) the kidney is usually the critical organ i.e. the organ exhibiting the first signs of adverse effects following long term moderate exposure to cadmium by inhalation or by ingestion. 2) Cadmium interferes not only with the tubular reabsorption process(es) for low molecular weight proteins (e.g. beta 2 . microglobulin, retinol binding protein) but also with the glomerular or tubular mechanism determining the excretion of high molecular weight proteins (e.g. albumin, transferrin). Both types of proteinuria may occur independently. 3) The renal functional disturbances induced by cadmium and compatible not only with a tubular dysfunction but also a glomerular dysfunction. 4) The early detection of renal disturbances induced by cadmium should not rely only on the determination of total proteinuria but necessitates the analysis in urine of at least one low molecular weight protein (beta 2-microglobulin or retinol binding protein) and one high molecular weight protein (albumin). 5) Before the occurrence of renal dysfunction and providing the intensity of exposure to cadmium is moderate, urinary cadmium reflects mainly the body burden whereas blood cadmium reflects mainly the last few months exposure. 6) In adult male workers occupationally exposed to cadmium, the critical concentration of cadmium in the renal cortex is in the order of 200 ppm. The corresponding critical urinary level is approximately 10 micrograms/g creatinine. The critical level of cadmium in the renal cortex is not reached if the exposure is kept at a level where cadmium in blood does no exceed 1 microgram/100 ml. 7) Comparison of literature data on current exposure of the general population to cadmium and the critical exposure level indicates that

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

    PubMed Central

    Lim, Kean Tatt; Lim, Vuanghao; Chin, Jin Han

    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. PMID:23593574

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

    PubMed

    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

  8. ECVAM's ongoing activities in the area of acute oral toxicity.

    PubMed

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

    2009-12-01

    The 7th Amendment of the Cosmetics Directive (2003/15/EC) set up timelines for banning animal testing and marketing of cosmetic products and their ingredients tested on animals. For most of the human health effects, including acute toxicity, the deadline for these bans was in March 2009. Moreover, the new Regulation EC 1907/2006 on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) provided a strong impetus towards the application of alternative approaches to reduce the number of animals used for toxicological testing. Therefore, the European Centre for the Validation of Alternative Methods (ECVAM) is currently putting considerable effort into developing and validating alternative methods in the field of acute toxicity. The main activities in this area include: (1) the Integrated Project ACuteTox, funded by the European Commission's 6th Framework Programme in 2005 with the aim to develop and pre-validate a testing strategy to fully replace acute oral toxicity testing in vivo; (2) a follow-up validation study to assess the predictive capacity of the validated BALB/3T3 Neutral Red Uptake cytotoxicity assay to discriminate between toxic/hazardous (LD(50)<2,000 mg/kg) substances and substances not classified for acute toxicity (LD(50)>2,000 mg/kg); (3) an approach to identify compounds with LD(50)>2,000 mg/kg using information from 28-days repeated dose toxicity studies. PMID:19591916

  9. PROSPECTIVE PREGNANCY STUDY DESIGNS FOR ASSESSING REPRODUCTIVE AND DEVELOPMENTAL TOXICANTS

    EPA Science Inventory

    Prospective Pregnancy Study Designs for Assessing Reproductive and Developmental Toxicants
    Germaine M. Buck,1 Courtney D. Johnson,1 Joseph Stanford,2 Anne Sweeney,3 Laura Schieve,4 John Rockett,5 Sherry G. Selevan,6 Steve Schrader 7

    Abstract
    The origin of successfu...

  10. Malaria in cynomolgus monkeys used in toxicity studies in Japan.

    PubMed

    Ohta, Etsuko; Nagayama, Yuko; Koyama, Naoki; Kakiuchi, Dai; Hosokawa, Satoru

    2016-01-01

    Plasmodium spp. protozoa cause malaria and are known to infect humans and a variety of animal species including macaque monkeys. Here we report both our experience with malaria recrudescence in cynomolgus monkeys (Macaca fascicularis) in a toxicity study and the results of a survey on Plasmodium infection in cynomolgus monkeys imported to Japan for laboratory use. A cynomolgus monkey from the toxicity study presented with severe anemia and Plasmodium protozoa in erythrocytes on a thin blood smear and was subsequently diagnosed with symptomatic malaria. In this animal, congestion and accumulation of hemozoin (malaria pigment) in macrophages were noted in the enlarged and darkly discolored spleen. As a follow-up for the experience, spleen sections from 800 cynomolgus monkeys in toxicity studies conducted between 2003 and 2013 were retrospectively examined for hemozoin deposition as a marker of Plasmodium infection. The origin of the animals included Cambodia, China, Indonesia, and Vietnam. Hemozoin deposition was confirmed in 44% of all examined monkeys. Monkeys from Indonesia showed the highest incidence of hemozoin deposition (approx. 80%). A high prevalence of Plasmodium infection in laboratory monkeys was also confirmed with polymerase chain reaction (PCR) by using Plasmodium genus-specific primers. Although Japan is not a country with endemic malaria, it is important to be aware of the prevalence and potential impact of background infection with Plasmodium spp. and recrudescence of symptomatic malaria in imported laboratory monkeys on pharmaceutical toxicity studies. PMID:26989299

  11. Pulmonary Toxicity Studies of Lunar Dusts in Rodents

    NASA Technical Reports Server (NTRS)

    Lam, C.-W.; James, J. T.; Taylor, L.; Zeidler-Erdely, P. C.; Castranova, V.

    2009-01-01

    NASA will build an outpost on the Moon for prolonged human habitation and research. The lunar surface is covered by a layer of fine, reactive dust. Astronauts on the Moon will go in and out of the base for various activities, and will inevitably bring some dust into the living quarters. Depressurizing the airlock so that astronauts can exit for outdoor activities could also bring dust inside the airlock to the habitable area. Concerned about the potential health effects on astronauts exposed to airborne lunar dust, NASA directed the JSC Toxicology Laboratory to determine the pulmonary toxicity of lunar dust. The toxicity data also will be needed by toxicologists to establish safe exposure limits for astronauts residing in the lunar habitat and by environmental engineers to design an appropriate dust mitigation strategy. We conducted a study to examine biomarkers of toxicity (inflammation and cytotoxicity) in lung lavage fluids from mice intrapharyngeally instilled with lunar dust samples; we also collected lung tissue from the mice for histopathological examination 3 months after the dust instillation. Reference dusts (TiO2 and quartz) having known toxicities and industrial exposure limits were studied in parallel with lunar dust so that the relative toxicity of lunar dust can be determined. A 6-month histopathology study has been planned. These instillation experiments will be followed by inhalation studies, which are more labor intensive and technologically difficult. The animal inhalation studies will be conducted first with an appropriate lunar dust simulant to ensure that the exposure techniques to be used with actual lunar dust will be successful. The results of these studies collectively will reveal the toxicological risk of exposures and enable us to establish exposure limits on lunar dust for astronauts living in the lunar habitat.

  12. Some scientific landmarks of the MIT radium toxicity studies

    SciTech Connect

    Maletskos, C.J.

    1996-12-31

    Until the recent forced termination of the studies on radium toxicity, more than six decades of investigation and research have been devoted to them. These studies involve {approximately}2400 subjects who were exposed to long-term internally deposited radium [high linear energy transfer (LET)], whose health status was evaluated in great detail and whose radiation dosimetry was based on measurements of their actual radium body burdens. The quality and usefulness of these studies are, therefore, in sharp contrast to other human radiation-exposure studies that involve instantaneous or somewhat protracted external low-LET exposures and inferred radiation dose, as in the atomic-bomb survivor studies. As a consequence of national news in 1932 concerning the gruesome death of a prominent Pittsburgh businessman and sportsman, Robley D. Evans became involved with radium toxicity, and its study became an important project when he joined the faculty of the Massachusetts Institute of Technology physics department and set up the interdisciplinary Radioactivity Center.

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

    PubMed

    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. PMID:25857839

  14. Ozonation of ibuprofen: a degradation and toxicity study.

    PubMed

    Quero-Pastor, M J; Garrido-Perez, M C; Acevedo, A; Quiroga, J M

    2014-01-01

    This paper presents the results obtained in the degradation of ibuprofen by ozonation. This study aims to evaluate the degradation of ibuprofen by ozonation once the operating variables have been optimized, investigating the degradation and degradation efficiency of the compound and assessing the toxic effect of ibuprofen and of the intermediate compounds generated during oxidative treatment. Work was carried out to optimize the four operating variables: pH, conductivity, hydraulic retention time and the use of a maze of pipes to enhance contact between the ozone and the drug. All the trials were conducted in a purpose-built pilot-scale reactor. Analyses of the compound were carried out after solid-liquid phase extraction on high resolution liquid chromatography (HPLC). Working under optimal operating conditions (pH=9, HRT=20 min and 12 ± 2 gN/m(3)), a degradation value of 99% was obtained, although degradation efficiency or mineralization of the compound was not achieved. The toxicity of ibuprofen and its intermediate compounds formed during the oxidative process was likewise studied. This toxicity was found to increase with increasing initial concentrations of the compound, with the intermediate compounds thus formed being more toxic than the starting compound. PMID:23988743

  15. ILSI/HESI Maternal Toxicity Workshop Summary: Maternal Toxicity and its Impact on Study Design and Data Interpretation

    EPA Science Inventory

    Workshops on maternal toxicity were held at the annual meetings of the Society of Toxicology, Teratology Society, and European Teratology Society in 2009. Prior to a general discussion of the issues involved with maternal toxicity and its impact on study design and data interpret...

  16. In vivo toxicity studies of europium hydroxide nanorods in mice

    SciTech Connect

    Patra, Chitta Ranjan Abdel Moneim, Soha S.; Wang, Enfeng; Dutta, Shamit; Patra, Sujata; Eshed, Michal; Mukherjee, Priyabrata; Gedanken, Aharon; Shah, Vijay H.; Mukhopadhyay, Debabrata

    2009-10-01

    Lanthanide nanoparticles and nanorods have been widely used for diagnostic and therapeutic applications in biomedical nanotechnology due to their fluorescence and pro-angiogenic properties to endothelial cells, respectively. Recently, we have demonstrated that europium (III) hydroxide [Eu{sup III}(OH){sub 3}] nanorods, synthesized by the microwave technique and characterized by several physico-chemical techniques, can be used as pro-angiogenic agents which introduce future therapeutic treatment strategies for severe ischemic heart/limb disease, and peripheral ischemic disease. The toxicity of these inorganic nanorods to endothelial cells was supported by several in vitro assays. To determine the in vivo toxicity, these nanorods were administered to mice through intraperitoneal injection (IP) everyday over a period of seven days in a dose dependent (1.25 to 125 mg kg{sup -1} day{sup -1}) and time dependent manner (8-60 days). Bio-distribution of europium elements in different organs was analyzed by inductively coupled plasma mass spectrometry (ICPMS). Short-term (S-T) and long-term (L-T) toxicity studies (mice euthanized on days 8 and 60 for S-T and L-T, respectively) show normal blood hematology and serum clinical chemistry with the exception of a slight elevation of liver enzymes. Histological examination of nanorod-treated vital organs (liver, kidney, spleen and lungs) showed no or only mild histological changes that indicate mild toxicity at the higher dose of nanorods.

  17. In Vivo Toxicity Studies of Europium Hydroxide Nanorods in Mice

    PubMed Central

    Patra, Chitta Ranjan; Abdel Moneim, Soha S.; Wang, Enfeng; Dutta, Shamit; Patra, Sujata; Eshed, Michal; Mukherjee, Priyabrata; Gedanken, Aharon; Shah, Vijay H; Mukhopadhyay, Debabrata

    2009-01-01

    Lanthanide nanoparticles and nanorods have been widely used for diagnostic and therapeutic applications in biomedical nanotechnology due to their fluorescence properties and pro-angiogenic to endothelial cells, respectively. Recently, we have demonstrated that europium (III) hydroxide [EuIII(OH)3] nanorods, synthesized by the microwave technique and characterized by several physico-chemical techniques, can be used as pro-angiogenic agents which introduce future therapeutic treatment strategies for severe ischemic heart/limb disease, and peripheral ischemic disease. The toxicity of these inorganic nanorods to endothelial cells was supported by several in vitro assays. To determine the in vivo toxicity, these nanorods were administered to mice through intraperitoneal injection (IP) everyday over a period of seven days in a dose dependent (1.25 to 125 mgKg−1day−1) and time dependent manner (8–60 days). Bio-distribution of europium elements in different organs was analyzed by inductively coupled plasma mass spectrometry (ICPMS). Short-term (S-T) and long-term (L-T) toxicity studies (mice sacrificed on day 8 and 60 for S-T and L-T, respectively) show normal blood hematology and serum clinical chemistry with the exception of a slight elevation of liver enzymes. Histological examination of nanorod treated vital organs (liver, kidney, spleen and lungs) showed no or only mild histological changes that indicate mild toxicity at the higher dose of nanorods. PMID:19616569

  18. Metabolomics and its application to studying metal toxicity.

    PubMed

    Booth, Sean C; Workentine, Matthew L; Weljie, Aalim M; Turner, Raymond J

    2011-11-01

    Here we explain the omics approach of metabolomics and how it can be applied to study a physiological response to toxic metal exposure. This review aims to educate the metallomics field to the tool of metabolomics. Metabolomics is becoming an increasingly used tool to compare natural and challenged states of various organisms, from disease states in humans to toxin exposure to environmental systems. This approach is key to understanding and identifying the cellular or biochemical targets of metals and the underlying physiological response. Metabolomics steps are described and overviews of its application to metal toxicity to organisms are given. As this approach is very new there are yet only a small number of total studies and therefore only a brief overview of some metal metabolomics studies is described. A frank critical evaluation of the approach is given to provide newcomers to the method a clear idea of the challenges and the rewards of applying metabolomics to their research. PMID:21922109

  19. Toxicity study of isolated polypeptide from wool hydrolysate.

    PubMed

    Li, Jiashen; Li, Yi; Zhang, Yu; Liu, Xuan; Zhao, Zheng; Zhang, Jing; Han, Yanxia; Zhou, Dangxia

    2013-07-01

    The cytotoxicity of wool polypeptide has been evaluated by both cell and animal models. Wool was dissolved in sodium hydroxide solution, the pH value of the solution was adjusted to 5.55 and the precipitate was harvested as wool polypeptide. The spray-dried polypeptide was collected as powders and characterized by SEM, FTIR and TG-DSC. The cell culturing results showed that wool polypeptide had no obvious negative effect on cell viability in vitro. Both acute oral toxicity and subacute 30-day oral toxicology studies showed that wool polypeptide had no influence on body weight, feed consumption, blood chemistry, and hematology at any dose levels. There were no treatment related findings on gross or detailed necroscopy, organ weights, organ/body weight ratios and histology. Our study indicated the absence of toxicity in wool polypeptide and supported its safe use as a food ingredient or drug carrier. PMID:23597444

  20. Multiple Air-Toxics Exposure Study Working Paper Number 3. Urban air-toxics exposure model: development and application

    SciTech Connect

    Not Available

    1988-11-01

    The South Coast Air Quality Management District of California completed a Multiple Air Toxics Exposure Study (MATES) that examines the additive risk from a number of air toxics on an urban area. The project, though partially funded by EPA, is an example of how a State or local agency may approach assessing their local air-toxics risks as is encouraged by EPA's Urban Air Toxics Program which results from EPA's Air Toxic Strategy. The report is a summary of the methods used by the California agency. Though not intended as an endorsement of the entire contents of the report, EPA is reproducing their report (Working Paper Number 3) to benefit and encourage other agencies that may be contemplating such an assessment.

  1. Studies of embryo toxicity in rats and rabbits.

    PubMed

    Lorke, D; Machemer, L

    1975-01-01

    Embryo toxicity studies were carried out to investigate the effects of different doses of fluorescent whitening agents (FWAs) after oral administration to pregnant rats from the 6th to the 15th day of pregnancy and to rabbits from the 6th to the 18the day of pregnancy. In own studies two FWAs of the bis(triazinylamino or triazoly)stilbenedisulfonic acid type showed no embryo-toxic or teratogenic effect on wither species at daily doses up to 1000 mg/kg. Also the toxic dose to the mothers, 3000 mg/kg, given to rabbits in case of one FWA was without these effects. In the studies of KEPLINGER, et al. (Toxicol. Appl. Parmacol. 27: 494-506, 1974) a triazolylstilbenemonosulfonic acid derivative, two bis(triazinylamino)stilbenedisulfonic acid derivatives and a bis(sulfostyryl)diphenyl derivative had no terato-enic effect on rabbits when administered orally in doses of up to 30 mg/kg/day. PMID:1064542

  2. Haematological and immunological effects of repeated dose exposure of rats to integerrimine N-oxide from Senecio brasiliensis.

    PubMed

    Elias, Fabiana; Latorre, Andreia O; Pípole, Fernando; Haraguchi, Mitsue; Górniak, Silvana L; Hueza, Isis M

    2011-09-01

    This study is the first in the literature to focus attention on the possible immunotoxic effect of integerrimine N-oxide content in the butanolic residue (BR) of Senecio brasiliensis, a poisonous hepatotoxic plant that contains pyrrolizidine alkaloids (PAs). PAs have been reported as a pasture and food contaminant and as herbal medicine used worldwide and are responsible for poisoning events in livestock and human beings. After the plant extraction, BR extracted from Senecio brasiliensis was found to contain approximately 70% integerrimine N-oxide by elemental and spectral analyses ((1)H and (13)C NMR), which was administered to adult male Wistar Hannover rats at doses of 3, 6 and 9 mg/kg for 28 days. Body weight gain, food consumption, lymphoid organs, neutrophil analysis, humoural immune response, cellular immune response and lymphocyte analysis were evaluated. Our study showed that integerrimine N-oxide could promote an impairment in the body weight gain, interference with blood cell counts and a reducing T cell proliferative activity in rats; however, no differences in the neutrophil activities, lymphocytes phenotyping and humoural and cellular immune responses were observed. It is concluded that doses of integerrimine N-oxide here employed did not produce marked immunotoxic effects. PMID:21722699

  3. Misonidazole with dexamethasone rescue: an escalating dose toxicity study

    SciTech Connect

    Tanasichuk, H.; Urtasun, R.C.; Fulton, D.S.; Raleigh, J.

    1984-09-01

    Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, the authors reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. The authors are presently investigating the use of DEXA, with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO given in 9 equally divided doses over 3 weeks. DEXA is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M/sub 2/. One grade I PN occurred in the first four patients receiving 15.5 gm/M/sub 2/. Six additional patients were entered at this dose level and no further incidence of PN was observed.

  4. Photocatalytic degradation of rosuvastatin: analytical studies and toxicity evaluations.

    PubMed

    Machado, Tiele Caprioli; Pizzolato, Tânia Mara; Arenzon, Alexandre; Segalin, Jeferson; Lansarin, Marla Azário

    2015-01-01

    Photocatalytic degradation of rosuvastatin, which is a drug that has been used to reduce blood cholesterol levels, was studied in this work employing ZnO as catalyst. The experiments were carried out in a temperature-controlled batch reactor that was irradiated with UV light. Preliminary the effects of the photocatalyst loading, the initial pH and the initial rosuvastatin concentration were evaluated. The experimental results showed that rosuvastatin degradation is primarily a photocatalytic process, with pseudo-first order kinetics. The byproducts that were generated during the oxidative process were identified using nano-ultra performance liquid chromatography tandem mass spectrometry (nano-UPLC-MS/MS) and acute toxicity tests using Daphnia magna were done to evaluate the toxicity of the untreated rosuvastatin solution and the reactor effluent. PMID:25300021

  5. Histopathology of Incidental Findings in Beagles Used in Toxicity Studies

    PubMed Central

    Sato, Junko; Doi, Takuya; Wako, Yumi; Hamamura, Masao; Kanno, Takeshi; Tsuchitani, Minoru; Narama, Isao

    2012-01-01

    The purpose of our publication is to widely communicate the pictures of spontaneous findings occurring in beagles. Spontaneous arteritis occurs commonly in beagles. Frequent sites of arteritis are the heart, spleen, pancreas, epididymis and spinal cord. Morphological similarities between spontaneous and drug-induced arterial lesions may cause confusion when evaluating vascular toxicity of chemicals such as vasodilating agents. Focal and minimal inflammatory lesions are occasionally seen in the lung and may be associated with aspiration of food particles or of unknown causes. A cystic change with copious mucin production occurs occasionally in the mucosal epithelium of the gall bladder. Nesidioblastosis is seen rarely in the pancreas of beagles. C-cell complex and lymphocytic thyroiditis are common thyroid lesions. Spontaneous focal hypospermatogenesis and lobular Sertoli-cell-only seminiferous tubules occurring frequently in beagles must be distinguished from drug-induced damage of the seminiferous tubules in toxicity studies. The morphological differences of the female genital system in each cycle need to be understood; therefore, we present the normal features of the cyclic changes of the female genital organs. Further, we provide more information on spontaneous findings in beagles for exact diagnoses in toxicity studies. PMID:22481862

  6. Antithrombotic effect of repeated doses of the ethanolic extract of local olive (Olea europaea L.) leaves in rabbits.

    PubMed

    Dub, Abdallah M; Dugani, Aisha M

    2013-01-01

    The incidence of thromboembolic diseases is increasing, and they are a major cause of mortality and morbidity worldwide. Mediterranean diet is known for its high content of olive products, especially olive oil, which has known cardiovascular health benefits, including those on blood pressure, cholesterol level, and thrombogenesis. All previous animal and clinical studies investigating the beneficial antithrombotic effects of olives have focused on olive oil and a few on olive leaves (OLEs). In this study, the ethanolic extract of OLE was evaluated for its antithrombotic activity in the rabbit model of thrombosis induced by ligature of the vena cava and intravenous administration of tissue thromboplastin. Pre-treatment with 100 or 200 mg/kg per day of the ethanolic extract for 8 weeks significantly prolonged the prothrombin time (PT) in comparison to the control group (12.10 ± 0.35 sec and 14.38 ± 0.29 sec vs. 10.8 ± 0.32 sec, p < 0.05 and 0.001, respectively). In comparison to the control group, the same doses had no statistically significant effect on thrombus weight (16.85 ± 0.67 mg, 16.32 ± 0.35 mg, and 17.81 ± 0.75 mg; p = 0.18 and 0.06) or on activated partial thromboplastin time (APTT) (19.17 ± 0.33 sec, 19.12 ± 0.73 sec, and 18.97 ± 0.41 sec; p = 0.36 and 0.43, respectively). One important finding in this study concerns thrombus morphology. In the extract treatment groups, the thrombus was filament-like and did not adhere to blood vessel walls, whereas in the control group the thrombus was thick and almost completely occluded the vein. Therefore, these results suggest that OLE ethanolic extract can modify the extrinsic coagulation pathway as evidenced by the prolongation of PT and changes in thrombus morphology, enough to justify further research to evaluate its possible antithrombotic effects. PMID:23702352

  7. Adhesion of leukocytes to dermal endothelial cells is induced after single-dose, but reduced after repeated doses of UVA.

    PubMed

    Heckmann, M; Pirthauer, M; Plewig, G

    1997-12-01

    Approximately 20-50% of ultraviolet A (UVA) irradiation delivered to the skin surface may reach the human dermal microvascular endothelial cells (HDMEC) that play a pivotal role in cellular inflammatory tissue; however, the pathophysiologic role of HDMEC in UVA-induced skin changes is largely unknown. Based on previous in vivo and in vitro studies revealing UVA-induced expression of endothelial adhesion molecules, we studied isolated HDMEC under various conditions in order to further delineate the impact of UVA on these cells. The expression of cell adhesion molecules was determined by flow cytometry and the resulting changes of stable adhesion of leukocytes to endothelial cells were quantitated for granulocytes, lymphocytes, and monocytes using a newly developed multicellular adhesion assay. Additionally, antibody blocking experiments were performed to delineate the role of individual cell adhesion molecules in UVA-induced leukocyte adherence. High-dose polychromatic UVA (25 J per cm2, maximal emission at 375 nm) induced intercellular adhesion molecule-1 and E-selectin with different kinetics but correlating the adhesion of leukocyte subsets. This effect subsided, however, in the course of 3-6 daily applied UVA doses. Moreover, pro-inflammatory cytokine challenge by tumor necrosis factor-alpha and interleukin-1-alpha resulted in significantly weaker induction of intercellular adhesion molecule-1 and E-selectin in repeatedly UVA-exposed HDMEC. Differential quantitation of peripheral blood derived granulocytes, lymphocytes, and monocytes revealed reduced adhesion particularly of lymphocytes followed by monocytes and granulocytes compared with leukocyte adhesion to nonirradiated but cytokine-stimulated HDMEC. It is concluded that UVA substantially influences endothelial cell adhesion molecules expression and thus directly interferes with leukocyte adhesion to endothelial cells. Divergent UVA-induced effects in this respect can be attributed to the mode of UV exposure

  8. Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028 — For human safety in clinical study

    SciTech Connect

    Nishizato, Yohei; Imai, Satoki; Okahashi, Noriko; Yabunaka, Atsushi; Kunimatsu, Takeshi; Kikuchi, Kaoru; Yabuki, Masashi

    2014-05-01

    SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies. - Highlights: • SMP-028 inhibits neutral CEase more strongly than other steroidogenic enzymes in rats. • Inhibition of neutral CEase in rats by SMP-028 suppresses steroidogenesis in vivo. • SMP-028 does not inhibit neutral CEase in monkeys in vivo. • Steroidogenesis pathway in monkeys treated with SMP-028 was not suppressed. • SMP-028 may not inhibit LIPE in humans in vivo.

  9. SAR STUDY OF NASAL TOXICITY: LESSONS FOR MODELING SMALL TOXICITY DATASETS

    EPA Science Inventory

    Most toxicity data, particularly from whole animal bioassays, are generated without the needs or capabilities of structure-activity relationship (SAR) modeling in mind. Some toxicity endpoints have been of sufficient regulatory concern to warrant large scale testing efforts (e.g....

  10. Review of toxicity studies performed on an underground coal gasification condensate water

    SciTech Connect

    Barker, F.P.

    1987-09-01

    Three studies related to the toxicity of underground coal gasification (UCG) waters have bee conducted: (1) toxicity study of UCG water and its fractions as determined by the Microtox test, (2) toxicity study of biotreated UCG water as determined by the Microtox test, and (3) toxicity study of UCG water to macroinvertebrates. The results of these studies are summarized herein. The gas condensate water from the UCG process is extremely toxic as determined by assays with photoluminescent bacteria (Microtox), benthic (bottom-dwelling) macroinvertebrates (mayflies), and Daphnia magna (water flea). Microtox bioassays reveal that the toxic components of the water reside in both the organophilic and hydrophilic fractions, although the organophilic fraction is notably more toxic. A sequential treatment process reduced the toxicity of the UCG water, as measured by the Microtox test. Solvent extraction (to remove phenols) followed by ammonia stripping yielded a less toxic water. Additional treatment by activated sludge further reduced toxicity. Finally, the addition of powdered activated carbon to the activated sludge yielded the least toxic water. A bioassay technique was developed for lotic (running water) macroinvertebrates (Drunella doddsi and Iron longimanus). The toxicity results were compared with results from the traditional test animal, Daphnia magna. Short-term exposures to the UCG waters were more toxic to Daphnia magna than to Drunella doddsi or Iron longimanus, although the toxicity values begin to merge with longer test exposure. The greater toxicity seems to be related to a thinner exoskeleton. 26 refs., 2 figs., 6 tabs.

  11. Prospective pregnancy study designs for assessing reproductive and developmental toxicants.

    PubMed Central

    Buck, Germaine M; Lynch, Courtney D; Stanford, Joseph B; Sweeney, Anne M; Schieve, Laura A; Rockett, John C; Selevan, Sherry G; Schrader, Steven M

    2004-01-01

    The determinants of successful human reproduction and development may act as early as periconceptionally, underscoring the need to capture exposures during these critical windows when assessing potential toxicants. To identify such toxicants, couples must be studied longitudinally prior to conception without regard to a couple's ability to ascertain a clinically recognized pregnancy. We examined the utility and feasibility of prospective pregnancy study designs by conducting a systematic review of the literature to summarize relevant information regarding the planning, implementation, and success of previously published prospective pregnancy studies. Information concerning design elements and participation was abstracted from 15 eligible studies (from a total of 20 identified studies) using a standardized form. The primary author of each study was contacted to review our summary of their work and obtain missing information. Our findings confirm the ability to recruit women/couples from diverse populations using a variety of recruitment strategies. Among the studies we reviewed, 4-97% of eligible individuals were successfully contacted, with enrollment rates ranging from 42 to 100%. Length of follow-up varied from 3 to 12 months. A high percentage of women provided urine (57-98%) and blood (86-91%) specimens and most male partners (94-100%) provided semen samples. These data support the feasibility of this design. PMID:14698935

  12. An amphibian model for studies of developmental reproductive toxicity.

    PubMed

    Berg, Cecilia

    2012-01-01

    The developmental programming of the reproductive system is vulnerable to chemical exposure. It is therefore important to evaluate long-term consequences of early life-stage exposure to endocrine disrupting chemicals. The African clawed frog Xenopus tropicalis has several characteristics which facilitates studies of developmental reproductive toxicity. Here, I present a X. tropicalis test protocol, including study design, exposure regime, and endpoints for chemical disruption of sex differentiation, reproductive organ development, the thyroxin-regulated metamorphosis, oestrogen synthesis (activity of the CYP19 aromatase enzyme), and fertility. PMID:22669660

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

    PubMed Central

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

    2014-01-01

    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. PMID:25071922

  14. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome. PMID:26525505

  15. Acute phase response in toxicity studies. I. Survey of beagle dogs subjected to single-dose toxicity studies.

    PubMed

    Hoshiya, T; Watanabe, D; Akagi, K; Mizoguchi, Y; Kamiya, K; Mizuguchi, H; Kumahara, M; Toya, H; Nagashima, Y; Okaniwa, A

    2001-05-01

    In the field of routine single-dose toxicity studies, we occasionally meet with transient leukocytosis associated with an increase in fibrinogen in beagle dogs within a few days after treatment with the test article. Only a little is known, however, about the toxicological significance of these changes. However, these changes were thought to belong to the category of "Acute Phase Response, APR," which has been known for a long time in connection with injury, trauma or infection. Aiming at proper understanding of these experiences, we surveyed 25 single-dose toxicity studies (7 intravenous bolus, 5 intravenous infusion, 12 oral and 1 subcutaneous treatment, hereafter referred to simply as i.v. bolus, i.v. infusion, oral and s.c.) in beagle dogs, provided with data from hematological examinations. We set the following criteria as a positive response in the present survey: increases of 50% or more in either or both WBC or fibrinogen compared to the predosing value, transiently from Day 1 to Day 3 of the study. Among 25 studies surveyed, about 1/2 of the studies exhibited increases of 50% or more in either or both fibrinogen or WBC counts compared to the predosing values showing dose-dependency transiently on Day 1 or Day 2. These changes were remarkable after intravenous application. Oral application produced similar effects, although the incidence and severity were low compared to the i.v. routes. Regarding blood chemical and hematological changes other than changes in fibrinogen and WBC counts, there were no essential differences between the groups of studies with and without the changes in fibrinogen and WBC counts. These changes were thought to be characteristic and to have occurred as incidents unrelated to other changes. The reported changes seen in single-dose toxicity studies may belong to the category of APR as the non-specific mechanism of living bodies as stated by Burns et al. (1996). PMID:11429972

  16. Safety assessment of aditoprim acute, subchronic toxicity and mutagenicity studies.

    PubMed

    Wang, Xu; Tan, Ziqiang; Pan, Yuanhu; Ihsan, Awais; Liu, Qianying; Huang, Lingli; Cheng, Guyue; Chen, Dongmei; Tao, Yanfei; Liu, Zhenli; Yuan, Zonghui

    2015-11-01

    Aditoprim (ADP), a new developed dihydrofolate reductase (DHFR) inhibitor, has great potential in clinical veterinary medicine because of its greater pharmacokinetic properties than structural analogs. Preclinical toxicology studies were performed to assess the safety of ADP including an acute oral toxicity test, a subchronic toxicity test and five mutagenicity tests. In the acute oral toxicity test, ADP was administered singly by oral gavage to Wistar rats and Kunming mice. The LD50 calculated was 1400 mg kg(-1) body weight (BW) day(-1) in rats and 1130 mg kg(-1) BW day(-1) in mice. In a subchronic study, Wistar rats were administered ADP at dose levels of 0, 20, 100 and 1000 mg kg(-1) diet for 90 days. Significant decreases were observed on body weight and food efficiency in the high-dose group. Treatment-related changes in clinical serum biochemistry were found in the medium- and high-dose groups. Significant increases in the relative weights of livers and kidneys in females and testis in males in the 1000 mg kg(-1) diet, and significant decrease in relative weights of livers in males in the 100 mg kg(-1) diet were noted. Histopathological observations revealed that the 1000 mg kg(-1) ADP diet could induce lymphocytic infiltration and hepatocytic necrosis near the hepatic portal area. The genotoxicity of ADP was negative in tests, such as the bacterial reverse mutation assay, mice bone marrow erythrocyte micronucleus assay, in vitro chromosomal aberration test, in vitro cho/hgprt mammalian cell mutagenesis assay and mice testicle cells chromosome aberration. Based on the subchronic study, the no-observed-adverse-effect level for ADP was a 20 mg kg(-1) diet, which is about 1.44-1.53 mg kg(-1) BW day(-1) in rats. PMID:25663419

  17. Pulmonary Toxicity Studies of Lunar Dust in Rodents

    NASA Technical Reports Server (NTRS)

    Lam, Chiu-Wing; James, John T.

    2012-01-01

    NASA has been contemplating returning astronauts to the moon for long-duration habitation and research and using it as a stepping-stone to Mars. Other spacefaring nations are planning to send humans to the moon for the first time. The surface of the moon is covered by a layer of fine dust. Fine terrestrial dusts, if inhaled, are known to pose a health risk to humans. Some Apollo crews briefly exposed to moon dust that adhered to spacesuits and became airborne in the Lunar Module reported eye and throat irritation. The habitable area of any lunar landing vehicle or outpost would inevitably become contaminated with lunar dust. To assess the health risks of exposure of humans to airborne lunar dust, we evaluated the toxicity of Apollo 14 moon dust in animal lungs. Studies of the pulmonary toxicity of a dust are generally first done by intratracheal instillation (ITI) of aqueous suspensions of the test dust into the lungs of rodents. If a test dust is irritating or cytotoxic to the lungs, the alveolar macrophages, after phagocytizing the dust particles, will release cellular messengers to recruit white blood cells (WBCs) and to induce dilation of blood capillary walls to make them porous, allowing the WBCs to gain access to the alveolar space. The dilation of capillary walls also allows serum proteins and water entering the lung. Besides altering capillary integrity, a toxic dust can also directly kill the cells that come into contact with it or ingest it, after which the dead cells would release their contents, including lactate dehydrogenase (a common enzyme marker of cell death or tissue damage). In the treated animals, we lavaged the lungs 1 and 4 weeks after the dust instillation and measured the concentrations of these biomarkers of toxicity in the bronchioalveolar lavage fluids to determine the toxicity of the dust. To assess whether the inflammation and cellular injury observed in the biomarker study would lead to persistent or progressive histopathological

  18. Use of Autometallography in Studies of Nanosilver Distribution and Toxicity

    PubMed Central

    Miller, David L.; Yu, Il Je; Genter, Mary Beth

    2016-01-01

    With the increasing use of and interest in nanoparticles in medicine and technology, the tissue and cell-specific localization of the particles are important considerations when the nanomaterials find their way into biological systems. This brief communication shows the utility of autometallography in determining the location of metal deposition at the light microscopic level. Although primarily focusing on studies of the toxicity and deposition of silver nanoparticles, use of autometallography to localize zinc and other metals at the tissue and subcellular localization is also recognized. PMID:26634628

  19. Toxicity study of Lauha Bhasma (calcined iron) in albino rats

    PubMed Central

    Joshi, Namrata; Dash, Manoj Kumar; Dwivedi, Laxmikant; Khilnani, G. D.

    2016-01-01

    Background: Lauha Bhasma (LB) is a complex herbomineral preparation widely used as an Ayurvedic hematinic agent. It is an effective remedy for chronic fever (jīrṇa jvara), phthisis (kṣaya), Breathlessness (śvāsa) etc., and possesses vitality enhancing (vājīkara), strength promoting and anti aging (rasāyana) properties. Objectives: The present work was conducted to establish the safety aspects of the use of Lauha bhasma. Setting and Design: LB was prepared by Ayurvedic procedures of purification (śodhana), sun drying (bhānupāka), sthālīpāka, followed by repeated calcination (māraṇa) and “nectarization” (amṛtīkaraṇa). The resultant product was subjected to acute and sub acute toxicity studies. Materials and Methods: Acute and subacute toxicity study of LB was conducted in albino rats. Criteria for assessment included ponderal changes, change in biochemical parameters viz., LFT and KFT and hematological parameters. Histopathological studies of different organs including liver, kidney, spleen, testis etc., were also conducted to observe pathological changes if any. Results: In the acute toxicity study, the animal group did not manifest any signs of toxicity and no mortality was observed up to 100 times the therapeutic dose (TD). Significant increase in blood urea (27.83%, P < 0.01), serum creatinine (30.92%, P < 0.05), Aspartate aminotransferase (15.09%, P < 0.05), and serum alkaline phosphatase (27.5%, P < 0.01) was evident in group IV (10 TD). A significant increase in serum total protein (6.04%, P < 0.05) level was observed in group III (5 TD). Histopathological examination of livers in group IV (10 TD) showed mild inflammation in terms of bile stasis, peri-portal hepatic inflammation and sinusoidal congestion; lymphocyte infiltration in kidney and intracellular deposits in the splenic tissue. Conclusion: Lauha Bhasma was found to be safe at the therapeutic dose and also at five times the therapeutic dose levels. However, alteration in

  20. Use of Autometallography in Studies of Nanosilver Distribution and Toxicity.

    PubMed

    Miller, David L; Yu, Il Je; Genter, Mary Beth

    2016-01-01

    With the increasing use of and interest in nanoparticles in medicine and technology, the tissue and cell-specific localization of the particles are important considerations when the nanomaterials find their way into biological systems. This brief communication shows the utility of autometallography in determining the location of metal deposition at the light microscopic level. Although primarily focusing on studies of the toxicity and deposition of silver nanoparticles, use of autometallography to localize zinc and other metals at the tissue and subcellular localization is also recognized. PMID:26634628

  1. GENE INDUCTION STUDIES AND TOXICITY OF CHEMICAL MIXTURES

    EPA Science Inventory

    As part of its mixtures program the Agency for Toxic Substances and Disease Registry (ATSDR) supports in vitro and limited in vivo toxicity testing to further our understanding of the toxicity and health effects of chemical mixtures. There are increasing concerns that environment...

  2. Summary of Dose-Response Modeling for Developmental Toxicity Studies

    PubMed Central

    Hunt, Daniel L.; Rai, Shesh N.; Li, Chin-Shang

    2008-01-01

    Developmental toxicity studies are an important area in the field of toxicology. Endpoints measured on fetuses include weight and indicators of death and malformation. Binary indicator measures are typically summed over the litter and a discrete distribution is assumed to model the number of adversely affected fetuses. Additionally, there is noticeable variation in the litter responses within dose groups that should be taken into account when modeling. Finally, the dose-response pattern in these studies exhibits a threshold effect. The threshold dose-response model is the default model for non-carcinogenic risk assessment, according to the USEPA, and is encouraged by the agency for the use in the risk assessment process. Two statistical models are proposed to estimate dose-response pattern of data from the developmental toxicity study: the threshold model and the spline model. The models were applied to two data sets. The advantages and disadvantages of these models, potential other models, and future research possibilities will be summarized. PMID:19088901

  3. A Study on Subchronic Inhalation Toxicity of 1-Chloropropane

    PubMed Central

    Chung, Yong Hyun; Han, Jeong Hee

    2015-01-01

    This study was conducted to measure toxicity of 1-chloropropane (CAS No. : 540-54-5). According to the OECD Test Guideline 413 (Subchronic inhalation toxicity: 90-day study), SD rats were exposed to 0, 310, 1,250, and 5,000 ppm of 1-chloropropane for 6 h/day, 5 day/week for 13 weeks via whole-body inhalation. Mortality, clinical signs, body weights, food consumption, motor activity, ophthalmoscopy, hematology, serum chemistry, urinalysis, organ weights, gross and histopathological findings were compared between control and all tested groups. No mortality or remarkable clinical signs were examined during the study. No gross lesions or adverse effects on body weight, food consumption, motor activity, ophthalmoscopy, urinalysis, hematology, organ weights were observed in any of male or female rats in all tested groups. In serum biochemistry, glucose was significantly decreased in males of 1,250 and 5,000 ppm groups compared to control group in dose-dependent relationship. In histopathological examination, vacuolation of acinar cells was observed in pancreas of all male and female groups exposed to 1-chloropropane. In conclusion, no observable adverse effect level (NOAEL) was considered to be below 310 ppm/6 h/day, 5 day/week for rats. PMID:26877841

  4. Subchronic Inhalation Toxicity Study of n-pentane in Rats

    PubMed Central

    Cho, Hae-Won; Han, Jeong-Hee; Lee, Sung-Bae; Chung, Yong-Hyun; Rim, Kyung-Taek; Yang, Jeong-Sun

    2012-01-01

    Objectives This study was conducted in order to obtain information concerning the health hazards that may result from a 13 week inhalation exposure of n-pentane in Sprague-Dawley rats. Methods This study was conducted in accordance with the Organization for Economic Co-operation and Development (OECD) guidelines for the testing of chemicals No. 413 'Subchronic inhalation toxicity: 90-day study (as revised in 2009)'. The rats were divided into 4 groups (10 male and 10 female rats in each group), and were exposed to 0, 340, 1,530, and 6,885 ppm n-pentane in each exposure chamber for 6 hour/day, 5 days/week, for 13 weeks. All of the rats were sacrificed at the end of the treatment period. During the test period, clinical signs, mortality, body weights, food consumption, ophthalmoscopy, locomotion activity, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were assessed. Results During the period of testing, there were no treatment related effects on the clinical findings, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, relative organ weight, and histopathological findings. Conclusion The no-observable-adverse-effect level (NOAEL) of n-pentane is evaluated as being more than 6,885 ppm (20.3 mg/L) in both male and female rats. n-pentane was not a classified specific target organ toxicity in the globally harmonized classification system (GHS). PMID:23019535

  5. Phase I study of the combination of two hypoxic cell radiosensitizers, Ro 03-8799 and SR-2508: toxicity and pharmacokinetics

    SciTech Connect

    Newman, H.F.; Bleehen, N.M.; Workman, P.

    1986-07-01

    The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m/sup 2/, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses greater than 3.0 g/m/sup 2/, but causes peripheral neuropathy at cumulative doses of 30 g/m/sup 2/. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m/sup 2/ of each agent, and proceeding to a fixed dose of 0.75 g/m/sup 2/ Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m/sup 2/ SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m/sup 2/ Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 micrograms/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone.

  6. Critical appraisal of the duration of chronic animal toxicity studies

    SciTech Connect

    Lumley, C.E.; Walker, S.R.

    1986-03-01

    One method of assessing the contribution of studies of longer than 6 months to a safety evaluation program is to compare retrospectively the findings in toxicity tests carried out for 6 months or less with those observed after 6 months. The Center for Medicines Research has therefore established a databank comprising animal toxicological data obtained from pharmaceutical companies in Europe. Twenty-one companies have provided data for 124 compounds (214 studies), including 88 studies of 65 compounds where comparable short-term (less than or equal to 6 months) and long-term (greater than 6 months) data are available. The results from the 88 studies show that, excluding the possibility of identifying carcinogens, tests of longer than 6 months have not added to the overall safety evaluation of these compounds.

  7. Studies of the toxic interaction of disinfection by-products

    SciTech Connect

    Laurie, R.D.; Bercz, J.P.; Wessendarp, T.K.; Condie, L.W.

    1986-11-01

    A large number and variety of compounds are formed in the process of chlorinating drinking water. Many of the compounds have been shown to be toxic and are currently being further evaluated by the US Environmental Protection Agency (EPA). One group of the halopropanones found in chlorinated drinking water is the dichloropropanones. The toxicological properties of this group have not been well characterized. In addition, a number of investigators have shown that ketones potentiate the hepatotoxicity of haloalkanes. The authors conducted a series of studies to explore both the toxicity of the dichloropropanones and their potential interaction with a well-characterized haloalkane, carbon tetrachloride. A variety of toxicological and biochemical endpoints were used to evaluate the toxicity of the dichloropropanones and their interaction with CCl/sub 4/, including cytochrome P-450 concentration, reduced glutathione levels, pentane generation, serum enzyme activities, and histopathology. Administration of 1,1-dichloropropanone (DCP) resulted in elevated serum enzymes associated with periportal necrosis. Glutathione levels were reduced by the administration of 1,1-DCP; pentane generation was not increased. When 1,1-DCP was given prior to CCl/sub 4/, the data were consistent with additivity. Administration of 1,3-DCP did not result in elevated serum enzymes, nor was there histopathologic evidence of necrosis. Glutathione levels and pentane generation in the 1,3-DCP-treated groups were the same as those of controls. Inhibition of the toxicologic effects of CCl/sub 4/ in a dose-related manner was observed when 1,3-DCP was administered prior to CCl/sub 4/.

  8. Study designs for the nonclinical safety testing of new vaccine products.

    PubMed

    Forster, Roy

    2012-07-01

    During the development of a new vaccine, the purpose of nonclinical studies is to provide safety information to support the clinical development and licensure of the product. In this article the study designs currently accepted for the nonclinical safety testing of new vaccines are described for single dose, local tolerance, repeat dose toxicity and safety pharmacology studies; these studies together form the basis of a typical nonclinical safety evaluation dossier. The detailed design of the preclinical package must take account of the intended clinical use, patient population, route of administration, formulation, dose level and immunisation schedule. The test item that is used for these studies must be adequately representative of the intended clinical formulation. The animal model used for these studies must be selected on criteria of relevance. Single dose toxicity studies provide information on acute actions or the potential effect of accidental overdose, but this information is often available from the repeat dose toxicity study, obviating the need for the acute study. Local tolerance studies provide information on tissue reactions at the site of administration. Evaluation of the findings must distinguish between normal tissue responses to injected material and findings indicative of undesirable pathological changes. The repeated dose toxicity studies are the principal studies that support the safety profile of the vaccines. The design of these studies must take full account of the features of the vaccine in the choice of treatment regime, dose levels, pharmacodynamic monitoring and timing of investigations and sacrifice. Safety pharmacology studies are performed to evaluate the potential for undesirable secondary pharmacological actions of vaccines if there is data to suggest that such studies are needed; this evaluation is made on a case by case basis. In the absence of specific guidance the design of studies for therapeutic vaccines follows the same

  9. Hospital waste management and toxicity evaluation: A case study

    SciTech Connect

    Tsakona, M.; Anagnostopoulou, E.; Gidarakos, E.

    2007-07-01

    Hospital waste management is an imperative environmental and public safety issue, due to the waste's infectious and hazardous character. This paper examines the existing waste strategy of a typical hospital in Greece with a bed capacity of 400-600. The segregation, collection, packaging, storage, transportation and disposal of waste were monitored and the observed problematic areas documented. The concentrations of BOD, COD and heavy metals were measured in the wastewater the hospital generated. The wastewater's toxicity was also investigated. During the study, omissions and negligence were observed at every stage of the waste management system, particularly with regard to the treatment of infectious waste. Inappropriate collection and transportation procedures for infectious waste, which jeopardized the safety of staff and patients, were recorded. However, inappropriate segregation practices were the dominant problem, which led to increased quantities of generated infectious waste and hence higher costs for their disposal. Infectious waste production was estimated using two different methods: one by weighing the incinerated waste (880 kg day{sup -1}) and the other by estimating the number of waste bags produced each day (650 kg day{sup -1}). Furthermore, measurements of the EC{sub 50} parameter in wastewater samples revealed an increased toxicity in all samples. In addition, hazardous organic compounds were detected in wastewater samples using a gas chromatograph/mass spectrograph. Proposals recommending the application of a comprehensive hospital waste management system are presented that will ensure that any potential risks hospital wastes pose to public health and to the environment are minimized.

  10. Dose Ranging, Expanded Acute Toxicity and Safety Pharmacology Studies for Intravenously Administered Functionalized Graphene Nanoparticle Formulations

    PubMed Central

    Kanakia, Shruti; Toussaint, Jimmy; Chowdhury, Sayan Mullick; Tembulkar, Tanuf; Lee, Stephen; Jiang, Ya-Ping; Lin, Richard Z.; Shroyer, Kenneth R.; Moore, William; Sitharaman, Balaji

    2014-01-01

    Graphene nanoparticles dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10 – 100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1–500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 minutes, and majority of nanoparticles excreted within 24 hours through feces. Histopathology changes were noted at ≥ 250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application. PMID:24854092

  11. STARA (STUDIES ON TOXICITY APPLICABLE TO RISK ASSESSMENT) TOXICITY DATA BASE

    EPA Science Inventory

    The Environmental Criteria and Assessment Office of the U.S. Environmental Protection Agency (EPA) has developed a toxicity data base to aid in the development of risk assessment methodologies and the assessment of health hazards from hazardous waste sites and chemical spills. Th...

  12. Metabolism and toxicity studies supporting the safety of rebaudioside D.

    PubMed

    Nikiforov, Andrey I; Rihner, Marisa O; Eapen, Alex K; Thomas, Jennifer A

    2013-07-01

    Rebaudioside D (Reb D) is one of the several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) which has been identified as a potential sweetener. The metabolism of Reb A and Reb D was evaluated in various in vitro matrices (simulated gastrointestinal fluids, rat liver microsomes, and rat cecal contents) and through analysis of plasma collected from rats in a dietary toxicity study. Reb A and Reb D showed similar stability when exposed to simulated stomach and small intestine fluids, with susceptibility to hydrolytic degradation by enteric bacteria collected from the cecum. Incubations with rat liver microsomes indicated that neither compound is expected to be metabolized by the liver enzymes. Plasma concentrations of Reb D, Reb A, and/or the final hydrolysis product of each compound, free/conjugated steviol, were consistent between animals administered either Reb D or Reb A in the diet. A repeated exposure dietary toxicity study was conducted to compare the safety of Reb D, when administered at target exposure levels of 500, 1000, and 2000 mg/kg body weight (bw)/d to Sprague-Dawley rats for 28 days, to that of Reb A administered at a target exposure level of 2000 mg/kg bw/d. There were no treatment-related effects on the general condition and behavior of the animals and 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. Results were comparable between the group administered 2000 mg/kg/d Reb D and the group administered 2000 mg/kg/d Reb A. PMID:23766392

  13. Toxicity and toxicokinetics of metformin in rats

    SciTech Connect

    Quaile, Michael P.; Melich, David H.; Jordan, Holly L.; Nold, James B.; Chism, Jack P.; Polli, Joseph W.; Smith, Glenn A.; Rhodes, Melissa C.

    2010-03-15

    Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of >= 900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given >= 600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses >= 600 mg/kg/day. There were no significant sex differences in mean AUC{sub 0-24} or C{sub max} nor were there significant differences in mean AUC{sub 0-24} or C{sub max} following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC{sub 0-24} = 41.1 mug h/mL; mean C{sub max} = 10.3 mug/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.

  14. Toxicity and recovery studies of two ayurvedic preparations of iron.

    PubMed

    Sarkar, P K; Prajapati, P K; Shukla, V J; Ravishankar, B; Choudhary, A K

    2009-12-01

    Lauha Bhasma and Mandura Bhasma in 55 mg/kg dose (5 times the therapeutic effective dose) for 60 days exhibited no serious toxic effects in Charles Foster albino rats. Both the drugs showed significant recovery from chronic toxic effect after 45 days of recovery period. PMID:20329703

  15. A Study on the D. magna and V. fischeri Toxicity Relationship of Industrial Wastewater from Korea

    NASA Astrophysics Data System (ADS)

    Pyo, S.; Lee, S.; Chun Sang, H.; Park, T. J.; Kim, M. S.

    2015-12-01

    It is well known that high concentration of TDS (total dissolved solid) in industrial effluent gives rise to the toxicity to the Daphnia magna toxicity test. D. magna is vulnerable to relatively low TDS concentration showing the 24-hr EC50 of Salinity 0.6% (as the sea salt concentration). Recently, standard mandatory toxicity testing using Daphnia magna has been used to monitor industrial effluent toxicity according to Korea standard method (Acute Toxicity Test Method of the Daphnia magna Straus (Cladocera, Crustacea), ES 04704. 1a) under regulation. Since only one acute toxicity testing is applied in the present, we are trying to introduce microbial battery for more complete toxicity assessment. In this study, the acute toxicities between daphnids and microbes were compared. The results of D. magna and Vibrio fischeri toxicity test from 165 industrial wastewater effluents showed high positive correlation. In addition, the possibility of predicting daphnia toxicity from the bacterial toxicity data amounts to 92.6% if we consider salinity effect (>5ppt) together. From this study, we found that the V. fischeri toxicity test is a powerful battery tool to assess the industrial wastewater toxicity. Here, we suggest that luminescent bacteria toxicity test be useful not only for complete toxicity assessment which can't be obtained by daphnia toxicity testing only but also for the reduction cost, time, and labor in the Korean society. Keywords : D. magna, V. fischeri, Industrial waste water, battery test Acknowledgement This research was supported by a grant (15IFIP-B089908-02) from Plant Research Program funded by Ministry of Land, Infrastructure and Transport of Korean government

  16. Tri-isobutylphosphate: a prenatal toxicity study in rats.

    PubMed

    Ruckman, S A; Green, O P; Palmer, A K; Klimisch, H J

    1999-04-12

    To assess the prenatal toxicity to rats of the anti-foaming agent, tri-isobutylphosphate (CAS 126-71-6), a study was conducted in which daily dosages of 0, 100, 300 and 1000 mg/kg were administered to different treatment groups by gavage from day 6 to 15 of pregnancy. Dams were killed and foetuses examined on day 20 of pregnancy. Maternal effects during the dosing period included a dosage-related increase in the frequency, persistence and severity of post dosing salivation in all test groups and significantly increased water consumption at 1000 mg/kg. Bodyweight gain at 1000 and 300 mg/kg was lower than that of controls but the differences were not statistically significant. The lowest dosage of 100 mg/kg could be considered as the maternal 'lowest observed adverse effect level' (LOAEL) or 'no observed adverse effect level' (NOAEL) according to whether increased salivation is perceived to be a true toxic effect or simply a reaction to the taste of the test material. Neither litter values nor the prevalence of foetuses with abnormalities indicated any embryotoxic effects (including teratogenicity) at any dosage. The most notable feature of the results was the occurrence of a cluster of foetuses with the congenital abnormality referred to as 'hunched posture syndrome' or 'squat foetus syndrome'. However, the incidence of this finding was similar to that noted among background data for the same strain and, in the absence of any other embryotoxic findings, was considered likely to have arisen coincidentally. PMID:10355544

  17. Chronic toxicity, reproductive, and teratogenic studies of hexazinone.

    PubMed

    Kennedy, G L; Kaplan, A M

    1984-12-01

    Hexazinone [3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine 2,4(1H,3H)-dione; CAS 51235-04-2] was tested for oral toxicity in rats (both 90-day and 2-year feeding studies), mice (8-week and 2-year feeding studies), and dogs (90-day feeding study). The teratogenic potential was evaluated in rabbits and rats and functional reproductive capacity was studied in rats. Ninety-day feeding of up to 1000 ppm produced no signs of a toxic response in rats. Rats fed 5000 ppm had growth curves slightly inferior to those of the controls as the only detectable difference. Extending the feeding period to 2 years produced decreased body weights in males fed 2500 ppm (top level tested) and in females fed either 1000 or 2500 ppm. All other indices of response, including the type and distribution of tumors, were similar in the test and control rats with the no-effect level being 200 ppm. Eight-week feeding of up to 10,000 ppm in mice produced increased liver weight only at the highest level without any other changes. Two-year feeding of either 200, 2500, or 10,000 ppm resulted in sloughing of the distal tip of the tail and increased liver weights among mice fed 10,000 ppm. Hypertrophy of centrilobular hepatocytes and hyperplasic nodules were increased in mice fed either 2500 or 10,000 ppm. No evidence of a tumorigenic response was evident. The no-effect level was 200 ppm. Dogs fed 5000 ppm for 90 days had decreased rate of body weight gain with clinical enzyme changes suggestive of liver damage. Microscopic examination of the liver failed to reveal any alterations and dogs fed either 200 or 1000 ppm were indistinguishable from controls. The no-effect level in the dog was 1000 ppm. No evidence of a teratogenic response was seen in either rats or rabbits and reproduction capacity in rats fed up to 2500 ppm for three generations was unaffected. PMID:6519376

  18. A brief study of toxic effects of some medicinal herbs on kidney

    PubMed Central

    Asif, Mohammad

    2012-01-01

    Increased use of complementary and alternative herbal medicines in the treatment of various diseases.Some herbal therapies may be causes of potential toxicity that may be renal toxicity caused by the ingestion of herbs. The goal of this study is the toxic and beneficial effects of medicinal herbs on renal health by which evidence for benefit or toxicity has been found. Included are nephrotoxicity from aristolochic acid and other components within herbs, herb-drug interactions, heavy metal toxicity in herbs and adulterants during careless preparation of herbal medicine, resulting in adverse renal effects and renal toxicity from contaminants within the extracts. The review aims to provide knowledge and guide to encourage future toxicity studies on the kidney by medicinal herbs. PMID:23326775

  19. Broccoli seed extract: Genotoxicity and subchronic toxicity studies.

    PubMed

    Zhou, Yu; Yang, Hui; Li, Yongning; Lynch, B; Jia, Xudong

    2015-10-01

    Potential health benefits have been attributed to broccoli consumption. Hence, there is potential for use of broccoli seed extract (BSE) in food or for use as a dietary supplement. To assess the potential safety of a BSE product, three genotoxicity experiments, including an Ames, in vivo mouse micronucleus, and in vivo mouse sperm abnormality assay, were carried out. BSE was subject to an acute oral toxicity test and was evaluated in a 30-day feeding study in rats. BSE showed no mutagenic activity in the Ames assay and no evidence of genotoxic potential in the in vivo assays at doses up to 10 g/kg body weight (bw). The LD50 of BSE in rats was >10 g/kg bw/d. In the 30-day feeding study, in which BSE was administered in the diet to provide doses of 0, 0.3, 1.0, or 3.0 g/kg bw/d, no toxicological significant effects were noted on body weight, body weight gain, organ weights, or on the results of hematological, clinical chemistry and histopathological evaluations. The no-observed-adverse-effect level was considered to be 3.0 g/kg bw/d, the highest dose tested. Collectively, these results support the safe use of BSE as a food ingredient or product. PMID:26271574

  20. [Advance in study on zearalenone's toxicity and determination].

    PubMed

    He, Qing-Hua; Xu, Yang

    2005-07-01

    The article is intended to introduce the zearalenone's toxicity, determination methods and prevention. Zearalenone is one of the most widely distributed mycotoxins produces by Fusarium Species, it is harm to animals and human. And it can induce human liver cancer,carcinoma of tesis esophagus cancer. Now we use high-performance liquid chromatography, gas chromatography, thin layer chromatography, non-toxicity determinations to detect it. PMID:16229288

  1. Study of Subchronic Toxicity of Relatox on Sexually Immature Animals.

    PubMed

    Churin, A A; Fomina, T I; Ermolaeva, L A; Vetoshkina, T V; Dubskaya, T Yu; Lamzina, T Yu; Fedorova, E P; Neupokoeva, O V; Nikiforova, A N

    2015-11-01

    Intramuscular injections of Relatox in therapeutic and toxic doses to young outbred laboratory rats for 14 days caused no changes in the peripheral blood and bone marrow parameters, serum biochemical parameters, and morphology of the major viscera. In the toxic dose, the drug caused local irritation (inflammation, atrophy, and sclerosis in muscle tissue). Regeneration processes started in muscle tissue 7 days after Relatox withdrawal. PMID:26593416

  2. Acute and subchronic (13-week) toxicity of fermented Acanthopanax koreanum extracts in Sprague Dawley rats.

    PubMed

    Cho, MyoungLae; Shin, Gi-Hae; Kim, Jae-Min; Lee, Jin-Ha; Park, Sun-Ok; Lee, Sang-Jong; Shin, HyunMu; Lee, Boo-Yong; Kang, Il-Jun; Lee, Ok-Hwan

    2016-06-01

    The biological fermentation of plants is usually used to improve their product properties, including their biological activity. Acanthopanax koreanum is a plant indigenous to Jeju, Korea; however, fermented A. koreanum (FAK) has not been guaranteed to be safe. Therefore, in this study, a safety evaluation of aqueous extracts of FAK was performed using Sprague Dawley rats. The acute toxicity of FAK did not influence animal mortality, body weight changes or the animals' clinical appearance at a concentration of 5000 mg/kg body weight. Using doses of 500, 1000 and 2000 mg/kg/day in a subchronic (13-week) toxicity study, the administration of FAK in male rats increased their body weight, food consumption, absolute liver weight, liver-associated enzymes and total cholesterol content. However, these effects of FAK were not considered toxic because the changes were not accompanied by any evidence of clinical signs or any change in the histopathological examination. On the other hand, the FAK-treated female rats did not exhibit significant changes in their body weight, food consumption, absolute and relative organ weights or liver enzymes. These results suggest that the acute oral administration of FAK is non-toxic to rats, and 13 weeks of repeated dosing demonstrated no FAK-related toxicity at a concentration of 2000 mg/kg. Therefore, the no-observed-adverse-effect level (NOAEL) of FAK was determined to be 2000 mg/kg/day for both male and female rats. PMID:26925497

  3. Studies of toxic aerosols via elastic and inelastic light scattering

    SciTech Connect

    Foss, W.; Li, W.; Allen, T.M.; Blair, D.S.; Davis, E.J. )

    1993-02-01

    Evaporation rates and chemical characteristics of potentially toxic aerosols have been determined by elastic and inelastic light-scattering measurements. The aerosol systems examined were a commercial catalyst consisting of a mixture of stannous octanoate (SNO) and 2-ethylhexanoic acid (EHA) and droplets emitted from open tanks of chromic acid solutions used for anodizing aluminum. The heavy metals contained in these aerosols represent a danger to the workplace if such materials are inhaled. Nanogram amounts of the solutions were studied by suspending single microdroplets in electrodynamic balances in a flow of air to measure evaporation rates and to obtain Raman spectra. Elastic scattering data include phase functions and morphological resonance spectra from which droplet sizes are determined. The inelastic light-scattering data or Raman spectra provide molecular vibrational bond information. It was found that EHA spectra agree with bulk data in the literature, and that SNO Raman spectra, which are not available in the literature, are consistent with infrared spectra for bulk SNO. At room temperature the vapor pressure of SNO is on the order of 0.01 Pa while that of EHA is on the order of 0.1 Pa. Raman data for the residue of evaporated chromic acid solutions show the presence of chromium oxides (Cr[sup 6+] compounds), surfactants, and bound (nonvolatile) water. 31 refs., 14 figs.

  4. Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats.

    PubMed

    Elshama, Said Said; El-Kenawy, Ayman El-Meghawry; Osman, Hosam-Eldin Hussein

    2016-01-01

    Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID:26941796

  5. Clinical toxicity study of Semecarpus anacardium Linn. f.

    PubMed

    Murty, G K

    1974-09-01

    Semecarpus anacardium was administered to 266 cases in 3 formulations: Amrit Bhallatak (186 cases), RB 3 (48 cases), and Garsin (32 cases). The Amrit Bhallatak is a compound formulation containing extract of both the cotyledons and the pericarp of the fruit of Semecarpus anacardium. RB3 is composed of the whole cotyledon (300 mg); the daily dose of cotyledons was 3.6 g. Garsin contained 200 g of cotyledons. The extract is derived by separating the oil by a physical process. The daily dosage of Amrit Bhallatak was 10 g/day, that of Garsin, 2.4 g/day. No toxicity or side effects were observed. The therapeutic value of Semecarpus anacardium in arthropathies, atopic dermatitis, leucoderma, leprosy, hypothyroidism, oligospermia, and azoospermia and its value as an oral contraceptive have been studied. The most significant effect was on the ovaries and testes. The drug probably acts via the hypophysics. Out of 266 patients, 189 were men, 77 women between 30-45 years of age. The treatment was restricted to internal medication by mouth. No external contact or application of the drug was applied. Of the 77 women treated with the drug, 41 were followed up after treatment. 12 had become pregnant and none showed any teratogenecity. PMID:4448495

  6. Studies on the toxicity and maximum allowable concentration of chloroform.

    PubMed

    Li, L H; Jiang, X Z; Liang, Y X; Chen, Z Q; Zhou, Y F; Wang, Y L

    1993-06-01

    Chloroform has obvious hepato-, nephro-toxicity and carcinogenicity. In order to get necessary data for recommendation of maximum allowable concentration of chloroform in workplace, a series of studies were carried out. The results showed that exposed workers mainly distributed in the industries of perspex processing, production of refrigerants, drugs and pesticides. The exposure level ranged 4.27-147.91 mg/m3 in 119 air samples collected from 3 representative worksites, with 45.4% air samples below 20 mg/m3. The workers exposed to chloroform at 29.51 mg/m3 had slight liver damage indicated by the higher rates of abnormal serum prealbumin and transferrin levels than those of control workers. The neurobehavioral functions of these workers were also obviously affected, manifested as increases in scores of passive mood states and dose-related negative changes in neurobehavioral testing. The observed effect threshold concentration of subacute inhalation in rats was 592 mg/m3 according to the observation on the biochemical changes in liver tissue and abnormal activities of serum enzymes. Mainly based on the above results, we recommended 20 mg/m3 as the Maximum Allowable Concentration in workplace in China at present. PMID:8397901

  7. Short-term toxicity studies of loline alkaloids in mice.

    PubMed

    Finch, S C; Munday, J S; Munday, R; Kerby, J W F

    2016-08-01

    Epichloë endophytes have been used successfully in pastoral systems to reduce the impact of insect pests through the expression of secondary metabolites. The use of endophytes could be extended to other plant species, such as cereal crops, where the production of bioactive secondary metabolites would reduce the reliance on pesticides for insect control. The success of this approach is dependent on the selection of an appropriate secondary metabolite target which must not only be effective against insect pests but also be safe for grazing and monogastric animals. The loline alkaloids have been identified as possible target metabolites as they are associated with potent effects on insects and low toxicity to grazing animals. The purpose of the current study was to generate toxicological data on the loline alkaloids in a monogastric system using mice. Male and female mice were fed 415 mg/kg/day total lolines for a 3-week period. The loline treatment caused no statistically significant effect on gross pathology, histology, haematology, blood chemistry, heart rate, blood pressure or motor coordination. Reduced weight gain and food consumption were noted in the loline groups during the initial stages of the experiment. This experiment raises no food safety concerns for the loline alkaloids. PMID:27276360

  8. Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats

    PubMed Central

    Elshama, Said Said; EL-Kenawy, Ayman El-Meghawry; Osman, Hosam-Eldin Hussein

    2016-01-01

    Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID:26941796

  9. 13-week oral toxicity study of vinyl laurate in rats.

    PubMed

    Lina, Ben A R; Messinger, Horst; Bär, Albert

    2015-02-01

    Vinyl laurate (VL) is used as a monomer in the production of polyvinyl acetate vinyl laurate copolymer, a component of chewing gum base. The safety of VL was examined in a 13-week oral toxicity study in Wistar rats. VL was administered in corn coil by daily gavage (5 ml/kg bw/d) to four main groups (10 rats/sex) at doses of 0 (vehicle only), 50, 250 and 1000 mg/kg bw/d, respectively. The control and high-dose group comprised an additional 5 rats/sex which were kept untreated for a further 4 weeks until sacrifice (recovery groups). In addition to standard parameters, male and female fertility parameters were determined as well. There were no mortalities and treatment-related clinical signs. Neurobehavioral observations and motor activity assessment, ophthalmoscopic examinations, body weights, feed and water intakes, blood cell counts, coagulation time, standard clinical chemical parameters and urinalyses, absolute and relative organ weights at the end of the treatment as well as macroscopic examination at necropsy and microscopic examination of standard organs and tissues did not show any treatment-related changes. Female and male fertility parameters (estrus cyclicity, testicular and epididymal sperm counts, sperm motility and morphology) were not affected by the treatment. Accordingly, the no-observed-adverse-effect level (NOAEL) for VL was determined to be 1000 mg/kg bw/d, i.e. the highest dose level tested. PMID:25445296

  10. Study of apoptosis in human lymphocytes by toxic substances implicated in toxic oil syndrome.

    PubMed

    Gallardo, S; Cárdaba, B; del Pozo, V; de Andrés, B; Cortegano, I; Jurado, A; Tramón, P; Palomino, P; Lahoz, C

    1997-03-14

    Toxic Oil Syndrome is a multisystemic disease that occurred in epidemic proportions in Spain in 1981 caused by the ingestion of rapeseed oil denatured with aniline. Several data implicate T cells in the pathogenesis of the disease. We evaluated the mechanisms of cytotoxicity in human lymphocytes of TOS-related products: aniline, 3-(N-phenylamino)-1,2-propanediol and its mono- and di-oleyl esters and eosinophilia myalgia-related product such as 3-(phenylamino)-L-alanine, which is chemically similar to 3-(N-phenylamino)-1,2-propanediol, and has been found in manufactured L-tryptophan. Our results show that only di-oleyl ester of 3-(N-phenylamino)-1,2-propanediol induces apoptosis in human lymphocytes, in a concentration and time-dependent way, confirmed by morphology, expression of phosphatidylserine in membrane and analysis of DNA degradation. PMID:9074655

  11. Toxic effects of isoproturon on periphyton communities a microcosm study

    NASA Astrophysics Data System (ADS)

    Schmitt-Jansen, Mechthild; Altenburger, Rolf

    2005-02-01

    Coastal and estuarine ecosystems are increasingly exposed to herbicide contamination. To study the potential risks of these pollutants, the establishment of periphyton communities under exposure of a concentration series of isoproturon in a range of 0.0024-0.312 mg L -1 was investigated in a microcosm study. After two weeks of growth, chronic effects on biomass development, measured as Chl a fluorescence, taxonomic composition and photosynthetic capacity of PS II of attached microalgae were analysed using a pulse-amplitude modulated (PAM) fluorescence-based method. Algal classes were differentiated according to their pigment systems using four excitation wavelengths. Biomass remained constant up to pre-exposure concentrations of 0.02 mg L -1 isoproturon but decreased within one order of magnitude at the highest test concentration. Algal classes shifted from diatoms to chlorophytes at pre-exposure concentrations of 0.02-0.39 mg L -1. Community structure of diatoms representing the dominant group of attached algae at lower test concentrations was studied by microscopic analysis revealing that species numbers were highest at lowest test concentrations as compared to controls. At higher test concentrations Navicula halophila dominated with 89% of the diatom biomass but was abnormally shaped. Pollution-induced community tolerance (PICT) of periphyton to isoproturon was determined by short-term inhibition tests of photosynthesis. Pre-exposed communities increased their effect concentrations (EC 50) up to threefold within the 0.039 mg L -1 pre-treatment. Our results suggest that attached microalgal communities have a high potential of tolerance development to isoproturon at lower levels of contamination due to the replacement of sensitive species by more tolerant algae, although these species seemed to be affected too. We conclude that herbicide concentrations in river basins, estuaries or coastal zones may change community structure and primary production of

  12. Is Boric Acid Toxic to Reproduction in Humans? Assessment of the Animal Reproductive Toxicity Data and Epidemiological Study Results.

    PubMed

    Duydu, Yalçın; Başaran, Nurşen; Ustündağ, Aylin; Aydın, Sevtap; Undeğer, Ulkü; Ataman, Osman Yavuz; Aydos, Kaan; Düker, Yalçın; Ickstadt, Katja; Waltrup, Brita Schulze; Golka, Klaus; Bolt, Hermann Maximilian

    2016-01-01

    Boric acid and sodium borates are classified as toxic to reproduction in the CLP Regulation under "Category 1B" with the hazard statement of "H360FD". This classification is based on the reprotoxic effects of boric acid and sodium borates in animal experiments at high doses. However, boron mediated reprotoxic effects have not been proven in epidemiological studies so far. The epidemiological study performed in Bandırma boric acid production plant is the most comprehensive published study in this field with 204 voluntarily participated male workers. Sperm quality parameters (sperm morphology, concentration and motility parameters), FSH, LH and testosterone levels were determined in all participated employees as the reproductive toxicity biomarkers of males. However, boron mediated unfavorable effects on reproduction in male workers have not been determined even in the workers under very high daily boron exposure (0.21 mg B/kg-bw/day) conditions. The NOAEL for rat reproductive toxicity is equivalent to a blood boron level of 2020 ng/g. This level is higher than the mean blood boron concentration (223.89 ± 69.49 ng/g) of the high exposure group workers in Bandırma boric acid production plant (Turkey) by a factor of 9. Accordingly, classifying boric acid and sodium borates under "Category 1B" as "presumed reproductive human toxicant in the CLP regulation seems scientifically not reasonable. The results of the epidemiological studies (including the study performed in China) support for a down-classification of boric acid from the category 1B, H360FD to category 2, H361d, (suspected of damaging the unborn child). PMID:26511087

  13. Prenatal development toxicity study of zinc oxide nanoparticles in rats.

    PubMed

    Hong, Jeong-Sup; Park, Myeong-Kyu; Kim, Min-Seok; Lim, Jeong-Hyeon; Park, Gil-Jong; Maeng, Eun-Ho; Shin, Jae-Ho; Kim, Meyoung-Kon; Jeong, Jayoung; Park, Jin-A; Kim, Jong-Choon; Shin, Ho-Chul

    2014-01-01

    This study investigated the potential adverse effects of zinc oxide nanoparticles ([ZnO(SM20(+)) NPs] zinc oxide nanoparticles, positively charged, 20 nm) on pregnant dams and embryo-fetal development after maternal exposure over the period of gestational days 5-19 with Sprague-Dawley rats. ZnO(SM20(+)) NPs were administered to pregnant rats by gavage at 0, 100, 200, and 400 mg/kg/day. All dams were subjected to a cesarean section on gestational day 20, and all of the fetuses were examined for external, visceral, and skeletal alterations. Toxicity in the dams manifested as significantly decreased body weight after administration of 400 mg/kg/day NPs; reduced food consumption after administration of 200 and 400 mg/kg/day NPs; and decreased liver weight and increased adrenal glands weight after administration of 400 mg/kg/day NPs. However, no treatment-related difference in: number of corpora lutea; number of implantation sites; implantation rate (%); resorption; dead fetuses; litter size; fetal deaths and placental weights; and sex ratio were observed between the groups. On the other hand, significant decreases between treatment groups and controls were seen for fetal weights after administration of 400 mg/kg/day NPs. Morphological examinations of the fetuses demonstrated significant differences in incidences of abnormalities in the group administered 400mg/kg/day. Meanwhile, no significant difference was found in the Zn content of fetal tissue between the control and high-dose groups. These results showed that oral doses for the study with 15-days repeated of ZnO(SM20(+)) NPs were maternotoxic in the 200 mg/kg/day group, and embryotoxic in the 400 mg/kg/day group. PMID:25565834

  14. Prenatal development toxicity study of zinc oxide nanoparticles in rats

    PubMed Central

    Hong, Jeong-Sup; Park, Myeong-Kyu; Kim, Min-Seok; Lim, Jeong-Hyeon; Park, Gil-Jong; Maeng, Eun-Ho; Shin, Jae-Ho; Kim, Meyoung-Kon; Jeong, Jayoung; Park, Jin-A; Kim, Jong-Choon; Shin, Ho-Chul

    2014-01-01

    This study investigated the potential adverse effects of zinc oxide nanoparticles ([ZnOSM20(+) NPs] zinc oxide nanoparticles, positively charged, 20 nm) on pregnant dams and embryo–fetal development after maternal exposure over the period of gestational days 5–19 with Sprague-Dawley rats. ZnOSM20(+) NPs were administered to pregnant rats by gavage at 0, 100, 200, and 400 mg/kg/day. All dams were subjected to a cesarean section on gestational day 20, and all of the fetuses were examined for external, visceral, and skeletal alterations. Toxicity in the dams manifested as significantly decreased body weight after administration of 400 mg/kg/day NPs; reduced food consumption after administration of 200 and 400 mg/kg/day NPs; and decreased liver weight and increased adrenal glands weight after administration of 400 mg/kg/day NPs. However, no treatment-related difference in: number of corpora lutea; number of implantation sites; implantation rate (%); resorption; dead fetuses; litter size; fetal deaths and placental weights; and sex ratio were observed between the groups. On the other hand, significant decreases between treatment groups and controls were seen for fetal weights after administration of 400 mg/kg/day NPs. Morphological examinations of the fetuses demonstrated significant differences in incidences of abnormalities in the group administered 400mg/kg/day. Meanwhile, no significant difference was found in the Zn content of fetal tissue between the control and high-dose groups. These results showed that oral doses for the study with 15-days repeated of ZnOSM20(+) NPs were maternotoxic in the 200 mg/kg/day group, and embryotoxic in the 400 mg/kg/day group. PMID:25565834

  15. Studies on a toxic metabolite from the mould Wallemia.

    PubMed

    Wood, G M; Mann, P J; Lewis, D F; Reid, W J; Moss, M O

    1990-01-01

    While monitoring the occurrence of toxigenic moulds in foods, using a bioassay screen, it was shown that an isolate of Wallemia sebi produced toxic effects in several of the bioassays. The toxic metabolite was isolated and purified using solvent extraction, TLC and HPLC coupled with the brine shrimp assay to monitor the toxic fractions. The purified toxin, which we propose to call walleminol A, has been partially characterized by mass spectroscopy, nuclear magnetic resonance, ultraviolet and infrared spectroscopy. It can be provisionally interpreted as a tricyclic dihydroxy compound, C15H24O2, with structural features characteristic of a sesquiterpene with an isolated double bond, but further work is required to characterize this compound unequivocally. The minimum inhibitory dose of walleminol A in the bioassays is approximately 50 micrograms/ml, which is comparable with a number of mycotoxins such as citrinin and penicillic acid. PMID:2106458

  16. Developmental Toxicity

    EPA Science Inventory

    This chapter provides an overview the developmental toxicity resulting from exposure to perfluorinated alkyl acids (PFAAs). The majority of studies of PFAA-induced developmental toxicity have examined effects of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) a...

  17. Evaluation and interpretation of maternal toxicity in Segment II studies: Issues, some answers, and data needs

    SciTech Connect

    Rogers, John M. . E-mail: rogers.john@epa.gov; Chernoff, Neil; Keen, Carl L.; Daston, George P.

    2005-09-01

    Biologically rational regulatory policies with regards to developmental toxicity are often based on the extrapolation of standard laboratory rodent bioassay results to the human population. Significantly contributing to the difficulty of this task is the possibility that general toxic effects on the maternal organism may affect the developing conceptus. This review examines maternal factors which may bear directly or indirectly upon developmental outcome, with emphasis on those of greatest relevance to the hazard assessment process. Standard teratology testing protocols call for top dosage levels that induce overt maternal toxicity, and the developmental effects of this toxicity (both alone, and with concurrent embryo/fetal insult) continue to present regulators with considerable interpretive difficulties. In response to these problems, there have been both research and literature review efforts dealing with the relationship of maternal and developmental toxicity. Maternally mediated developmental toxicity occurs with a number of agents, and toxicant-induced alterations in maternal physiology may affect the conceptus at dosages not causing overt maternal toxicity. Relevant studies are reviewed here, and suggestions for avenues of future research are offered including the identification of any syndromes of developmental effects occurring at maternally toxic levels irrespective of the causative agent, and experimental approaches for the characterization of maternal toxicity.

  18. DOSE-DEPENDENT TRANSITIONS IN MECHANISMS OF TOXICITY: CASE STUDIES

    EPA Science Inventory

    Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed ...

  19. The National Near-Road Mobile Source Air Toxics Study

    EPA Science Inventory

    Recently, much attention has been directed at understanding the impact of mobile sources on near-road air quality, especially PM and its components, NOx and CO, but little information exists for mobile source air toxics (MSATs). MSATs of interest to this project are 1,3-butadiene...

  20. AQUATIC TOXICITY MODE OF ACTION STUDIES APPLIED TO QSAR DEVELOPMENT

    EPA Science Inventory

    A series of QSAR models for predicting fish acute lethality were developed using systematically collected data on more than 600 chemicals. These models were developed based on the assumption that chemicals producing toxicity through a common mechanism will have commonality in the...

  1. TOXICITY STUDIES WITH DECAMETHRIN, A SYNTHETIC PYRETHROID INSECTICIDE

    EPA Science Inventory

    Decamethrin is a synthetic pyrethroid insecticide that has been under investigation by the World Health Organization for use in some vector control programs. Decamethrin proved to be a highly toxic pyrethroid ester. The acute LD50 for adult female rats was 31 mg/kg by the oral ro...

  2. Sediment toxicity identification evaluation (TIE) studies at marine sites suspected of ordnance contamination

    USGS Publications Warehouse

    Carr, R.S.; Nipper, M.; Biedenbach, J.M.; Hooten, R.L.; Miller, K.; Saepoff, S.

    2001-01-01

    A sediment quality assessment survey and subsequent toxicity identification evaluation (TIE) study was conducted at several sites in Puget Sound, Washington. The sites were previously suspected of contamination with ordnance compounds. The initial survey employed sea urchin porewater toxicity tests to locate the most toxic stations. Sediments from the most toxic stations were selected for comprehensive chemical analyses. Based on the combined information from the toxicity and chemical data, three adjacent stations in Ostrich Bay were selected for the TIE study. The results of the phase I TIE suggested that organics and metals were primarily responsible for the observed toxicity in the sea urchin fertilization test. In addition to these contaminants, ammonia was also contributing to the toxicity for the sea urchin embryological development test. The phase II TIE study isolated the majority of the toxicity in the fraction containing nonpolar organics with high log Kow, but chemical analyses failed to identify a compound present at a concentration high enough to be responsible for the observed toxicity. The data suggest that some organic or organometallic contaminant(s) that were not included in the comprehensive suite of chemical analyses caused the observed toxicological responses.

  3. Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

    PubMed

    Hu, Boqi; Wang, Juan; Guo, Yingying; Chen, Tanxiu; Ni, Weihua; Yuan, Hongyan; Zhang, Nannan; Xie, Fei; Tai, Guixiang

    2016-04-01

    Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial. PMID:26896668

  4. Toxicologic evaluations of DHA-rich algal oil in rats: developmental toxicity study and 3-month dietary toxicity study with an in utero exposure phase.

    PubMed

    Schmitt, D; Tran, N; Peach, J; Edwards, T; Greeley, M

    2012-11-01

    DHA-rich algal oil ONC-T18, tested for subchronic, reproductive, and developmental toxicity in the rat, did not produce any significant toxicologic manifestations. Based on the absence of maternal or developmental toxicity at any dosage level, a dosage level of 2000 mg/kg/day was considered to be the no observed adverse-effect level (NOAEL) for maternal toxicity and embryo/fetal development when DHA-rich algal oil was administered orally by gavage to pregnant Crl:CD(SD) rats during gestation days 6-19. In a dietary combined one-generation/90-day reproductive toxicity study in rats, the NOAEL for F0 male and female and F1 male systemic toxicity was considered to be 50,000 ppm (highest concentration administered) and 25,000 ppm for F1 female systemic toxicity (higher mean body weight, body weight gain, and food consumption). F0 reproductive performance values, estrous cycle length, gestation length, or the process of parturition, and the numbers of former implantation sites and unaccounted-for sites were unaffected by algal oil exposure. Postnatal survival and developmental parameters in the F1 generation were unaffected by algal oil exposure at all dietary concentrations. There were no neurotoxic effects noted at any algal oil exposure level. The results support the safety of DHA-rich algal oil for its proposed use in food. PMID:22960629

  5. EFFECT OF NITRATE-BASED BIOREMEDIATION ON CONTAMINANT DISTRIBUTION AND SEDIMENT TOXICITY-COLUMN STUDY

    EPA Science Inventory

    A laboratory column study was set up to evaluate changes in contaminant distribution and sediment toxicity following nitrate-based bioremediation and to correlate toxicity reduction with loss of fuel components. Glass columns were packed with sediment from an aquifer that had be...

  6. ORAL TOXICITY OF CARBON TETRACHLORIDE: ACUTE, SUBACUTE, AND SUBCHRONIC STUDIES IN RATS

    EPA Science Inventory

    The investigation was conducted to characterize the acute, subacute and subchronic toxic potency of ingested carbon tetrachloride (CCl4). In the first acute and subchronic toxicity study, male Sprague-Dawley rats of 300-350 g were gavaged with 0, 20, 40 or 80 mg CCl4/kg once dail...

  7. PLANT EXPOSURE CHAMBERS FOR STUDY OF TOXIC CHEMICAL-PLANT INTERACTIONS (JOURNAL VERSION)

    EPA Science Inventory

    Chambers for the study of plant uptake and phytotoxicity of toxic, radio-labeled chemicals are described. The chambers are designed to meet the criteria of continuously stirred tank reactors while providing containment for toxic chemical. They are computer managed and operated wi...

  8. A comparative study on toxicity identification of industrial effluents using Daphnia magna.

    PubMed

    Yi, Xianliang; Kim, Eunhee; Jo, Hun-Je; Han, Taejun; Jung, Jinho

    2011-09-01

    In this study, acute toxicity monitoring and toxicity identification evaluation procedures were applied to identify causative toxicants in industrial effluents. Effluents from a metal plating factory and a rubber products factory were acutely toxic toward Daphnia magna and the toxicity varied over different sampling events (2.9-5.9 and 1.7-7.6 TU, respectively). For the rubber products effluent, it was confirmed that zinc (5.65-13.18 mg L(-1)) was found to be a major cause of toxicity, which is likely originated from zinc 2-mercaptobenzothiazole and zinc diethyldithiocarbamate used as vulcanization accelerators. For the metal plating effluent, it appeared that the presence of high concentrations of Cl(-) and SO(4)(2-) (8,539-11,400 and 3,588-4,850 mg L(-1), respectively) caused the observed toxicity. These toxicants likely originated from sodium bisulfate (NaHSO(3)) and sodium hypochlorite (NaOCl) used as reducing and oxidizing agents. Though copper was found to be present in levels much higher than the EC(50) (50% effective concentration) value, this was not attributable to the toxicity of metal plating effluent likely due to complexation with dissolved organic matter. PMID:21761172

  9. The effects of fasting on the acute oral toxicity of nine chemicals in the rat.

    PubMed

    Dashiell, O L; Kennedy, G L

    1984-12-01

    Nine chemicals, with a range from extremely to slightly toxic, were used to measure the oral LD50 in both fasted (24-h) and non-fasted rats. Each chemical was tested as a solution or suspension in corn oil, responses within 14 days post-treatment were evaluated, and LD50S were calculated. Hexachlorophene was more toxic in non-fasted rats. The LD50 values for tetraethyl lead, methomyl and hexamethylenediamine were essentially the same in both fasted and non-fasted rats. Adiponitrile, bromobenzene, caffeine, carbon tetrachloride and N-butyl-1,6-hexamediamine yielded lower LD50 values in fasted rats. The use of non-fasted rats in acute oral toxicity determinations allows both the establishment of relative potency and the estimation of dosage levels for further repeated dose oral studies. The LD50 values obtained were generally (7 of 9) higher in non-fasted rats, but the magnitude of the differences was not great enough to suggest routine use of both fasted and non-fasted rats in oral toxicity studies. PMID:6520321

  10. Assessing acute toxicities of pre- and post-treatment industrial wastewaters with Hydra attenuata: A comparative study of acute toxicity with the fathead minnow, Pimephales promelas

    SciTech Connect

    Fu, L.J.; Staples, R.E.; Stahl, R.G. Jr. . Haskell Lab. for Toxicology and Industrial Medicine)

    1994-04-01

    This study was undertaken to (a) determine wastewater treatment effectiveness using two freshwater organisms, (b) compare acute toxicity results from the two species exposed to the wastewaters, and (c) link acute and potential developmental toxicity of wastewaters in one organism. The acute toxicities of several pretreatment and post-treatment industrial waste-water samples wee evaluated with adult Hydra attenuata and fathead minnows. The acute LC50s agreed closely when results in Hydra attenuata were compared with those from fathead minnow tests. Acute LC50s ranged from 3 to >100% of samples with hydra, and from 1.0 to >100% of sample with fathead minnows. The results provided strong evidence of treatment effectiveness because toxicity decreased with progressive stages of treatment. Previously the Hydra Developmental Toxicity Assay was used as a prescreen mainly for in vitro assessment of developmental toxicity with pure compounds and to prioritized toxicants according to selective toxicity to the developing embryo. Recently the authors modified the assay for testing natural waters and wastewaters; hence, some of the wastewater samples also were tested for their developmental toxicity. In this case, the relative selective toxicity of these wastewater samples ranged from 0.7 to 2.1, indicating that no sample was uniquely toxic to the developing embryo, although acute toxicity was manifested. Overall, their results indicate the Hydra Assay functions appropriately in assessments of acute and developmental toxicity of industrial wastewaters and may be a simple and useful tool in a battery of tests for broader scale detection of environmental hazards.

  11. [The importance of using biological test objects in studying the toxicity of surface-active substances].

    PubMed

    Mudryĭ, I V; Debrivnaia, I E

    1996-01-01

    The Azotobacter agilis [correction of azobacter agile] culture appeared to be the most sensitive one among the studied test objects. Buckwheat as a test plant can be recommended in studying the toxicity of surface-active substances. PMID:9035856

  12. Toxicity studies on herbal formulation used in diabetes mellitus.

    PubMed

    Baig, Iftikhar Ahmad; Mehjabeen, -; Muhammed, Shafi; Jahan, Noor; Haq, Nomanul

    2014-11-01

    .255; female-43.50 ± 0.448) and significant (p<0.5) increased in WBC count (male-8.40 ± 0.401; female-9.10 ± 0.054). Significant (p<0.5) decrease in blood glucose level and HbA1c (male-3.36 ± 0.113; female-3.16 ± 0.076) was observed. In histopathological studies mild edema was observed in heart and there was no change in histo-architecture of liver and kidneys. It is concluded that formulation does not showed any chronic toxicity in adult dose. PMID:26045373

  13. A Structural Modelling Study on Marine Sediments Toxicity

    PubMed Central

    Jäntschi, Lorentz; Bolboacã, Sorana D.

    2008-01-01

    Quantitative structure-activity relationship models were obtained by applying the Molecular Descriptor Family approach to eight ordnance compounds with different toxicity on five marine species (arbacia punctulata, dinophilus gyrociliatus, sciaenops ocellatus, opossum shrimp, and ulva fasciata). The selection of the best among molecular descriptors generated and calculated from the ordnance compounds structures lead to accurate monovariate models. The resulting models obtained for six endpoints proved to be accurate in estimation (the squared correlation coefficient varied from 0.8186 to 0.9997) and prediction (the correlation coefficient obtained in leave-one-out analysis varied from 0.7263 to 0.9984). PMID:18728732

  14. A Mechanistic Study on the Amiodarone-Induced Pulmonary Toxicity

    PubMed Central

    Al-Shammari, Bader; Khalifa, Mohamed; Bakheet, Saleh A.; Yasser, Moustafa

    2016-01-01

    Amiodarone- (AM-) induced pulmonary toxicity (AIPT) is still a matter of research and is poorly understood. In attempting to resolve this issue, we treated Sprague-Dawley rats with AM doses of 80 mg/kg/day/i.p. for one, two, three, and four weeks. The rats were weighed at days 7, 14, 21, and 28 and bronchoalveolar lavages (BAL) were obtained to determine total leukocyte count (TLC). For each group, lung weighing, histopathology, and homogenization were performed. Fresh homogenates were used for determination of ATP content, lipid peroxides, GSH, catalase, SOD, GPx, GR activities, NO, and hydroxyproline levels. The results showed a significant decrease in body weight and GSH depletion together with an increase in both lung weight and lung/body weight coefficient in the first week. Considerable increases in lung hydroxyproline level with some histopathological alterations were apparent. Treatment for two weeks produced a significant increase in BAL fluid, TLC, GR activity, and NO level in lung homogenate. The loss of cellular ATP and inhibition of most antioxidative protective enzymatic system appeared along with alteration in SOD activity following daily treatment for three weeks, while, in rats treated with AM for four weeks, more severe toxicity was apparent. Histopathological diagnosis was mostly granulomatous inflammation and interstitial pneumonitis in rats treated for three and four weeks, respectively. As shown, it is obvious that slow oedema formation is the only initiating factor of AIPT; all other mechanisms may occur as a consequence. PMID:26933474

  15. Toxicity of leachate from weathering plastics: An exploratory screening study with Nitocra spinipes.

    PubMed

    Bejgarn, Sofia; MacLeod, Matthew; Bogdal, Christian; Breitholtz, Magnus

    2015-08-01

    Between 60% and 80% of all marine litter is plastic. Leachate from plastics has previously been shown to cause acute toxicity in the freshwater species Daphnia magna. Here, we present an initial screening of the marine environmental hazard properties of leachates from weathering plastics to the marine harpacticoid copepod [Crustacea] Nitocra spinipes. Twenty-one plastic products made of different polymeric materials were leached and irradiated with artificial sunlight. Eight of the twenty-one plastics (38%) produced leachates that caused acute toxicity. Differences in toxicity were seen for different plastic products, and depending on the duration of irradiation. There was no consistent trend in how toxicity of leachate from plastics changed as a function of irradiation time. Leachate from four plastics became significantly more toxic after irradiation, two became significantly less toxic and two did not change significantly. Analysis of leachates from polyvinyl chloride (PVC) by liquid chromatography coupled to a full-scan high-resolution mass spectrometer showed that the leachates were a mixture of substances, but did not show evidence of degradation of the polymer backbone. This screening study demonstrates that leachates from different plastics differ in toxicity to N. spinipes and that the toxicity varies under simulated weathering. PMID:25828916

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

    PubMed

    Ismail, Zakiah; Halim, Siti Zaleha; Abdullah, Noor Rain; Afzan, Adlin; Abdul Rashid, Badrul Amini; Jantan, Ibrahim

    2014-01-01

    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. PMID:25530788

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

    PubMed Central

    Ismail, Zakiah; Abdullah, Noor Rain; Abdul Rashid, Badrul Amini; Jantan, Ibrahim

    2014-01-01

    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. PMID:25530788

  18. Systematic and comprehensive investigation of the toxicity of curcuminoid-essential oil complex: A bioavailable turmeric formulation

    PubMed Central

    AGGARWAL, MADAN L.; CHACKO, KARAMPENDETHU M.; KURUVILLA, BINU T.

    2016-01-01

    Curcumin, the active component present in Curcuma longa of the family Zingiberaceae, has a number of pharmacological effects, including potential anti-inflammatory activity. One of the major limitations of curcumin/turmeric extract is its poor absorption through the gastrointestinal tract. Several approaches have been adopted to increase the bioavailability of curcumin, including loading curcumin into liposomes or nanoparticles, complexation with phospholipids, addition of essential oils and synthesizing structural analogues of curcumin. In the present study, the toxicity and safety of one such bioavailable turmeric formulation, curcuminoid-essential oil complex (CEC), the toxicity profile of which has not been reported, were examined using in vivo and in vitro models, as per the guidelines of the Organisation for Economic Co-operation and Development. Investigations of acute toxicity study were performed in rats and mice, and the results revealed no signs and symptoms or toxicity or mortality in any of the animals at the maximum recommended dose level of 5,000 mg/kg body weight. The repeated administration of CEC for 90 days in Wistar rats at a dose of 1,000 mg/kg body weight did not induce any observable toxic effects, compared with corresponding control animals. Mutagenicity/genotoxicity investigations were also performed using a bacterial reverse mutation assay (Ames test), a mammalian bone marrow chromosome aberration test and a mammalian erythrocyte micronucleus test in mice. CEC was found to be non-mutagenic in all three mutagenic investigations. Consequently, the present study indicated that CEC elicited no toxic effects in animals or in vitro. Therefore, following investigations of acute toxicity, repeated dose toxicity and mutagenicity, CEC was deemed a safe, non-toxic pharmacological formulation. PMID:26648561

  19. Systematic and comprehensive investigation of the toxicity of curcuminoid‑essential oil complex: A bioavailable turmeric formulation.

    PubMed

    Aggarwal, Madan L; Chacko, Karampendethu M; Kuruvilla, Binu T

    2016-01-01

    Curcumin, the active component present in Curcuma longa of the family Zingiberaceae, has a number of pharmacological effects, including potential anti‑inflammatory activity. One of the major limitations of curcumin/turmeric extract is its poor absorption through the gastrointestinal tract. Several approaches have been adopted to increase the bioavailability of curcumin, including loading curcumin into liposomes or nanoparticles, complexation with phospholipids, addition of essential oils and synthesizing structural analogues of curcumin. In the present study, the toxicity and safety of one such bioavailable turmeric formulation, curcuminoid‑essential oil complex (CEC), the toxicity profile of which has not been reported, were examined using in vivo and in vitro models, as per the guidelines of the Organisation for Economic Co-operation and Development. Investigations of acute toxicity study were performed in rats and mice, and the results revealed no signs and symptoms or toxicity or mortality in any of the animals at the maximum recommended dose level of 5,000 mg/kg body weight. The repeated administration of CEC for 90 days in Wistar rats at a dose of 1,000 mg/kg body weight did not induce any observable toxic effects, compared with corresponding control animals. Mutagenicity/genotoxicity investigations were also performed using a bacterial reverse mutation assay (Ames test), a mammalian bone marrow chromosome aberration test and a mammalian erythrocyte micronucleus test in mice. CEC was found to be non‑mutagenic in all three mutagenic investigations. Consequently, the present study indicated that CEC elicited no toxic effects in animals or in vitro. Therefore, following investigations of acute toxicity, repeated dose toxicity and mutagenicity, CEC was deemed a safe, non‑toxic pharmacological formulation. PMID:26648561

  20. Compilation of International Regulatory Guidance Documents for Neuropathology Assessment during Nonclinical Toxicity Studies

    EPA Science Inventory

    Neuropathology analysis as an endpoint during nonclinical efficacy and toxicity studies is a challenging prospect that requires trained personnel and particular equipment to achieve optimal results. Accordingly, many regulatory agencies have produced explicit guidelines for desig...

  1. Pharmacologic Alternatives to Riboflavin Photochemical Corneal Cross-Linking: A Comparison Study of Cell Toxicity Thresholds

    PubMed Central

    Kim, MiJung; Takaoka, Anna; Hoang, Quan V.; Trokel, Stephen L.; Paik, David C.

    2014-01-01

    Purpose. The efficacy of therapeutic cross-linking of the cornea using riboflavin photochemistry (commonly abbreviated as CXL) has caused its use to become widespread. Because there are known chemical agents that cross-link collagenous tissues, it may be possible to cross-link tissue pharmacologically. The present study was undertaken to compare the cell toxicity of such agents. Methods. Nine topical cross-linking agents (five nitroalcohols, glyceraldehyde [GLYC], genipin [GP], paraformaldehyde [FA], and glutaraldehyde [GLUT]) were tested with four different cell lines (immortalized human corneal epithelial cells, human skin fibroblasts, primary bovine corneal endothelial cells, and immortalized human retinal pigment epithelial cells [ARPE-19]). The cells were grown in planar culture and exposed to each agent in a range of concentrations (0.001 mM to 10 mM) for 24 hours followed by a 48-hour recovery phase. Toxicity thresholds were determined by using the trypan blue exclusion method. Results. A semiquantitative analysis using five categories of toxicity/fixation was carried out, based on plate attachment, uptake of trypan blue stain, and cellular fixation. The toxicity levels varied by a factor of 103 with the least toxic being mononitroalcohols and GLYC, intermediate toxicity for a nitrodiol and nitrotriol, and the most toxic being GLUT, FA, GP, and bronopol, a brominated nitrodiol. When comparing toxicity between different cell lines, the levels were generally in agreement. Conclusions. There are significant differences in cell toxicity among potential topical cross-linking compounds. The balance between cross-linking of tissue and cell toxicity should be borne in mind as compounds and strategies to improve mechanical tissue properties through therapeutic tissue cross-linking continue to develop. PMID:24722697

  2. Prostate Hypofractionated Radiation Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study

    SciTech Connect

    Chapet, Olivier; Decullier, Evelyne; Bin, Sylvie; Faix, Antoine; Ruffion, Alain; Jalade, Patrice; Fenoglietto, Pascal; Udrescu, Corina; Enachescu, Ciprian; Azria, David

    2015-03-15

    Purpose: Hypofractionated radiation therapy (RT) in prostate cancer can be developed only if the risk of rectal toxicity is controlled. In a multicenter phase 2 trial, hypofractionated irradiation was combined with an injection of hyaluronic acid (HA) to preserve the rectal wall. Tolerance of the injection and acute toxicity rates are reported. Methods and Materials: The study was designed to assess late grade 2 toxicity rates. The results described here correspond to the secondary objectives. Acute toxicity was defined as occurring during RT or within 3 months after RT and graded according to the Common Terminology Criteria for Adverse Events version 4.0. HA tolerance was evaluated with a visual analog scale during the injection and 30 minutes after injection and then by use of the Common Terminology Criteria at each visit. Results: From 2010 to 2012, 36 patients with low-risk to intermediate-risk prostate cancer were included. The HA injection induced a mean pain score of 4.6/10 ± 2.3. Thirty minutes after the injection, 2 patients still reported pain (2/10 and 3/10), which persisted after the intervention. Thirty-three patients experienced at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities. Conclusions: The injection of HA makes it possible to deliver hypofractionated irradiation over 4 weeks with a dose per fraction of > 3 Gy, with limited acute rectal toxicity.

  3. Pilot study for ambient toxicity testing in Chesapeake bay. Year two report

    SciTech Connect

    Hall, L.W.; Ziegenfuss, M.C.; Fischer, S.A.; Anderson, R.D.; Killen, W.D.

    1992-11-01

    The primary goal of the ambient toxicity testing pilot study was to identify toxic areas in living resource habitats of the Chesapeake Bay watershed by using a battery of standardized, directly modified or recently developed water column, sediment and suborganismal toxicity tests. Tests were conducted twice at the following stations: Potomac River-Morgantown, Potomac River-Dahlgren, Patapsco River and Wye River. A suite of inorganic and organic contaminants was evaluated in the water column and sediment during these tests. Standard water quality conditions were also evaluated in water and sediment from all stations.

  4. A review of toxicity studies of single-walled carbon nanotubes in laboratory animals.

    PubMed

    Ema, Makoto; Gamo, Masashi; Honda, Kazumasa

    2016-02-01

    We summarized the findings of in vivo toxicity studies of single-walled carbon nanotubes (SWCNTs) in laboratory animals. The large majority addressed the pulmonary toxicity of SWCNTs in rodents. Inhalation, pharyngeal aspiration, and intratracheal instillation studies revealed that SWCNTs caused acute and chronic inflammation, granuloma formation, collagen deposition, fibrosis, and genotoxic effects in the lungs. Pulmonary toxicity of well-dispersed SWCNTs was more potent than less dispersed ones. Airway exposure to SWCNTs also induced cardiovascular diseases in mice. Oxidative stress was caused by the administration of SWCNTs. Injected SWCNTs were distributed throughout most of the organs including the brain, mainly retained in the lungs, liver, and spleen, and eliminated through the kidney and bile duct. Orally administered SWCNTs are suggested to be absorbed from the gastrointestinal tract to the blood circulation in mice and rats. Although no definitive study on the carcinogenicity of SWCNTs is available at present, evidence of carcinogenicity has not been reported in toxicity studies cited in this review. Overall, the available data provides initial information on SWCNT toxicity. To further clarify their toxicity and risk assessment, studies should be conducted using well-characterized SWCNTs, standard protocols, and the relevant route and doses of human exposure. PMID:26619783

  5. Comparison of toxicity values across zebrafish early life stages and mammalian studies: Implications for chemical testing.

    PubMed

    Ducharme, Nicole A; Reif, David M; Gustafsson, Jan-Ake; Bondesson, Maria

    2015-08-01

    With the high cost and slow pace of toxicity testing in mammals, the vertebrate zebrafish has become a tractable model organism for high throughput toxicity testing. We present here a meta-analysis of 600 chemicals tested for toxicity in zebrafish embryos and larvae. Nineteen aggregated and 57 individual toxicity endpoints were recorded from published studies yielding 2695 unique data points. These data points were compared to lethality and reproductive toxicology endpoints analyzed in rodents and rabbits and to exposure values for humans. We show that although many zebrafish endpoints did not correlate to rodent or rabbit acute toxicity data, zebrafish could be used to accurately predict relative acute toxicity through the rat inhalation, rabbit dermal, and rat oral exposure routes. Ranking of the chemicals based on toxicity and teratogenicity in zebrafish, as well as human exposure levels, revealed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo(a)pyrene, and chlorpyrifos ranked in the top nine of all chemicals for these three categories, and as such should be considered high priority chemicals for testing in higher vertebrates. PMID:25261610

  6. Modified toxicity identification evaluation studies for achieving mining sector MISA compliance

    SciTech Connect

    Cotton, K.; Sferrazza, J.; Shriner, G.

    1995-12-31

    Results of initial MISA toxicity compliance monitoring for a multiple effluent stream mining operation indicated the presence of sporadic acute toxicity. Traditionally, only small scale acute and sub-lethal species (i.e. D. magna, C. dubia, P. promelas, Microtox) have been utilized during Toxicity Identification Evaluation (TIE) studies. These methods had proven to be very expensive and of limit value in planning the future direction of mining effluent treatment. A more direct and economical approach to toxicity investigations was needed to prepare for the 1997 compliance deadline for non-lethality and water chemistry objectives. A modified EPA-TIE investigation was initiated on the problem effluent streams. Phase 1 modifications were made to include both MISA compliance organisms, D. magna and rainbow trout (O. mykiss). Phases 2 and 3 were replaced with effluent treatability assays derived from toxicity reduction/elimination information obtained during Phase 1 procedures. Information on potential toxicant speciation under the various treatment conditions was also collected. Preliminary results indicate that variations in the applied treatment, as well as the degree of treatment will be required for the different effluent streams to obtain non-acutely toxic effluent. Ongoing laboratory tests are being conducted to achieve consistency and confidence in the results, allowing plant operators to make informed decisions regarding the (expensive) changes to be made in their effluent treatment facilities over the next few years.

  7. Acute mouse and chronic dog toxicity studies of danthron, dioctyl sodium sulfosuccinate, poloxalkol and combinations.

    PubMed

    Case, M T; Smith, J K; Nelson, R A

    Because of an apparent typographic error in a US patent, there has been some confusion as to the acute oral toxicity of danthron and danthron in combination with dioctyl sodium sulfosuccinate (DSS). Acute oral toxicity studies in mice revealed LD50 values of greater than 7 gm/kg for danthron, 2.64 gm/kg for DSS and 3.42 gm/kg for danthron/DSS mixture (1:2 ratio). These results indicate that the lethality of these compounds is in the gm/kg range and not in the mg/kg range. A one year chronic toxicity study of danthron, dioctyl sodium sulfosuccinate, poloxalkol and combinations in dogs failed to reveal any toxic effects. In particular, there was no evidence of hepatotoxicity or of any changes in the myenteric plexuses in the chronically treated dogs. PMID:90594

  8. Juvenile toxicity study of faropenem medoxomil in beagle puppies.

    PubMed

    Faqi, Ali S; Lanphear, Chery; Gill, Stan; Colagiovanni, Dorothy B

    2010-12-01

    We determined the toxicity of faropenem medoxomil (FPM) in neonatal/juvenile dogs following 28 days of administration. The puppies received vehicle or FPM beginning on Postnatal Day (PND) 22 at respective dose levels of 0, 100, 300, 600, or 1400 mg/kg-d (four daily doses (QID) of 25, 75, 150, or 350 mg/kg/dose), respectively, at a dose volume of 5 mL/kg/dose. Body weight, food consumption, clinical observation, clinical pathology, urine analysis and TK were evaluated. Body weight in males and kidney findings at 1400 mg/kg-d were considered adverse. Comparison of Day 27 TK values with Day 1 parameters showed a change in FPM pharmacokinetic behavior over time with an apparent increase in the rate of clearance characterized by a decrease in AUC(0-6) and T(max) values on Day 27 with little to no change in C(max) values. Based on these results, the No Observed Adverse Effect Level was 600 mg/kg-d. PMID:20708074

  9. Studies of the developmental toxicity of polycarboxylate dispersing agents.

    PubMed

    Nolen, G A; Monroe, A; Hassall, C D; Iavicoli, J; Jamieson, R A; Daston, G P

    1989-06-01

    Three linear polycarboxylate compounds, two linear polyacrylates (90,000 MW and 4,500 MW) and one linear polyacrylate-maleate copolymer (12,000 MW), were tested for their teratogenic potential in female Sprague Dawley rats. These polymers, which were tested as sodium salts, are used as dispersing agents in detergent formulations at levels of 1-5%. All compounds were administered by gavage during organogenesis (days 6-15 of pregnancy). No adverse effects on development were seen with any of the three compounds at any of the doses tested. The highest dose, and therefore the minimum no-effect dose, for the three linear polymers was 1125 mg/kg/day for the 90,000 MW polyacrylate, 3000 mg/kg/day for the 4,500 MW polyacrylate, and 6670 mg/kg/day for the polyacrylate-maleate copolymer. Based on these data, these compounds are not developmentally toxic, even at very high dose levels. PMID:2598833

  10. A 4-week toxicity study of methionine in male rats.

    PubMed

    Chin, Keigi; Toue, Sakino; Kawamata, Yasuko; Watanabe, Akiko; Miwa, Tadashi; Smriga, Miro; Sakai, Ryosei

    2015-01-01

    To examine 4-week toxicity of l-methionine (methionine), 5-week-old Fisher strain male rats were fed on diets containing 0, 0.1, 0.3, 0.9, 2.7 (w/w) of added methionine. Although no deaths were recorded, the highest dose of methionine (2.7% [w/w] of diet) reduced food intake and significantly suppressed growth rate. Growth suppression was characterized by an increase in hemolysis, splenic, and hepatic accumulation of hemosiderin, hemolytic anemia, and promotion of hematopoiesis. Other changes observed in the highest methionine intake group were a decrease in white blood cell count, thymus atrophy, and histological abnormalities in the adrenal gland and testis. Small, but significant, growth suppression, accompanied by some minor changes in plasma biochemical parameters, was also seen in rats fed on a test diet containing 0.9% (w/w) of additional methionine. Thus, no-observed-adverse-effect-level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of diet-added methionine were determined at 0.3% and 0.9% (w/w), corresponding to 236 and 705 mg/kg/d body weight, respectively. Since the basal diet contained protein-bound methionine at 0.5% (w/w), NOAEL and LOAEL of total dietary methionine were estimated at 0.8% and 1.4% (w/w) of diet. PMID:25939350