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It was shown in experiments on rats on models of toxic and traumatic edemas-swellings that etimizol (5 and 1 mg/kg) prevented changes in total content of water and the cerebral tissue density.
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Mice intravenously injected with concentrated infectious influenza B/Lee/40 virus (LD50 = 6400 hemagglutinin units) developed lethargy, seizures, coma, and death 1 to 3 days later. The cerebrospinal fluid cell count was normal. Serum glutamic oxaloacetic transaminase levels increased 19-fold and plasma ammonia levels elevated 2.6-fold over control values. Serum bilirubin levels remained normal. Microvesicular fatty metamorphosis developed in the liver, whereas the brain showed mild cerebral edema without inflammatory changes. Viral propagation did not occur in liver or brain, but viral hemagglutinin, neuraminidase, and probably nucleoprotein antigens were produced in hepatocytes. Many of the clinical, biochemical, and pathologic features of the mouse illness are similar to those seen in Reye's syndrome.
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The National Animal Poison Control Center received 28 calls of isoniazid (INH) exposures in dogs and cats between 1987 and 1993. The ingestion of a single 300 mg INH tablet was the most common complaint. Isoniazid has a low therapeutic margin and produces life threatening signs in dogs ingesting single 300 mg human tablets. The LD50 of INH in dogs is estimated at 50 mg/kg bw, which is probably similar to that for humans. However, rodents are among the species most resistant to INH and thus are not good animal models for toxic dose extrapolation. The more consistent clinical signs reported were recurrent clonic-tonic seizures followed by a stuporous state with poor response to stimulus. Ideal treatment combines vitamin B6 given as a single i.v. bolus at an equivalent dose to the amount of INH ingested and anticonvulsants such as 1 mg diazepam/kg bw. This combination acts synergistically to improve GABAergic transmission in the CNS and has proved effective in protecting animals from further convulsions and death, even after several seizure episodes, as often encountered in clinical situations.
Individual chemical logistic regression models were developed for 37 chemicals of potential concern in contaminated sediments to predict the probability of toxicity, based on the standard 10-d survival test for the marine amphipods Ampelisca abdita and Rhepoxynius abronius. These models were derived from a large database of matching sediment chemistry and toxicity data, which includes contaminant gradients from a variety of habitats in coastal North America. Chemical concentrations corresponding to a 20, 50, and 80% probability of observing sediment toxicity (T20, T50, and T80 values) were calculated to illustrate the potential for deriving application-specific sediment effect concentrations and to provide probability ranges for evaluating the reliability of the models. The individual chemical regression models were combined into a single model, using either the maximum (P(Max) model) or average (P(Avg) model) probability predicted from the chemicals analyzed in a sample, to estimate the probability of toxicity for a sample. The average predicted probability of toxicity (from the P(Max) model) within probability quartiles closely matched the incidence of toxicity within the same ranges, demonstrating the overall reliability of the P(Max) model for the database that was used to derive the model. The magnitude of the toxic effect (decreased survival) in the amphipod test increased as the predicted probability of toxicity increased. Users have a number of options for applying the logistic models, including estimating the probability of observing acute toxicity to estuarine and marine amphipods in 10-d toxicity tests at any given chemical concentration or estimating the chemical concentrations that correspond to specific probabilities of observing sediment toxicity.
Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.
Despite fission yeast's history of modeling salient cellular processes, it has not yet been used to model human neurodegeneration-linked protein misfolding. Because alpha-synuclein misfolding and aggregation are linked to Parkinson's disease (PD), here, we report a fission yeast (Schizosaccharomyces pombe) model that evaluates alpha-synuclein misfolding, aggregation, and toxicity and compare these properties with those recently characterized in budding yeast (Saccharomyces cerevisiae). Wild-type alpha-synuclein and three mutants (A30P, A53T, and A30P/A53T) were expressed with thiamine-repressible promoters (using vectors of increasing promoter strength: pNMT81, pNMT41, and pNMT1) to test directly in living cells the nucleation polymerization hypothesis for alpha-synuclein misfolding and aggregation. In support of the hypothesis, wild-type and A53T alpha-synuclein formed prominent intracellular cytoplasmic inclusions within fission yeast cells in a concentration- and time-dependent manner, whereas A30P and A30P/A53T remained diffuse throughout the cytoplasm. A53T alpha-synuclein formed aggregates faster than wild-type alpha-synuclein and at a lower alpha-synuclein concentration. Unexpectedly, unlike in budding yeast, wild-type and A53T alpha-synuclein did not target to the plasma membrane in fission yeast, not even at low alpha-synuclein concentrations or as a precursor step to forming aggregates. Despite alpha-synuclein's extensive aggregation, it was surprisingly nontoxic to fission yeast. Future genetic dissection might yield molecular insight into this protection against toxicity. We speculate that alpha-synuclein toxicity might be linked to its membrane binding capacity. To conclude, S. pombe and S. cerevisiae model similar yet distinct aspects of alpha-synuclein biology, and both organisms shed insight into alpha-synuclein's role in PD pathogenesis.
The tolerated dose of melphalan is limited by bone marrow suppression; when this complication is ameliorated by bone marrow transplantation, the dose-limiting toxicity becomes gastrointestinal mucositis. No intervention to date has been successful in modulating this life-threatening complication of melphalan. We conducted studies to develop a murine model of melphalan-induced gastrointestinal toxicity to facilitate the preclinical identification of effective strategies for reducing this toxicity. Melphalan given at the 90% lethal dosage produced severe gastrointestinal mucositis and mortality (13 of 23 treated mice). Syngeneic bone marrow transplantation, effective in preventing the myeloablation produced by total-body irradiation, was ineffective in preventing melphalan-induced mortality (16 of 23 treated mice), indicating that gastrointestinal mucositis was the dose-limiting toxicity. On the basis of the results of previous studies, which revealed that depletion of glutathione enhances the antineoplastic activity of melphalan and that glutathione is required for murine intestinal function, we attempted to modulate melphalan-induced gastrointestinal toxicity by the administration of glutathione (8-10 mmol/kg given in 1 ml sterile water by gavage at 12-h intervals for 4-8 doses). Glutathione therapy failed to produce a significant increase in mucosal glutathione content in animals treated with melphalan plus glutathione gavage as compared with those receiving melphalan alone (P > 0.05), and histologic mucosal injury secondary to melphalan was not reduced. The administration of glutathione in the presence or absence of concomitant bone marrow transplantation did not decrease melphalan-induced mortality (melphalan alone, 16/26 deaths; melphalan plus glutathione, 14/25 deaths; melphalan plus glutathione plus bone marrow transplantation, 20/26 deaths). Studies using a reduced melphalan dose (50% lethal dosage) produced similar results, with no survival benefit being seen following glutathione administration. Our studies suggest that melphalan-induced mucositis can be studied in a mouse model in which this complication is dose-limiting. Although glutathione administration at the dose and schedules initially studied is not effective in reducing this damage, other therapeutic strategies such as the use of alternative glutathione regimens or other thiols can be effectively studied in this system.
The Terrestrial Biotic Ligand Model (TBLM) is applied to a number of noncalcareous soils of the European Union for Cu and Ni toxicities using organisms and endpoints representing three levels of terrestrial organisms: higher plants, invertebrates, and microbes. A comparison of the TBLM predictions to soil metal concentration or free metal ion activity in the soil solution shows that the TBLM is able to achieve a better normalization of the wide variation in toxicological endpoints among soils of disparate properties considered in this study. The TBLM predictions of the EC50s were generally within a factor of 2 of the observed values. To our knowledge, this is the first study that incorporates Cu and Ni toxicities to multiple endpoints associated with higher plants, invertebrates, and microbes for up to eleven noncalcareous soils of disparate properties, into a single theoretical framework. The results of this study clearly demonstrate that the TBLM can provide a general framework for modeling metals ecotoxicity in soils.
The ultimate intention of quantitative structure-activity relationship (QSAR) study in toxicology is to predict the toxic potential of untested compounds with great accuracy. As QSAR has been based on the assumption that compounds from the same chemical domain will behave in similar manner, the QSAR model built upon the analogical chemicals is hypothesized to exhibit better performance than that derived from the miscellaneous data set. In this paper, the acute toxicity, 96 h LC(50) (median lethal concentration) for the fathead minnow from database EPAFHM_v2a_617_1Mar05 served as the interested toxicity endpoint, and the mode of action (MOA) in toxic response was employed as a criterion to compartmentalize the chemical domains. MOA-based local QSAR models were built by partial least squares (PLS) regression for each subset with single mode of action such as Narcosis I, Narcosis II or Reactive, and global model was also developed for the combined data set containing several subsets above. By comparing the performances of these two types of models, the local models were superior to the global model in that the relative standard error (R.S.E.) of the former was much lower for both the training set and the test set of any subset. In addition, the influence of the reliability of MOA determination on the performance of local model was also investigated and the statistical results for subsets with MOAs at A and B confidence level were better than those at C and D confidence level. Therefore, the MOA-based local QSAR models are promising to improve the accuracy of toxicity prediction as long as the assessment of MOA is of high reliability.
Inorganic arsenic has strong human carcinogenic potential, but the availability of an animal model to study toxicity is extremely limited. Here, we used the transgenic zebrafish line Tg(k18(2.9):RFP) as an animal model to study arsenite toxicity. This line was chosen because the red fluorescent protein (RFP) is expressed in stratified epithelia (including skin), due to the RFP reporter driven by the promoter of the zebrafish keratin 18 gene. We titrated doses of inorganic arsenite for zebrafish embryos and found that arsenite exposure at 50 microM for 120 h was suitable for mimicking a long-term, chronic effect. When embryos derived from Tg(k18(2.9):RFP) adults were treated with this arsenite dose and time of exposure, abnormal phenotypes were not noticeable under the light microscope. However, arsenic keratosis was visible in the epithelial cells under the fluorescent microscope. Morphological defects became more severe with increased dose and exposure duration, suggesting that the severity of skin lesions was dose- and time-dependent. Histochemical examination of keratosis after 4',6'-diamidino-2-phenylindole hydrochloride (DAPI) staining showed that the epithelial cells overproliferated after treatment with arsenite. Therefore, this Tg(k18(2.9):RFP) zebrafish line is an excellent model for studying toxicity induced by inorganic arsenite and may have potential for studying other environmental pollutants.
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A canine model of theophylline toxicity was used to study the cardiovascular effects seen in severe theophylline poisoning. Eight mongrel dogs were divided equally into two groups. The dogs were anesthetized with pentobarbital and paralyzed with pancuronium bromide. They were ventilated with 100% oxygen and underwent the placement of pulmonary arterial, central venous, femoral arterial, and peripheral venous lines. Group 1 animals received 5.6 mL/kg D5W intravenously (IV) over 20 minutes. Group 2 animals received 140 mg/kg (5.6 mL/kg) of aminophylline IV over the same period. Peak theophylline levels in Group 2 animals averaged 208.9 micrograms/mL. Group 2 animals suffered a marked fall in mean arterial pressure (MAP) and an increase in heart rate. In spite of the fall in MAP (P less than .01), cardiac index actually was increased almost two-fold over Group 1 animals, due mainly to a fall in systemic vascular resistance index (P less than .01). There were no physiologically significant differences in ventricular filling pressures or stroke index between the two groups.
The performance of the rat chronic lowest observed adverse effect level (LOAEL, the lowest exposure level at which there are biologically significant increases in the severity of adverse effects) model in Toxicity Prediction by Komputer Assisted Technology (TOPKAT), a commercial quantitative structure-activity relationship software package, was tested on a database of chemicals that are of interest to the U.S. EPA's Office of Pesticide Programs. The testing was repeated on a database of chemicals from three U.S. EPA sources that report peer-reviewed LOAELs. The results of this study were also contrasted with the results of the testing performed during TOPKAT's model-building process.
Autocorrelation descriptors encoding lipophilicity, molar refractivity, the H-bonding acceptor ability and H-bonding donor ability of the molecules were used to describe glycols, glycol ethers, and xylenes characterized by their adult and developmental toxicities to Hydra attenuata. A PLS regression analysis was employed to derive a QSAR model allowing to simulate both endpoints. Comparisons were made with classical regression analyses using the 1-octanol/water partition coefficient as molecular descriptor.
INTRODUCTION: It is well known the depressor effect of alcohol on several inhibitory nervous centres. This can be due to the inhibition that induces in the release of different type of neurotransmitters, and because alcohol can increase the membrane fluidity and changes the function of proteins inserted in the membrane. Several aminopeptidases (AP) have been described as enzymes that regulate the activity of peptide neurotransmitters. In the present work, the influence of alcohol (25, 50 and 100 mM) on several aminopeptidase activities (alanyl AP, arginyl AP, cystinyl AP, leucyl AP and tyrosyl AP) has been determined in synaptosomes obtained from the cortex of mouse, under basal and K+ stimulated conditions and their calcium dependence, in a non toxic in vitro model. MATERIAL AND METHODS: AP activities were determined using aminoacyl ? naphthylamides as substrates. Non toxic in vitro model were demonstrated analyzing free radical generation, lipid peroxidation and oxidation of synaptosomal proteins. In addition, the bioenergetic behavior of synaptosomes was determined under different experimental protocols. RESULTS: In basal conditions, alcohol produces a dose related inhibition of alanyl AP activity. The rest of activities show a biphasic behavior. In this way, depending on the concentration of alcohol used, aminopeptidases are inhibited or stimulated. Depolarization with K+ 25 mM leads to a decrease of alanyl AP and tyrosyl AP activities but does not change the rest of activities. The presence of alcohol under stimulated conditions produces the inhibition of all the enzymatic activities, specially with the highest concentrations used. CONCLUSIONS: Alcohol modifies several aminopeptidase activities from synaptosomes of the cortex of mouse, acting in different ways under basal or stimulated conditions. These effects seem not to be related with degenerative events induced by alcohol. Therefore, a specific effect of this substance on the neurotransmisory/neuromodulatory systems mediated by neuropeptides must exist, modifying the enzymes that are responsible of their degradation.
The use of computers to model biological systems is a relatively new research tool. For example, it is possible to write mathematical systems to model neuronal activity involved in memory and learning and to model blood flow in any organ such as the brain. There is also an interest in designing computer-controlled machines to simulate human activities such as hand movements and vision. One of the most important uses of computer modeling is as a research tool to test hypotheses and aid in formulating new hypotheses. This enables the investigator to apply preliminary tests on several experimental strategies and select for animal experimentation the ones that are most likely to produce unambiguous and interpretable results. In the following article, we describe a computer model of neuron toxicity in the mammalian spinal cord.