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At least 793 records · Page 44Linked to original sources
PubMed2003

Galactose toxicity in the rat as a model for premature ovarian failure: an experimental approach readdressed.

BACKGROUND: The pathophysiological mechanisms underlying premature ovarian failure (POF) are largely unknown. Our objective was to develop a working animal model to explore the pathogenesis of POF. Since galactosaemic women eventually develop POF, we evaluated the potential of experimental galactose toxicity as the proposed model. METHODS: Pregnant rats were fed pellets supplemented with or without 35% galactose from day 3 of conception continuing through weaning of the litters. Female offspring were evaluated for serum levels of galactose and galactose-1-phosphate, growth rate, onset of puberty, reproductive cyclicity, ovarian complement of follicles, hypothalamo-pituitary-ovarian function and follicular response to gonadotrophins. RESULTS: Galactose toxicity delayed the onset of puberty and developed a state of hypergonadotrophic hypoestrogenism. The characteristic low FSH levels at weaning followed by pubertal spurts of gonadotrophins and estradiol (E(2)) secretion of the controls was replaced by a sustained high level of FSH and a low level of E(2) under galactose toxicity. The ovary developed with apparently normal or deficient complement of follicles. Ovarian response to exogenous gonadotrophin stimulation was blunted, but the response improved significantly when the stimulation was preceded by pituitary desensitization. CONCLUSION: Experimental galactose toxicity may serve as a model for exploring some of the basic tenets of POF.

Aging↗
PubMed2000

Inhibitory effects of subcutaneous dexamethasone treatment on rat pulmonary toxicity of KW-2149, a new mitomycin C analogue.

An experimental model for pulmonary toxicity of KW-2149, a new mitomycin C analogue, was established and the inhibitory effects of dexamethasone (DM) were investigated. KW-2149 was given to male rats 3 or 5 times at weekly intervals by intravenous injection of 3.28 or 8.2 mg/kg. As a suitable model for pulmonary toxicity, the dose of 3.28 mg/kg per week for 3 weeks was selected, this causing exudative pleural effusion in all animals but no deaths. For preventing this toxicity, DM was injected subcutaneously 3 times every week at 0.5, 1.0, 2.5 or 5.0 mg/kg. The 0.5 mg/kg dose was sufficient to completely prevent development of pleural effusions. Combined DM treatment may be an effective chemotherapy for KW-2149 induced pulmonary toxicity.

Animals↗
PubMed2004

Estimating spatial patterns of effluent exposure concentrations in direct toxicity assessment studies.

Hydrodynamic models of differing scale and complexity were used to estimate spatial patterns of effluent concentration in discharge plumes in the River Esk and the Lower Tees Estuary. The output from the Tees model was used, in conjunction with measurements of toxicity determined in short-term oyster embryo tests, to predict contours/zones of toxicity in the estuary associated with effluent discharges from four chemical processing sites. One of the discharges also combined the input from a municipal sewage treatment works. The models appeared to be effective in predicting patterns of dilution and dispersion of the effluent discharges in the respective receiving environments. Confirmation of the predictive capabilities of the Tees model was achieved by comparing predicted and measured toxicity in different regions of the plumes associated with the four discharges. Differences between predicted and measured toxicity for two of the four discharges were explicable in terms of failure to take account of the effects of real-time wind conditions when test samples were collected or overlap of adjacent discharge plumes. Suggested refinements to the models and measurement of effluent toxicity would further enhance the utility of this approach for determining the extent and significance of the effects of effluent discharges in receiving environments.

Animals↗
PubMed2001

An LD50 model for predicting psychotropic drug toxicity using biopartitioning micellar chromatography.

The LD50 determination is the main way to measure the acute toxicity of all types of substances. At the present time, however, there is increasing opposition to the use of living animals in research and testing activities from animal rights groups as well as some scientists. Nevertheless, the need to have a tool for estimating the potential toxicity of new compounds for human consumption has encouraged the development of alternative methods. Under adequate conditions, the partitioning in micellar liquid chromatography can describe the drug biopartitioning. We have named this chromatographic system biopartitioning micellar chromatography (BMC). In this paper, an LD50 QRAR model developed for psychotropic drugs from their retention data in BMC, is described. The model's ability to predict new psychotropic drug toxicity is statistically proved.

Chromatography, Liquid↗
PubMed1997

Oxidant mechanisms in toxic acute renal failure.

Over the last decade, there has been accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown in both in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, the results of recent studies suggest that cytochrome P-450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Cyclosporine A has been shown to enhance the generation of hydrogen peroxide in vitro and lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

Acute Kidney Injury↗
PubMed1979

Hepatotoxicity and halothane metabolism in an animal model with application for human toxicity.

Centrilobular necrosis and a ten-fold elevation in serum alanine amino-transferase (ALT) consistently followed 2 hours of 1% halothane anaesthesia in an animal model. Conditional factors were the presence of enzyme induction and moderate hypoxia (14% oxygen), indicating an association between reductive metabolism and hepatotoxicity. Under these conditions there was at least a four-fold increase in reductive metabolites detected in the exhaled air. In clinical studies, reductive metabolites were also detected in the exhaled air of all patients examined, even after halothane anaesthesia with 100% oxygen. The amounts of reductive metabolites were comparable in man and the model, following equivalent halothane doses. It appears that a model with a similar route and rate of halothane biotransformation to man has been identified. The lesion of halothane hepatotoxicity in this model appears to be similar to that reported in man - centrilobular hepatic necrosis.

Alanine Transaminase↗
PubMed2000

Development of a physiologically based pharmacokinetic model for hydroquinone.

Hydroquinone (HQ) produces nephrotoxicity and renal tubular adenomas in male F344 rats following 2 years of oral dosing. Female F344 and SD rats are comparatively resistant to these effects. Nephrotoxicity and tumorigenicity have been associated with a minor glutathione conjugation pathway following the oxidation of HQ to benzoquinone (BQ). The majority of administered doses (90-99%) consists of glucuronide and sulfate conjugates of HQ. An initial physiologically based pharmacokinetic model was developed to characterize the role of kinetics in the strain differences observed in HQ-induced renal toxicity and tumorigenicity. Partition coefficients, protein-binding, and metabolic rate constants were determined directly or estimated from a series of in vivo and in vitro studies. Metabolism was confined to the liver and GI tract. The total flux through the glutathione pathway represented the "internal dose" of HQ for nephrotoxicity. Simulations were compared to a variety of data from male and female F344 rats, male SD rats, and a single male human volunteer. Simulations of intraperitoneal administration resulted in higher amounts of glutathione conjugates than comparable oral doses. This was consistent with protein-binding and toxicity studies and emphasized the importance of first-pass GI tract metabolism. In addition, male F344 rats were predicted to form more total glutathione conjugates than SD rats at equivalent dose levels, which was also consistent with the observed strain differences in renal toxicity. This model represents the first stage in the development of a biologically based dose-response model for improving the scientific basis for human health risk assessments of HQ.

Adult↗
PubMed2006

Chemical structure indexing of toxicity data on the internet: moving toward a flat world.

Standardized chemical structure annotation of public toxicity databases and information resources is playing an increasingly important role in the 'flattening' and integration of diverse sets of biological activity data on the Internet. This review discusses public initiatives that are accelerating the pace of this transformation, with particular reference to toxicology-related chemical information. Chemical content annotators, structure locator services, large structure/data aggregator web sites, structure browsers, International Union of Pure and Applied Chemistry (IUPAC) International Chemical Identifier (InChI) codes, toxicity data models and public chemical/biological activity profiling initiatives are all playing a role in overcoming barriers to the integration of toxicity data, and are bringing researchers closer to the reality of a mineable chemical Semantic Web. An example of this integration of data is provided by the collaboration among researchers involved with the Distributed Structure-Searchable Toxicity (DSSTox) project, the Carcinogenic Potency Project, projects at the National Cancer Institute and the PubChem database.

Abstracting and Indexing↗
PubMed1999

Oxidant mechanisms in toxic acute renal failure.

Over the last decade, there is accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, cisplatin, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown both in in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free-radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, recent studies suggest that cytochrome P450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Several recent in vitro and in vivo studies indicate an important role of reactive oxygen metabolites in cisplatin-induced nephrotoxicity. Thus, catalytic iron is increased both in vitro and in vivo by cisplatin, and iron chelators as well as hydroxyl radical scavengers have been shown to be protective. Recent studies indicate that cytochrome P450 may also be an important source of the catalytic iron in cisplatin nephrotoxicity. Cyclosporine A has been shown to enhance generation of hydrogen peroxide in vitro and enhance lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

Acute Kidney Injury↗
PubMed1988

Comparative toxicity of halothane, isoflurane, hypoxia, and phenobarbital induction in monolayer cultures of rat hepatocytes.

Hypoxia, phenobarbital induction, and halothane anesthesia have been implicated in the pathogenesis of hepatotoxicity in the rat model. However, a controversy exists over the role of halothane in liver injury; does it act by reducing hepatic blood flow, thereby inducing hypoxia, or do its metabolites initiate the injury? These variables are difficult to separate during in vivo halothane exposure. In the present experiments, effects of halothane on hepatic perfusion were eliminated by exposing confluent monolayers of hepatocytes isolated from Fisher 344 rats livers, both with and without phenobarbital pretreatment, to 1.5% halothane or 2.0% isoflurane in 1%, 2%, or 4% (control) oxygen. Isoflurane exposure was included for a control of anesthetic effects on hepatocytes, because it is known to be metabolized minimally and probably is not associated with hepatic dysfunction. Oxygen levels were chosen to approximate those that may occur in the liver in vivo. Cell death was assayed via aspartate aminotransferase (AST) release, both immediately following a 2-h oxygen +/- anesthetic exposure and 6 h post-exposure. Per cent cell death data were analyzed using multiple regression techniques. Results obtained immediately, and 6 h after, exposure demonstrate that low oxygen levels, halothane, and phenobarbital were each highly significant factors (P less than .001) in relation to cell death, in agreement with the halothane-phenobarbital-hypoxia rat model. A toxic effect of isoflurane was not observed under identical experimental conditions. The results of the study clearly indicate that the origin of cell death in hepatocyte monolayers is multi-factorial; hypoxia, phenobarbital induction, and halothane exposure each contribute to the hepatocyte damage observed in our in vitro model.

Animals↗
PubMed2000

Toward development of an in vitro model of methamphetamine-induced dopamine nerve terminal toxicity.

To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA) neurotoxicity, striatal synaptosomes were incubated at 37 degrees C with METH for different periods of time (10-80 min), washed once, then tested for DA transporter function at 37 degrees C. METH produced time- and dose-dependent reductions in the V(max) of DA uptake, without producing any change in K(m). Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium ion, 6-hydroxydopamine, and amphetamine under similar conditions produced comparable effects. In contrast, incubation with fenfluramine, a serotonin neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar as striatal glutamate uptake was unaffected. Various DA transporter blockers (cocaine, methylphenidate, and bupropion) afforded complete protection against METH-induced decreases in DA uptake, without producing any effect themselves. METH's effects were also temperature dependent, with greater decreases in DA uptake occurring at higher temperatures. Tests for residual drug revealed small amounts (0.1-0.2 microM) of remaining METH, but kinetic studies indicated that decreases in DA uptake were not likely to be due to METH acting as a competitive inhibitor of DA uptake. Decreases in the V(max) of DA uptake were not accompanied by decreases in B(max) of [(3)H]WIN 35,428 binding, possibly because there is no mechanism for removing damaged DA nerve endings from the in vitro preparation Collectively, these results give good support to the development of a valid in vitro model that may prove helpful for elucidating the mechanisms underlying METH-induced DA neurotoxicity.

Animals↗
PubMed1988

Planning and using PB-PK models: an integrated inhalation and distribution model for nickel.

A general method is presented for the use of mathematical modeling in the design, execution, and interpretation of toxicology experiments. To illustrate the use of mathematical modeling toxicology, a case study is presented of how a dosimetry model for inhaled nickel was developed for use in cancer risk estimation. A physiologically based pharmacokinetic (PB-PK) dosimetry model is used to plan animal experiments and to extrapolate nickel kinetics from animals to humans. These data are then used to estimate human lung cancer risks from human exposure to nickel aerosols. To achieve this goal, a PB-PK dosimetry model for the lung was integrated with a PB-PK dosimetry model for the internal organs. Nickel removal from the lung was found to be saturable and to follow Michaelis-Menten kinetics. The PB-PK lung dosimetry model was used to design both short-term (single exposures) and long-term (multiple intermittent exposures) needed to validate the parameters (Km and Vmax) of the lung dosimetry model. A constant infusion experiment was planned using the PB-PK modeling approach to measure the distribution and elimination of intravenously administered nickel. The two PB-PK models were integrated to estimate the fate of nickel after inhalation and are being used to plan experiments for other routes of exposure such as ingestion of drinking water and dermal contact. The integrated model has been used to calculate a human cancer risk estimate in combination with short-term genotoxic experiments. Using PB-PK models in toxicology, as illustrated here, conserves experimental animals, aids in understanding new physiological phenomena (such as saturable clearance from the lung), incorporates in vitro tests with in vivo experiments, and provides a means of extrapolation to human health risks from multiple routes of exposure. Introducing the concepts of mathematical modeling into toxicity experiments at the beginning of the experiment improves the usefulness of the experiments in risk estimation. PB-PK models are suggested as a new basis for experimental design in toxicology.

Administration, Inhalation↗
PubMed1997

Predicting the toxicity of complex mixtures using artificial neural networks.

Industrial and municipal wastewaters constitute major sources of contamination of the aquatic compartment and represent a threat to aquatic life. Artificial neural networks based on three different learning paradigms were studied as a means of predicting acute toxicity to trout (5 days exposure to wastewaters) using input data from two simple microbiotests requiring only 5 or 15 min of incubation. These microbiotests were 1) the chemoluminescent peroxidase (Cl-Per) assay, which can detect radical scavengers and enzyme-inhibiting substances, and 2) the luminescent bacteria toxicity test (Microtox), in which reduction of light emission by bacteria during exposure is taken as a measure of toxicity. The responses obtained with the trout bioassay, the Cl-Per and the Microtox test were analyzed through statistical correlation (Pearson product-moment correlation), unsupervised learning by a self-organizing network, and assisted learning by the backpropagation and the Boltzmann machine (probabilistic) paradigms. No significant correlation (p < 0.05) was found between the responses obtained with either the Cl-Per assay (p = 0.121) or the Microtox (p = 0.061) microbiotest and those resulting from the trout bioassay. The self-organizing network was able to identify by itself a maximum of five classes that were more or less relevant for predicting toxicity to fish: class 1 contained 2 samples that were toxic to fish, class 2 contained 2/3 samples that were toxic, class 3 showed 6/8 samples that were non toxic, class 4 contained 5/6 samples that were non-toxic and class 5 comprised one sample that was toxic. Supervised learning with backpropagation analysis yielded two kinds of networks that hold potential. The first one was able to predict the actual toxic wastewater concentration with an overall performance of 65% when fed fresh data, while the second one, which was designed to differentiate between toxic and non-toxic effluents, exhibited a much better performance (90%). However, the probabilistic network also proved to be a very good predictive model for toxicity to fish, with an overall performance of 90%. Although more data are needed, the network based on the backpropagation paradigm seems to be a better predictor or classifier of trout toxicity when used with the Cl-Per and the Microtox microbiotests.

Algorithms↗
PubMed2000

Docetaxel-induced mobilization of hematopoietic stem cells in a murine model: kinetics, dose titration, and toxicity.

OBJECTIVE: Docetaxel (DXT) is an anticancer agent that has demonstrated therapeutic efficacy against solid tumors, particularly breast cancer. Based on the use of hematopoietic stem cell (HSC) transplantation to restore hematopoietic reconstitution after myeloablative therapy, this study was performed to determine if DXT could mobilize HSCs in vivo. MATERIALS AND METHODS: C57Bl/6 mice were injected intraperitoneally with varying doses of DXT (equivalent to human doses of 40 to 120 mg/m(2)). Spleens were harvested on days 2, 4, 6, 8, 10, and 12 after DXT administration for recovery of mononuclear cells (MNCs). The number of HSCs present within the MNCs was determined by clonogenic assay for colony-forming units in culture (CFU-C) and by FACS analysis for CD34(+) cells. Peripheral blood samples were obtained at the time of spleen harvest to determine the hematologic profile. Liver and renal function tests were performed to monitor toxicity. RESULTS: DXT mobilize d HSCs in a dose- and time-dependent manner. When measured by the CFU-C assay, maximal mobilization of HSC (>10-fold increase in control; p<0.01) was observed at a dose of 30 mg/kg (equivalent to human dose of 75 mg/m(2)) on day 7. The number of mobilized HSCs peaked on days 6 to 8 at all doses of DXT tested. There was no evidence of weight loss, liver, or renal toxicity at any of the DXT doses tested. CONCLUSION: These results indicate that DXT efficiently mobilizes HSCs in a murine model and provide the rationale for similar studies in a clinical trial.

Animals↗
PubMed1994

Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities.

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdink's grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction. Most patients were treated with a standard dose of 10 or 13 mg melphalan per liter of perfused tissue for leg and arm perfusions, respectively. Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion.

Adult↗
PubMed2001

QSAR prediction of toxicity of nitrobenzenes.

A QSAR analysis has been carried out on the toxicities of 40 mono-substituted nitrobenzenes using recently introduced PI and Sz indices, as well as older molecular redundancy (MRI) and Balaban indices (J). The results have shown that no statistically significant mono-parametric QSAR models are possible. Also, that along with PI, Sz, MRI and J indices are the appropriate parameters to be used in developing multiparametric QSAR models. The toxicities of nitrobenzenes are well predicted by a penta-parametric model consisting of PI, Sz, J, MRI and Ip(1) (an indicator parameter taking care of the effect of substitution at 2-position) as the correlating parameters. The predictive ability of the model is determined by a cross-validation method.

Animals↗
PubMed1997

Insulin improves survival in a canine model of acute beta-blocker toxicity.

STUDY OBJECTIVE: To compare the efficacy of a novel antidote, insulin, with standard treatments, glucagon and epinephrine, in a canine model of acute beta-blocker toxicity. METHODS: Anesthetized dogs were fitted with instruments by means of thoracotomy and vascular cutdown for multiple cardiodynamic, hemodynamic, metabolic, and electrical measures. After basal measurements were taken, animals received intravenous propranolol (.25 mg/kg/minute) continuously for the remainder of the experiment. Toxicity was defined as a 25% decrease in the product of heart rate times mean blood pressure. Thirty minutes after the development of toxicity, toxic measures were taken (treatment 0 minutes), and then the animals (n = 6 each group) received either sham (saline solution), insulin (4 IU/minute with glucose clamped), glucagon (50 micrograms/kg bolus, then 150 micrograms/kg/hour infusion), or epinephrine (1 microgram/kg/minute). Animals were monitored until death or for 240 minutes. RESULTS: Propranolol decreased contractility, left ventricular pressure, and systemic blood pressure, and resulted in death of all sham-treated animals by 150 minutes. Six of six insulin-treated, four of six glucagon-treated, and one of six epinephrine-treated animals survived. Survival was greater for insulin-treated animals, compared with either glucagon-treated (P < .05) or epinephrine-treated animals (P < .02) by the log-rank test. Insulin-treated animals were characterized by improved cardiodynamics and hemodynamics, increased myocardial glucose uptake, and decreased serum potassium. CONCLUSION: Insulin is a superior antidote compared with glucagon or epinephrine in an anesthetized canine model of acute beta-blocker toxicity.

Acute Disease↗
PubMed1993

Predictive value of liver slices for metabolism and toxicity in vivo: use of acetaminophen as a model hepatotoxicant.

To establish the usefulness of liver slices as predictive models for in vivo metabolism and toxicity, acetaminophen was used as a model hepatotoxicant for which the role of metabolism in toxicity is well documented. Acetaminophen was incubated with liver slices prepared from the rat and hamster since these species differ in susceptibility to acetaminophen-induced hepatotoxicity. Formation of acetaminophen metabolites (sulfate, glucuronide, and glutathione conjugate), slice glutathione levels, and slice histopathology were assessed. Acetaminophen (0.5, 1, and 2 mM) induced a dose-dependent depletion of glutathione in hamster slices (sensitive species) but not rat slices (insensitive species). Formation of the acetaminophen toxic metabolite, as measured by glutathione conjugate formation, was much lower in rat slices compared with hamster slices. Rat slices also showed greater activity of the nontoxic sulfation and glucuronidation pathways. These data predicted an 11-fold greater susceptibility to toxicity in the hamster based on the proportion of the dose metabolized to the reactive species. In vivo data, using hepatic glutathione depletion as an indicator of toxic metabolite formation, would predict a similar difference (13.3-fold) between the hamster and the rat. To ascertain if the characteristic centrilobular lesion induced by acetaminophen in vivo could be reproduced in vitro, liver slice histopathology was assessed 6 and 12 hr after a 2-hr treatment with acetaminophen (2 mM). Discrete damage to the centrilobular regions of the liver were noted in hamster but not rat slices. Overall, based on metabolite formation, glutathione depletion, and slice histopathology, the liver slices were excellent predictors of acetaminophen hepatotoxicity in vivo.

Acetaminophen↗