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At least 217 records · Page 12Linked to original sources
PubMed2003

Animal models of hepatic encephalopathy.

Hepatic encephalopathy is a neuropsychiatric syndrome associated with acute liver failure, chronic parenchymal liver disease, or portosystemic anastomosis. Many approaches have been used to develop suitable models of hepatic encephalopathy, each with specific advantages and disadvantages. The most commonly used models have been the surgical hepatectomy and liver devascularization procedures, and hepatotoxins such as galactosamine and acetaminophen. Drug-toxicity models may be clinically more relevant. The specific requirements of experiments to study a particular aspect of encephalopathy also influence the choice of animal model. Animal models will play a central role in future research into hepatic encephalopathy to better understand its pathophysiology and to develop newer therapeutic modalities for this condition.

Animals↗
PubMed2004

GIS modeling of air toxics releases from TRI-reporting and non-TRI-reporting facilities: impacts for environmental justice.

The Toxics Release Inventory (TRI) requires facilities with 10 or more full-time employees that process > 25,000 pounds in aggregate or use > 10,000 pounds of any one TRI chemical to report releases annually. However, little is known about releases from non-TRI-reporting facilities, nor has attention been given to the very localized equity impacts associated with air toxics releases. Using geographic information systems and industrial source complex dispersion modeling, we developed methods for characterizing air releases from TRI-reporting as well as non-TRI-reporting facilities at four levels of geographic resolution. We characterized the spatial distribution and concentration of air releases from one representative industry in Durham County, North Carolina (USA). Inclusive modeling of all facilities rather than modeling of TRI sites alone significantly alters the magnitude and spatial distribution of modeled air concentrations. Modeling exposure receptors at more refined levels of geographic resolution reveals localized, neighborhood-level exposure hot spots that are not apparent at coarser geographic scales. Multivariate analysis indicates that inclusive facility modeling at fine levels of geographic resolution reveals exposure disparities by income and race. These new methods significantly enhance the ability to model air toxics, perform equity analysis, and clarify conflicts in the literature regarding environmental justice findings. This work has substantial implications for how to structure TRI reporting requirements, as well as methods and types of analysis that will successfully elucidate the spatial distribution of exposure potentials across geographic, income, and racial lines.

Air Pollutants↗
PubMed1996

Use of artificial sediments in a comparative toxicity study with larvae and postlarvae of the grass shrimp, Palaemonetes pugio.

An artificial sediment was tested for use in evaluating the potential hazard of toxicants on benthic organisms. The seawater-sediment system was assessed by use of the pyrethroid insecticide, fenvalerate, as the model toxicant for testing with larvae of the grass shrimp, Palaemonetes pugio, an ecologically important estuarine species. The sediment was prepared from commercially available components, and mixed with the toxicant to provide concentrations of 1, 10 and 100 microg fenvalerate kg(-1) dry sediment in 20 ppt seawater. Sediment free of the insecticide served as the control. Throughout the study, fenvalerate was not detected in the water column, but was measured in sediment at the nominal concentration of 100 microg kg(-1). The P. pugio population was adversely affected by fenvalerate. The effect occurred at metamorphosis, when larvae changed from pelagic individuals to benthic organisms. At this period, larvae were in direct contact with sediment. A portion of the population was tolerant of the insecticide.

Journal Article↗
PubMed2006

Induction of decision trees using genetic programming for modelling ecotoxicity data: adaptive discretization of real-valued endpoints.

Recent literature has demonstrated the applicability of genetic programming to induction of decision trees for modelling toxicity endpoints. Compared with other decision tree induction techniques that are based upon recursive partitioning employing greedy searches to choose the best splitting attribute and value at each node that will necessarily miss regions of the search space, the genetic programming based approach can overcome the problem. However, the method still requires the discretization of the often continuous-valued toxicity endpoints prior to the tree induction. A novel extension of this method, YAdapt, is introduced in this work which models the original continuous endpoint by adaptively finding suitable ranges to describe the endpoints during the tree induction process, removing the need for discretization prior to tree induction and allowing the ordinal nature of the endpoint to be taken into account in the models built.

Decision Trees↗
PubMed2002

Combined effects of lowered oxygen and toxicants (copper and diazinon) on the mayfly Ephoron virgo.

In many large European rivers, the number of typical riverine insect species, such as mayflies, stoneflies, and caddisflies, is greatly reduced compared to historic records. This can no longer be explained by high concentrations of a relatively small number of dominant toxicants since many rivers have changed from heavily contaminated systems with a few selected key toxicants to systems with a complex contamination. This contamination consists of many substances in low concentrations coinciding with other unfavorable conditions, such as low oxygen concentrations. It was hypothesized that the joint adverse effects of such multiple stressors may be a steering factor in the distribution of riverine insect species. The aim of this study was therefore to determine the combined effects of toxicants and oxygen depletion. To this purpose, larvae of the indigenous riverine mayfly Ephoron virgo were exposed to two different model toxicants, copper and diazinon, under normoxia and hypoxia (50% air saturation) conditions. The median effective concentrations for mortality for copper were significantly lower in the hypoxia treatments than in the normoxia treatments. For diazinon, no differences were observed between two treatments differing in dissolved oxygen levels, and therefore we argue that interactions between multiple stressors may be compound specific. It is concluded that the combination of toxicants and lowered oxygen may have a stronger impact than can be expected based on the adverse effects of the individual factors and that standard toxicity tests may be insufficient alone to determine the impact of human activities on the ecological state of riverine communities. Instead, attention needs to be paid to more environmentally realistic nonoptimal conditions in toxicity testing to adequately fulfill the needs of ecological recovery programs.

Animals↗
PubMed2000

Effects of sediment geochemical properties on the toxicity of copper-spiked sediments to the marine amphipod Gammarus locusta.

The contribution of some sediment features, namely acid-volatile sulfide (AVS) and total organic carbon (TOC) in order to explain the toxicity of copper-spiked sediments was investigated. A 10-day assay with the marine amphipod Gammarus locusta was performed with three selected sediment types that consisted of different proportions of fine fractions (FF) and TOC (0.5% FF/1% TOC; 25% FF/2% TOC; and 75% FF/4% TOC). Copper toxic effects were observed for 0.5% FF/25% FF sediments when simultaneously extracted copper (SEM(Cu)) minus acid volatile sulfide (SEM(Cu) - AVS) were 0.3 and 3.4 micromol/g, respectively. However, no significant mortality was observed for 75% FF sediment even when the sulfide binding capacity was exceeded (1.1 micromol/g < or = SEM(Cu) - AVS < or = 8.9 micromol/g). These results indicate that mortality could not be described solely as a function of the SEM(Cu) - AVS, suggesting the presence of other binding phases in addition to AVS. Results of the normalized LC50 values to total organic carbon indicated that this component probably also interferes in the amphipod survival, although not completely. The estimated LC50 values were close (2 mg Cu/g C and 8 mg Cu/g C, respectively for 0% FF and 25% FF sediment) although there was still a fourfold difference between them. Considering that none of these sediment features by itself could fully explain copper toxicity, an attempt was made to describe G. locusta mortality as a function of simultaneous SEM(Cu) - AVS and copper concentrations normalized to TOC. Nevertheless, the limited set of data available from this study prevented an attempt to model toxicity as a function of both of these factors. These findings reinforce the need to develop integrated models that include more than one binding phase, sulfide and organic carbon, and also other compartments of the system (e.g. interstitial water) to improve current methodologies for predicting copper toxicity based on sediment geochemical features.

Animals↗
PubMed1999

A two-stage minibioreactor system for continuous toxicity monitoring.

A two-stage minibioreactor system was successfully developed for continuous toxicity monitoring. This system consists of two minibioreactors in series. Recombinant Escherichia coli DPD2794 containing a RecA::luxCDABE fusion as a model strain was utilized to monitor environmental insults to DNA, with mitomycin C as a model toxicant. Pulse type exposures were used to evaluate the system's reproducibility and reliability. Step inputs of mitomycin C have been adopted to show the system's stability. The system's ability to monitor the possible upsets or accidental discharges of toxic chemicals was also evaluated with these step insults. All the data demonstrated that this two-stage minibioreactor system using recombinant bacteria containing stress promoters fused with lux genes is quite appropriate for continuous toxicity monitoring. Long-term operation and minimized media-usage have been investigated. Thus application to many different areas, including an early warning system of wastewater biotreatment plant upsets and the monitoring and tracking of accidental spills, discharges or failures in plant operation are plausible.

Bioreactors↗
PubMed2006

Toxicokinetics/toxicodynamics of arsenic for farmed juvenile milkfish Chanos chanos and human consumption risk in BFD-endemic area of Taiwan.

This paper presents a toxicokinetic/toxicodynamic analysis to appraise arsenic (As) bioaccumulation in farmed juvenile milkfish Chanos chanos at blackfoot disease (BFD)-endemic area in Taiwan, whereas probabilistic incremental lifetime cancer risk (ILCR) and hazard quotient (HQ) models are also employed to assess the range of exposures for the fishers and non-fishers who eat the contaminated fish. We conducted a 7-day exposure experiment to obtain toxicokinetic parameters, whereas a simple critical body burden toxicity model was verified with LC50(t) data obtained from a 7-day acute toxicity bioassay. Acute toxicity bioassay indicates that 96-h LC50 for juvenile milkfish exposed to As is 7.29 (95% CI: 3.10-10.47) mg l(-1). Our risk analysis for milkfish reared in BFD-endemic area indicates a low likelihood that survival is being affected by waterborne As. Human risk analysis demonstrates that 90%-tile probability exposure ILCRs for fishers in BFD-endemic area have orders of magnitude of 10(-3), indicating a high potential carcinogenic risk, whereas there is no significant cancer risk for non-fishers (ILCRs around 10(-5)). All predicted 90%-tiles of HQ are less than 1 for non-fishers, yet larger than 10 for fishers which indicate larger contributions from farmed milkfish consumptions. Sensitivity analysis indicates that to increase the accuracy of the results, efforts should focus on a better definition of probability distributions for milkfish daily consumption rate and As level in milkfish. Here we show that theoretical human health risks for consuming As-contaminated milkfish in the BFD-endemic area are alarming under a conservative condition based on a probabilistic risk assessment model.

Animals↗
PubMed2002

Tolerance through bone marrow transplantation with costimulation blockade.

The routine induction of tolerance in organ transplant recipients remains an unattained goal. The creation of a state of mixed chimerism through allogeneic bone marrow transplantation leads to robust donor-specific tolerance in several experimental models and this approach has several features making it attractive for clinical development. One of its major drawbacks, however, has been the toxicity of the required host conditioning. The use of costimulation blocking reagents (anti-CD 154 monoclonal antibodies and the fusion protein CTLA4Ig) has led to much less toxic models of mixed chimerism in which global T cell depletion of the host is no longer necessary and which has even allowed the elimination of all cytoreductive treatment when combined with the injection of very high doses of bone marrow cells. In this overview we will briefly discuss general features of tolerance induction through bone marrow transplantation, will then describe recent models using costimulation blockade to induce mixed chimerism and will review the mechanisms of tolerance found with these regimens. Finally we will attempt to identify issues related to the clinical introduction of bone marrow transplantation with costimulation blockade which remain unresolved.

Abatacept↗
PubMed2004

Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease.

Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.

Animals↗
PubMed2002

Use of the PI index in predicting toxicity of nitrobenzene derivatives.

The PI Index is a Szeged-like topological index developed very recently. It has useful applications in chemistry which are yet to be investigated thoroughly. Herein, we report quantitative structure-toxicity relationship (QSTR) study using the PI Index. We have used 41 monosubstituted nitrobenzene for this purpose. The results have shown that the PI Index alone is not an appropriate index for modelling toxicity of nitrobenzene derivatives. Combinations of the PI Index with other distance-based topological indices resulted into statistically significant models and excellent results are obtained in pentaparametric models. The predictive potential of the models is discussed on the basis of cross-validation method, as well as by estimating root-mean-square error (RMS).

Animals↗
PubMed1989

Development of an acute model for the study of chloromethanediphosphonate nephrotoxicity.

Chloromethanediphosphonate (Cl2MDP), a cation chelator, is used as a therapeutic for hypercalcemia of malignancy. Cl2MDP exhibits nephrotoxic potential. Thus, a useful model has been developed to study the mechanism of injury. Intraperitoneal administration of highly exaggerated dosages, specifically 200 mg/kg b.i.d., resulted in a consistent mild to moderate extent of kidney damage after the third day of treatment in rats. Proteinuria and lowered serum phosphorus levels occur prior to onset of histopathologic changes. Injury was characterized as necrosis of proximal tubular epithelium with predilection for pars recta. Unlike many renal toxicity models, the necrosis occurs as cell lysis only after 24 to 48 hours of treatment. However, this model significantly reduces the time required to induce renal toxicity observed in routine toxicity studies from months of treatment to less than 1 week and will, thus, serve as a baseline for subsequent pathogenetic studies.

Animals↗
PubMed1987

Strategies for biological testing of biomaterials.

Current perspectives on empirical, modeling, and mechanistic methods of medical device safety testing are reviewed. Empirical approaches, such as the U.S. Pharmacopeial biological tests for plastics, evaluate the total system to discover aberrations and abnormalities. Models consist of a single aspect of an integrated approach, whereas mechanistic methods are based on a thorough knowledge of the materials and the organism's biological response. Empirical studies develop data on general hazard potential, such as overt toxicity. Model approaches target the specific application and specific hazard potential. Mechanistic studies identify the cause of toxicity and can produce advances in the biocompatibility of medical devices.

Biocompatible Materials↗
PubMed2000

Evaluation of biologically based dose-response modeling for developmental toxicity: a workshop report.

Biologically based dose-response (BBDR) modeling represents a novel approach for quantitative assessment of health risk by incorporating pharmacokinetic and pharmacodynamic characteristics of a chemical and by relating the immediate cellular responses to a cascade of aberrant biological actions that leads to detectable adverse outcomes. The quantitative relationship of each of the intervening events can be described in mathematical forms that are amenable for adjustment and extrapolation over a range of doses and across species. A team of investigators at the Reproductive Toxicology Division of the U.S. Environmental Protection Agency has explored the feasibility of BBDR modeling by examining the developmental toxicity of a known teratogen, 5-fluorouracil. A panel of researchers from academic and industrial laboratories, biomathematical modelers, and risk assessment scientists was convened in a workshop to evaluate the approaches undertaken by the EPA team and to discuss the future prospects of BBDR modeling. This report summarizes the lessons learned from one approach to BBDR modeling and comments from the panelists: while it is possible to incorporate mechanistic information into quantitative dose-response models for the assessment of health risks, the process is enormously data-intensive and costly; in addition, the confidence of the model is directly proportional to our current understanding of basic biology and can be enhanced only through the ongoing novel discoveries. More importantly, the extent of "uncertainty" (inherent with the default assumptions associated with the NOAEL or benchmark approach) reducible by BBDR modeling requires further scrutiny and comparison.

Abnormalities, Drug-Induced↗
PubMed2001

Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons.

Immunosuppressant drugs, like FK506, and nonimmunosuppressant compounds like, GPI1046 and L685818, are immunophilin ligands that specifically bind to immunophilins, like FK506 binding protein 12 (FKBP12). Several lines of evidence show that these ligands exert neurotrophic properties in neural injury models and in PC12 cells. However, the mechanism of the neurotrophic function of the immunophilin ligands is poorly known. In the present study, we use MPP+ and 6-OHDA toxicity models to examine both neuroprotective and neuroregenerative effects of immunophilin ligands on primary cultures of midbrain dopaminergic neurons. We find that FK506, GPI1046 and L685818 at concentrations from 0.01 to 1 microM partially, but significantly, protect dopaminergic neurons against both MPP+ and 6-OHDA toxicity. By Western blot analysis, we also find that all three compounds prevent tyrosine hydroxylase (TH) loss induced by MPP+ and 6-OHDA treatments. Morphologic analysis of dopaminergic neurons, by immunocytochemistry, shows that MPP+ and 6-OHDA cause the retraction and loss of neuronal processes, while FK506, GPI1046 and L685818 promote regeneration of these processes as indicated by increases in process number and length. To examine if FKBP12 is required for neurotrophic effects of immunophilin ligands, we cultured dopaminergic neurons from FKBP12 knockout mice and find that FK506 still protects dopaminergic neurons against MPP+ toxicity. These results suggest that FKBP12 is not essential for the neurotrophic properties of immunophilin ligands, and immunophilin ligands are a new class of neuroprotective and neuroregenerative agents that may have therapeutic potential in a variety of neurological disorders.

1-Methyl-4-phenylpyridinium↗
PubMed1996

Animal models for motor neuron diseases: research directions.

Animal models of motor neuron diseases fall into three categories, hereditary (e.g., the motor neuron degenerative, wobbler, wasted, and autosomal-recessive progressive motor neuropathy mouse models), sporadically occurring (e.g., equine motor neuron disease), and experimentally induced (e.g., transgenic mice carrying a mutation in the gene encoding human Cu/Zn superoxide dismutase, toxic models) disorders. The models currently have three major drawbacks. First, there is no model imitating the progressive course of human disease with deficits of the upper and lower motor neurons. Second, experimentally induced conditions are based on a hypothesis of the pathogenetic mechanisms of human motor neuron diseases. Motor deficits are usually induced by compounds or agents that represent a single possible pathogenetic mechanism, which reduces the value of the model. Finally, the molecular biology, biochemistry, and neuropathology of the hereditary disorders are ill-defined. Future approaches should minimize the drawbacks of the current models and focus on mechanisms that are part of the etiopathogenesis of the human diseases.

Animals↗
PubMed2006

Control of microglial neurotoxicity by the fractalkine receptor.

Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.

Analysis of Variance↗
PubMed2003

A multivariate biomarker-based model predicting population-level responses of Daphnia magna.

A multivariate model is proposed relating short-term biomarker measurements in Daphnia magna to chronic effects (21-d exposure) occurring at the population level (time to death, mean brood size, mean total young per female, intrinsic rate of natural increase, net reproductive rate, and growth). The results of the short-term exposure (48 h-96 h) to eight model toxicants (cadmium, chromium, mercury, tributyl tin, linear alkylsulfonic acid, sodium pentachlorophenolate, lindane, and 2,4-dichlorophenoxyacetic acid) on the following biomarkers were used for the multivariate model: digestive enzymes (amylase, cellulase, beta-galactosidase, trypsin, and esterase), enzymes of the intermediary metabolism (glycogen phosphorylase, glucose-6-phosphate dehydrogenase, pyruvate kinase, lactate dehydrogenase, and isocitrate dehydrogenase), cellular energy allocation (CEA) (protein, carbohydrate, and lipid content and electron transport activity), and DNA damage and antioxidative stress activity. Using partial least squares to latent structures (PLS), a two-component model was obtained with R2 of 0.68 and a Q2 value of 0.60 based on the combined analysis of a limited number of the 48- and 96-h biomarker responses. For the individual population-level responses, the R2 values varied from 0.66 to 0.77 and the Q2 values from 0.52 to 0.69. Energy-related biomarkers (cellular energy allocation, lipid contents, anaerobic metabolic activity--pyruvate kinase, and lactate dehydrogenase), combined with parameters related to oxidative stress (catalase) and DNA damage measured after 48 and 96 h of exposure, were able to predict long-term effects at higher levels of biological organization.

Animals↗