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At least 235 records · Page 13Linked to original sources
PubMed2003

Physiologically-based kinetic modeling of vapours toxic to the respiratory tract.

The respiratory tract is frequently identified as a site of toxicity for inhaled xenobiotic chemicals. Usually, these observations come from controlled animal studies. For these studies to be of quantitative value to human health risk assessment, species-specific factors governing dosimetry of inhaled substances must be taken into account. Toxicokinetics of vapours in the respiratory tract are defined by absorption, distribution, metabolism, and excretion, as they are in other tissues; however, these concepts take on new dimensions when considering respiratory tract toxicants, especially those that elicit portal of entry effects by directly interacting with the tissue lining the respiratory tract. Species-specific factors related to anatomy, physiology and biochemistry govern inter-species extrapolation of toxicokinetics. This article discusses critical factors of respiratory tract kinetics that should be considered when developing physiological-based toxicokinetic (PBTK) models for inhaled vapours. Important considerations such as impact of regional airflow-delivery, water solubility, reactivity, and rates of local biotransformation on respiratory tract tissue dosimetry are highlighted. These factors can be accounted for only to a limited extent when using default approaches to extrapolate dosimetry of inhaled substances across species. On the other hand, PBTK modeling has the flexibility to accommodate many of the critical determinants of respiratory tract toxicity. PBTK models can also help identify the most critical toxicokinetic data necessary to replace defaults. PBTK approaches have led to more informed estimates of human target tissue dose, and therefore human health risk, especially where these risk assessments have been based on extrapolation of animal dosimetry studies. Experience derived from the development of more intensive case studies have, in turn, enabled simplified approaches to the use of PBTK modeling for respiratory tract toxicants. Whether simplified or highly complex, PBTK modeling approaches are proven to be of great utility to risk assesors interested in applying quantitative information to informed risk assessment evaluations.

Animals↗
PubMed1999

Preclinical testing of neuroprotective neurotrophic factors in a model of chronic motor neuron degeneration.

Many neurotrophic factors have been shown to enhance survival of embryonic motor neurons or affect their response to injury. Few studies have investigated the potential effects of neurotrophic factors on more mature motor neurons that might be relevant for neurodegenerative diseases. Using organotypic spinal cord cultures from postnatal rats, we have demonstrated that insulin-like growth factor-I (IGF-I) and glial-derived neurotrophic factor (GDNF) significantly increase choline acetyltransferase (ChAT) activity, but brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) do not. Surprisingly, ciliary neurotrophic factor (CNTF) actually reduces ChAT activity compared to age-matched control cultures. Neurotrophic factors have also been shown to alter the sensitivity of some neurons to glutamate neurotoxicity, a postulated mechanism of injury in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Incubation of organotypic spinal cord cultures in the presence of the glutamate transport inhibitor threo-hydroxyaspartate (THA) reproducibly causes death of motor neurons which is glutamate-mediated. In this model of motor neuron degeneration, IGF-I, GDNF, and NT-4/5 are potently neuroprotective, but BDNF, CNTF, and NT-3 are not. The organotypic glutamate toxicity model appears to be the best preclinical predictor to date of success in human clinical trials in ALS.

Animals↗
PubMed2000

Role of aquaporin water channels in pleural fluid dynamics.

Continuous movement of fluid into and out of the pleural compartment occurs in normal chest physiology and in pathophysiological conditions associated with pleural effusions. RT-PCR screening and immunostaining revealed expression of water channel aquaporin-1 (AQP1) in microvascular endothelia near the visceral and parietal pleura and in mesothelial cells in visceral pleura. Comparative physiological measurements were done on wild-type vs. AQP1 null mice. Osmotically driven water transport was measured in anesthetized, mechanically ventilated mice from the kinetics of pleural fluid osmolality after instillation of 0.25 ml of hypertonic or hypotonic fluid into the pleural space. Osmotic equilibration of pleural fluid was rapid in wild-type mice (50% equilibration in <2 min) and remarkably slowed by greater than fourfold in AQP1 null mice. Small amounts of AQP3 transcript were also detected in pleura by RT-PCR, but osmotic water transport was not decreased in AQP3 null mice. In spontaneously breathing mice, the clearance of isosmolar saline instilled in the pleural space ( approximately 4 ml. kg(-1). h(-1)) was not affected by AQP1 deletion. In a fluid overload model produced by intraperitoneal saline administration and renal artery ligation, the accumulation of pleural fluid (approximately 0.035 ml/h) and was not affected by AQP1 deletion. Finally, in a thiourea toxicity model of acute endothelial injury causing pleural effusions and lung interstitial edema, pleural fluid accumulation in the first 3 h ( approximately 4 ml. kg(-1). h(-1)) was not affected by AQP1 deletion. These results indicate rapid osmotic equilibration across the pleural surface that is facilitated by AQP1 water channels. However, AQP1 does not appear to play a role in clinically relevant mechanisms of pleural fluid accumulation or clearance.

Animals↗
PubMed2004

Organophosphates, serine esterase inhibition, and modeling of organophosphate toxicity.

The highlighted article in this issue (Ashani and Pistinner, "Estimation of the Upper Limit of Human Butyrylcholinesterase Dose Required for Protection against Organophosphates toxicity: A Mathematically Based Toxicokinetic Model") is an innovative approach to modeling the amount of protective enzyme, human butyrylcholinesterase, that could be administered to humans to protect them from the lethal effects of organophosphate nerve agents. The threat of nerve agent exposures at lethal level regrettably remains a threat to military as well civilian populations, and the authors of this article have used their previous experimental data along with new in vitro data to devise and calibrate a mathematical model that could have practical utility in the prophylaxis of military personnel against chemical warfare agents.

Animals↗
PubMed2006

Validation of a QSAR model for acute toxicity.

In the present study, a quantitative structure--activity relationship (QSAR) model has been developed for predicting acute toxicity to the fathead minnow (Pimephales promelas), the aim being to demonstrate how statistical validation and domain definition are both required to establish model validity and to provide reliable predictions. A dataset of 408 heterogeneous chemicals was modelled by a diverse set of theoretical molecular descriptors by using multivariate linear regression (MLR) and Genetic Algorithm-Variable Subset Selection (GA-VSS). This QSAR model was developed to generate reliable predictions of toxicity for organic chemicals not yet tested, so particular emphasis was given to statistical validity and applicability domain. External validation was performed by using OECD Screening Information Data Set (SIDS) data for 177 High Production Volume (HPV) chemicals, and a good predictivity was obtained (=72.1). The model was evaluated according to the OECD principles for QSAR validation, and compliance with all five principles was established. The model could therefore be useful for the regulatory assessment of chemicals. For example, it could be used to fill data gaps within its chemical domain and contribute to the prioritization of chemicals for aquatic toxicity testing.

Animals↗
PubMed2006

Toxicodynamic modeling of highly toxic organophosphorus compounds.

Although the in vitro effect of organophosphorus (OP) compounds on acetylcholine-esterase (AChE) has been studied extensively, the hypothesis that OP inhibition of AChE is the primary mechanism of acute in vivo OP toxicity has been controversial. For example, a recent review (Pope and Liu, 2004) suggested that OP compounds have direct toxic effects on other enzymes, ACh receptors, and receptor/ channel complexes that are independent of AChE inhibition. The purpose of this report is to examine the hypothesis that AChE inhibition is the mechanism of acute toxicity of OP compounds by mathematically modeling the in vivo lethal effects of highly toxic OP compounds and determining the amount of variation in OP toxicity that is explained by AChE inhibition.

Animals↗
PubMed2006

Comparison of two types of inocula during acclimation and stable operation for nitrophenol biodegradation in an anaerobic-aerobic SBR.

This work presents a comparison of two inocula used for the acclimation of two anaerobic-aerobic sequencing batch bioreactors used for toxic wastewater treatment. The bioreactors were acclimated with different types of sludge: one coming from an anaerobic wastewater treatment plant and the other one from a conventional aerobic activated sludge plant. The model toxic compound was p-nitrophenol, which is reduced to p-aminophenol during the initial anaerobic phase of the reaction, and later mineralized during a posterior aerated reaction phase. Biodegradation of the compounds was monitored using UV/Vis spectrophotometry. After acclimation stabilization of the sludge and of the process was also monitored. Results show that there is no significant difference in acclimation times and stability of the process between the two employed inocula, and thus an originally anaerobic inoculum presents no apparent advantage over a more easily accessible aerobic one.

Aerobiosis↗
PubMed2004

Determination of toxicity of Campylobacter jejuni isolated from humans and from poultry carcasses acquired at various stages of production.

AIM: The research focused on the determination of the toxicity variation associated with Campylobacter jejuni isolated from humans and chickens. METHODS AND RESULTS: Campylobacter jejuni isolates were obtained from chicken carcasses and from humans exhibiting symptoms of campylobacteriosis. Using HeLa cells as the in vitro model, toxicity was determined for each isolate. The mean toxicity level of the chicken isolates was significantly lower than that of the human isolates (P < 0.001). There was a wide range of toxicity in C. jejuni isolated from chickens and the percentage of isolates exhibiting low toxicity remaining relatively constant. All C. jejuni isolates from humans possessed either medium or high levels of toxicity. CONCLUSIONS: All wildtype C. jejuni isolates obtained from poultry carcasses may not be equally important as a human foodborne pathogen. SIGNIFICANCE AND IMPACT OF STUDY: Campylobacter jejuni remains a primary foodborne pathogen and increased efforts are needed to determine the impact of wildtype isolates in causing human illness. The present research indicates that all isolates may not be equally important in regards to disease potential. The information found should be included in efforts to develop C. jejuni detection, control and infection modelling.

Animals↗
PubMed2006

A bioavailability model predicting the toxicity of nickel to rainbow trout (Oncorhynchus mykiss) and fathead minnow (Pimephales promelas) in synthetic and natural waters.

The effects of Ca, Mg and pH on the toxicity of Ni to juvenile rainbow trout (Oncorhynchus mykiss) were examined during 17-26-day exposures to Ni in 15 synthetic test solutions. Higher chemical activities of Ca2+, Mg2+ and H+ reduced Ni toxicity, as demonstrated by increased 17-day median lethal concentrations expressed as Ni2+ activity (17-d LC50(Ni2+)). A non-linear increase of the 17-d LC50(Ni2+) with increasing H+ suggested that the effect of pH could not be appropriately described by single-site competition between Ni(2+) and H+ for sensitive sites on the fish gill. Instead, a linear increase of pNi2+ (=-log 17-d LC50(Ni2+)) with increasing pH was observed with a slope of 0.32. This slope was used as the basis for modelling the effect of pH. The effects of Ca and Mg were modelled according to single-site competition with logK(CaBL)=logK(MgBL)=3.6, both assumed to be independent of pH. The effect of pH was superimposed on this competition effect and was also assumed to be independent of Ca and Mg concentrations. The model was able to predict 17-d LC50s (expressed as dissolved Ni) in most synthetic test waters within a factor 2 deviation from observed toxicity. The model's predictive capacity was also evaluated using results of similar laboratory toxicity tests with juvenile rainbow trout in Ni-spiked European natural surface waters. For most of these waters, predicted 17-d LC50s did not deviate more than a factor 2 from observed toxicity. The same model, calibrated to account for sensitivity differences between species, life stages and/or exposure durations, was able to accurately predict 96-h LC50s for larval and juvenile fathead minnow (Pimephales promelas) and juvenile rainbow trout, based on data taken from literature. Although the developed model seems very promising, the uncertainty around the role of alkalinity and the exact mechanisms by which Ca, Mg and pH modify Ni toxicity need to be further explored.

Age Factors↗
PubMed2001

Toward a biologically based dose-response model for developmental toxicity of 5-fluorouracil in the rat: acquisition of experimental data.

Biologically based dose-response (BBDR) models represent an emerging approach to improving the current practice of human health-risk assessment. The concept of BBDR modeling is to incorporate mechanistic information about a chemical that is relevant to the expression of its toxicity into descriptive mathematical terms, thereby providing a quantitative model that will enhance the ability for low-dose and cross-species extrapolation. Construction of a BBDR model for developmental toxicity is particularly complicated by the multitude of possible mechanisms. Thus, a few model assumptions were made. The current study illustrates the processes involved in selecting the relevant information for BBDR modeling, using an established developmental toxicant, 5-fluorouracil (5-FU), as a prototypic example. The primary BBDR model for 5-FU is based on inhibition of thymidylate synthetase (TS) and resultant changes in nucleotide pools, DNA synthesis, cell-cycle progression, and somatic growth. A single subcutaneous injection of 5-FU at doses ranging from 1 to 40 mg/kg was given to pregnant Sprague-Dawley rats at gestational day 14; controls received saline. 5-FU was absorbed rapidly into the maternal circulation, and AUC estimates were linear with administered doses. We found metabolites of 5-FU directly incorporated into embryonic nucleic acids, although the levels of incorporation were low and lacked correlation with administered doses. On the other hand, 5-FU produced dose-dependent inhibition of thymidylate synthetase in the whole embryo, and recovery from enzyme inhibition was also related to the administered dose. As a consequence of TS inhibition, embryonic dTTP and dGTP were markedly reduced, while dCTP was profoundly elevated, perhaps due to feedback regulation of intracellular nucleotide pools. The total contents of embryonic macromolecules (DNA and protein) were also reduced, most notably at the high doses. Correspondingly, dose-related reductions of fetal weight were seen as early as GD 15, and these deficits persisted for the remainder of gestation. These detailed dose-response parameters involved in the expression of 5-FU developmental toxicity were incorporated into mathematical terms for BBDR modeling. Such quantitative models should be instrumental to the improvement of high-to-low dose and cross-species extrapolation in health-risk assessment.

Abnormalities, Drug-Induced↗
PubMed2002

Optimization of nonviral transfection: variables influencing liposome-mediated gene transfer in proliferating vs. quiescent cells in culture and in vivo using a porcine restenosis model.

Cationic liposomes/DNA complexes are widely used vectors for delivering genes in clinical and experimental trials. Relatively low transfer efficiencies in vivo compared with viral gene transfer may be improved using local application. In addition, markedly increased transfer efficiency may be achieved in vitro and in vivo via optimization of known variables influencing liposomal transfection. Lipofection under different conditions was performed in various cell lines and primary porcine smooth muscle cells. Optimized conditions found in vitro were verified in vivo using a porcine restenosis model. Toxicity was monitored analyzing cell metabolism. Transfer efficiency and safety were determined using morphometry, histology, galactosidase assays, PCR, and RT-PCR. The most important variables enabling maximum transfer efficiency were firstly the appropriate selection of cationic lipids for the cell type to be transfected, secondly the DNA/liposome ratio chosen, which depended on the cell type and cationic lipids used, and thirdly the state of proliferation of the targeted cells. Transfection in vivo demonstrated two- to fivefold higher transfer efficiencies when transfer conditions were extrapolated from optimization experiments in stationary cells compared with the use of conditions established in proliferating cells. Application of the therapeutic gene for cecropin using optimized transfer conditions resulted in a significantly reduced neointima formation compared with the transfection using a control gene for ss-galactosidase. Thus, in this vascular model, initial optimization of lipofection in stationary cells in culture followed by local delivery in vivo and with selection of a suitable therapeutic gene led to markedly improved transfer efficiencies, gene expression, and biological effect. Stationary cell cultures simulate more realistically the in vivo situation and may therefore represent a better model for future in vivo experiments. In addition, the advantages of liposomes are easy handling, low toxicity, and the lack of carcinogenicity or immunogenic reactions.

Animals↗
PubMed1997

Theoretical models for drug delivery to solid tumors.

The effectiveness of anti-cancer drug therapies is often limited by the difficulty of achieving drug delivery throughout solid tumors. Mathematical models permit an analysis of the factors leading to inadequate drug delivery to tumors and can suggest strategies for improving delivery. An overview is given of key factors that influence drug delivery and the extent to which they have been incorporated into existing theoretical models. These factors include spatial gradients of drug concentration and other variables within tumors and other parts of the body, and the relative magnitudes of the time scales involved in drug transport, tumor cell kinetics, and host toxicity. Models for both systemic and regional delivery methods are considered, including intravenous, intraarterial, intraperitoneal, intrathecal, and intratumoral delivery. Strategies for improving delivery are discussed, including use of two-step therapies, hyperthermia, liposome encapsulation, and magnetic targeting. Until now, modeling has mainly developed in separate subfields of tumor growth and cell kill kinetics, compartmental modeling of the body, spatially distributed models for single tissues, radiation dose calculations, tumor oxygenation, tumor blood flow, and cellular pharmacokinetics. In the future, models that integrate these subfields should be developed.

Animals↗
PubMed2003

Decision tree SAR models for developmental toxicity based on an FDA/TERIS database.

Humans are exposed to thousands of environmental chemicals for which no developmental toxicity information is available. Structure-activity relationships (SARs) are models that could be used to efficiently predict the biological activity of potential developmental toxicants. However, at this time, no adequate SAR models of developmental toxicity are available for risk assessment. In the present study, a new developmental database was compiled by combining toxicity information from the Teratogen Information System (TERIS) and the Food and Drug Administration (FDA) guidelines. We implemented a decision tree modeling procedure, using Classification and Regression Tree software and a model ensemble approach termed bagging. We then assessed the empirical distributions of the prediction accuracy measures of the single and ensemble-based models, achieved by repeating our modeling experiment many times by repeated random partitioning of the working database. The decision tree developmental SAR models exhibited modest prediction accuracy. Bagging tended to enhance the accuracy of prediction. Also, the model ensemble approach reduced the variability of prediction measures compared to the single model approach. Further research with data derived from animal species- and endpoint-specific components of an extended and refined FDA/TERIS database has the potential to derive SAR models that would be useful in the developmental risk assessment of the thousands of untested chemicals.

Abnormalities, Drug-Induced↗
PubMed2006

Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine.

Silymarin, a flavonolignan from 'milk thistle' (Silybum marianum) plant is used almost exclusively for hepatoprotection and amounts to 180 million US dollars business in Germany alone. In this review we discuss about its safety, efficacy and future uses in liver diseases. The use of silymarin may replace the polyherbal formulations and will avoid the major problems of standardization, quality control and contamination with heavy metals or bacterial toxins. Silymarin consists of four flavonolignan isomers namely--silybin, isosilybin, silydianin and silychristin. Among them, silybin being the most active and commonly used. Silymarin is orally absorbed and is excreted mainly through bile as sulphates and conjugates. Silymarin offers good protection in various toxic models of experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms. Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, Amanita mushroom poisoning, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Though silymarin does not have antiviral properties against hepatitis virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation, enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to be a useful drug for hepatoprotection in hepatobiliary diseases and in hepatotoxicity due to drugs. The non traditional use of silymarin may make a breakthrough as a new approach to protect other organs in addition to liver. As it is having a good safety profile, better patient tolerability and an effective drug at an affordable price, in near future new derivatives or new combinations of this drug may prove to be useful.

Clinical Trials as Topic↗
PubMed2002

Embryo-larval toxicity tests with the African catfish (Clarias gariepinus): comparative sensitivity of endpoints.

Embryo-larval toxicity tests with the African catfish (Clarias gariepinus) were performed to assess the comparative sensitivity of different endpoints. Measured test responses included embryo and larval survival, hatching, morphological development, and larval growth. Chromium, cadmium, copper, sodium pentachlorphenol (NaPCP), and malathion were used as model toxicants. Hatching was not affected by any of the chemicals tested, and embryo survival was only affected by chromium at > or = 36 mg/L. The growth of larvae was significantly reduced at > or = 11 mg/L Cr, > or = 0.63 mg/L Cu, > or = 0.03 mg/L NaPCP, and > or = 1.25 mg/L malathion. Morphological development of C. gariepinus was affected by all of the toxicants tested. Different types of morphological aberrations were observed, i.e., reduction of pigmentation in fish exposed to cadmium and copper, yolk sac edema in fish exposed to NaPCP and malathion, and deformation of the notochord in fish exposed to chromium and malathion. The sensitivity of the endpoints measured can be summarized as follows: growth > abnormality > larval survival > embryo survival > hatching.

Animals↗
PubMed2006

Development of a zebrafish 4-day embryo-larval bioassay to assess toxicity of chemicals.

A 4-day embryo-larval zebrafish test, from blastula stage to hatching included, was developed. The observations of embryo developmental were made at different development stages, for which morphological, physiological, and behavioral endpoints were selected and quantified for unexposed and exposed embryos. The sensitivity and the ability of these endpoints to inform about mode of action (MoA) were established in testing three model toxicants with well-known toxic effects (propranolol, malathion, cadmium). Lethal, sublethal (heart rate/edema, spontaneous movements, and hatching rate/time disturbance), and teratogenic effects were detected for all the studied compounds. This bioassay allows characterization of impairments at different biological levels: neuromuscular, physiological, morphological, and behavioral, and brings useful information about the toxic MoA of the chemicals on nontarget organisms. In this sense to answers the chemical industries and international organization (EMEA) requirements for the environmental risk assessment of new chemicals and pharmaceuticals.

Animals↗
PubMed1998

Structure-toxicity relationships for three mechanisms of action of toxicity to Vibrio fischeri.

Quantitative structure-activity relationships (QSARs) have been developed with the logarithm of the inverse of 15-min toxicity (pT15) to Vibrio fischeri (the acute Microtox test). Statistically, robust QSARs were found for alkanones acting by the nonreactive, baseline narcosis mechanism of action [pT15 = 0.99 (log Kow)-2.08, n = 6, s = 0.24, r2 = 0.988, F = 405]; aldehydes acting by the Schiff base-forming mechanism of electrophilicity [pT15 = 0.55(log Kow)-0.58, n = 6, s = 0.07, r2 = 0.994, F = 782]; and alkenals acting by the Michael-type acceptor mechanism of electrophilicity [pT15 = 0.52(log Kow) + 0.35, n = 6, s = 0.19, r2 = 0.914, F = 54.5]. Efforts to model toxicity across mechanism of action resulted in the development of a response surface [pT15 = 0.79(log Kow)-1.17 (ELUMO)-0.41, n = 19, s = 0.46, r2 = 0.892, F = 75.3]. In addition, an excellent correlation was found between Tetrahymena pyriformis [log(1/IGC50)] and V. fischeri. [log(1/IGC50) = 0.86(pT15)-0.25, n = 19, s = 0.25, r2 = 0.957, F = 405] toxicity.

Aldehydes↗
PubMed2004

Evaluating the toxicity of Triton X-100 to protozoan, fish, and mammalian cells using fluorescent dyes as indicators of cell viability.

Three viability assays using fluorescent dyes effectively detected a loss of viability in cultures of three mammalian cell lines (H4IIE, Caco2, and HepG-2), two fish cell lines (RTgill-W1 and RTL-W1), and a ciliated protozoan, Tetrahymena thermophila, after exposure to Triton X-100, used as a model toxicant. The dyes were Alamar Blue (AB), neutral red (NR), and propidium iodide, which respectively monitored energy metabolism, lysosomal activity, and membrane integrity. A fourth fluorescent dye, 5-carboxyfluorescein diacetate acetoxymethyl ester, was problematic. For 2-h Triton X-100 exposures, mammalian cell lines were as susceptible as piscine cell lines, whereas T. thermophila was approximately twofold less sensitive as detected with AB and NR. Despite being less sensitive, cytotoxicity tests on T. thermophila could be done in spring water, which means that unlike animal cells they could be directly exposed to most industrial effluents without osmolality adjustments. Therefore, T. thermophila could be a useful complement to animal cells as alternatives to fish in toxicity testing.

Animal Testing Alternatives↗