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PubMed1983

An open-ended rat tracheal implant model: toxic effects of formaldehyde on the respiratory epithelium.

An open-ended rat tracheal implant model was developed to permit quantitative and repetitive exposure of respiratory epithelia to test substances of a variety of physical forms. To investigate the acute toxicity of formaldehyde with this new model, tracheas were exposed to formaldehyde solutions twice a week, for up to 12 weeks. At the higher formaldehyde concentrations (1.0, 0.6, 0.3%) the tracheal lumens became obstructed by granulation tissue. At the lower concentrations (0.2, 0.1, 0.01%), the appearance of flattened and atrophic epithelium as well as hyperplasia and squamous metaplasia were observed. The extent of these epithelial alterations was, for the most part, formaldehyde dose-dependent.

Animals↗
PubMed1992

Evaluating new red cell substitutes: a critical analysis of toxicity models.

Because red cell substitutes (RCS) will improve oxygen delivery to tissues rendered hypoxic or anoxic they are presumed to be effective. Prior to clinical application the safety--toxicity of any proposed solution must be established. Models used to demonstrate efficacy do not necessarily evaluate toxicity. Infusion of human hemoglobin (Hb) solutions into animals raises one issue of immune response but obviates looking at the human response to similar materials. Differentiating the cause of an immunologic effect may be difficult. Effects seen in acute models may not have chronic implications; they may be transients of no consequence. Differentiating the effects of volume load intravascularly from the effects of the solution is also a problem. Identification of proper controls is essential for evaluation. However, the control solution may have problems of its own that must be defined. For any proposed RBS a menu of models exploring cellular, tissue, organ and organism responses to the solution, its residual modifiers and the products of metabolism are needed to define primary and secondary effects.

Animals↗
PubMed2006

Struggles for equivalence: in vitro developmental toxicity model evolution in pharmaceuticals in 2006.

Our group has been using the ECVAM Embryonic Stem Cell assay to predict developmental toxicity. In order to improve the separation of non-teratogens from weak teratogens, we have employed measures of gene expression, and different statistical methods from those originally used to develop the test. These approaches have fundamentally not improved the discrimination of 'weaks' from 'nons'. A realization that a very low value for cytotoxicity IC50 would drive a final result for the test in ways that were inappropriate for pharmaceuticals has led us to re-examine the cytotoxicity component. Our current efforts are focused on other, perhaps more sensitive, measures of cytotoxicity, combined with gene expression changes in mouse stem cells in an attempt to correctly identify weak teratogens and non-teratogens.

Animal Testing Alternatives↗
PubMed2006

Toxicity models of pulsed copper exposure to Pimephales promelas and Daphnia magna.

Semiempirical models are useful for interpreting the response of aquatic organisms to toxicants as a function of exposure concentration and duration. Most applications predict cumulative mortality at the end of the test for constant exposure concentrations. Summary measures, such as the median lethal concentration, are then estimated as a function of concentration. Real-world exposures are not constant. Effects may depend on pulse timing, and cumulative analysis based only on integrated exposure concentration is not sufficient to interpret results. We undertook a series of pulsed-exposure experiments using standard toxicological protocols and interpreted the results (mortality, biomass, and reproduction) using a dynamic generalization of a Mancini/Breck--type model that includes two compartments, one for internal concentration as a function of exposure and one for site-of-action concentration or accumulated damage as a function of the internal dose. At exposure concentrations near the effects level, the model explained approximately 50% of the variability in the observed time history of survival, 43% of the change in biomass, and 83% of the variability in net reproduction. Unexplained variability may result from differences in organism susceptibility, amplified by the effects of small sample sizes in standard tests. The results suggest that response is sensitive to prior conditions and that constant-exposure experiments can underestimate the risk from intermittent exposures to the same concentration. For pulsed exposures, neither the average nor the maximum concentration alone is an adequate index of risk, which depends on both the magnitude, duration, and timing of exposure pulses. Better understanding about the impacts of pulsed exposures will require use of experimental protocols with significantly greater numbers of replicates.

Animals↗
PubMed2003

Role of predictive metabolism and toxicity modeling in drug discovery--a summary of some recent advancements.

In this article, we discuss recent advances and selected publications in the area of computer-based (in silico) metabolism and toxicity prediction, and comment on the opportunities for prediction of metabolism-based toxicity. The article also discusses the growing interest and importance of in silico prediction of metabolism and toxicity as tools to assist in library design and lead optimization. In addition, we consider the status of commercial metabolism and toxicity databases, and the need for future improvement, since data is often from older studies and from structures not typically considered as 'drug-like'. The article highlights the current status and potential of in silico models for property prediction, and the potential for linkage with vivo models to improve the integration of metabolism and toxicity into the drug discovery process and extrapolation to clinical studies. The article underscores that the future development, integration and application of in silico models will require a balance of local and global model approaches. The article also indicates that implementation and integration of models into drug discovery processes needs to be carried out in a rational and systematic manner, if we are to fully capitalize on the opportunity presented by in silico predictive modeling.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Long-term in vitro toxicity models: comparisons between a flow-cell bioreactor, a static-cell bioreactor and static cell cultures.

In vitro long-term toxicity testing is becoming an important issue in the field of toxicology, and there is a need to develop new model systems that mimic human chronic exposure and its effects. The aim of this work was to test two long-term in vitro toxicity systems which are available, a flow-cell bioreactor (Tecnomouse, Integra, Wallisellen, Switzerland) and a static cell bioreactor system (CELLine CL 6-well, Integra), and to compare them with the use of conventional cell culture flasks. A human cell line, Int 407, was exposed to cadmium chloride (CdCl(2); 10-(7-)10-(8)M) for 4 weeks. Cell numbers and cell viabilities were determined by the trypan blue (TB) exclusion assay and from exclusion of propidium iodide (PI) as determined by flow cytometry; and cell viability and metabolic activity were determined by the MTT assay. In addition, total protein determination and cadmium uptake measurements were performed. The results obtained with TB and PI exclusion did not show clear differences in cell viability with increasing CdCl(2) concentration. However, in the static cell-culture systems, an increase in MTT reduction was found at low concentrations of CdCl(2). Expression of heat-shock protein (Hsp27 and Hsp70) increased differently, depending on the CdCl(2) concentration applied and the system used. In summary, of the two bioreactors, the CELLine CL 6-well bioreactor was shown to be the more efficient system for performing long-term cytotoxicity studies. It is easy to handle, it permits the assessment of several endpoints, and sufficient replicates can be made available.

Animal Testing Alternatives↗
PubMed1991

Contaminant reduction by ventilation in a confined space model--toxic concentrations versus oxygen deficiency.

Airborne contaminants can create hazardous conditions in confined spaces (CS) across a broad range of concentrations, e.g., from relatively low, potentially toxic levels (ppm) to much higher levels (%) causing oxygen deficiency. This study investigated ventilation characteristics for isobutylene (IBE) at relatively low concentrations, simulating toxic levels. Experimental data were compared to results from previous studies of oxygen deficiency. Data were obtained at several locations in a cubical CS model, with several variable test parameters: ventilation mode (exhaust and supply), volume flow rate ("air changes" per hour), and ventilation inlet/outlet elevation (% of model height). Findings indicated similar ventilation characteristics, in general, for simulated toxic (IBE) levels compared to oxygen deficiency. Both IBE and O2 deficiency data have shown that supply ventilation is typically more effective than exhaust and that CS locations aligned with supply outlets experience much more rapid contaminant reduction than do other locations. The data suggest that highly accurate predictions of ventilation characteristics cannot be expected for all cases with widely different contaminants and concentrations. Findings from this study indicate that ventilation guidelines for one range of contaminant concentration (e.g., causing oxygen deficiency) can be extended reasonably to encompass a broader range of concentration (e.g., to include toxic or flammable atmospheres).

Air Pollutants, Occupational↗
PubMed1984

A methylmercury toxicity model to test for possible adverse effects resulting from chelating agent therapy.

A daily dosing model for methylmercury (MM) intoxication was developed for the purpose of testing for possible adverse effects resulting from the administration of complexing agents used in the treatment of MM poisoning. The dithiol complexing agents 2,3-dimercaptopropanol (BAL) and meso-2,3-dimercaptosuccinic acid (DMSA) were chosen to test the discriminative ability of this model, since the former is contraindicated for MM poisoning and causes an increase in target organ MM burden, while the latter compound is known to be efficacious in reducing both toxicity and brain MM content. The basic design of the model called for daily observation of treated animals with identification of the following signs of MM intoxication: loss of body weight, onset of signs of toxicity, and mortality. The degree of toxicity was evaluated, and a toxicity score (0-5) was provided for each animal. A dose-dependent decrease in body weight was found in MM-treated mice. The latent period for development of signs of intoxication varied inversely with the dose rate. The rate of progression of severity of signs of intoxication was also dependent upon the dose. A dose rate of 14 mg Hg per kg per day was utilized to test the effects of BAL and DMSA on the onset and progression of signs of MM intoxication. Onset and progression of signs of methylmercury intoxication were similar for animals receiving methylmercury either alone or with administration of BAL at 2 mg per kg per day. Animals which received BAL at a dose rate of 20 mg per kg per day developed signs of intoxication significantly earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress.

Parkinson's disease (PD) is a common neurodegenerative disorder that results from the selective loss of midbrain dopaminergic neurons. Misfolding and aggregation of the protein alpha-synuclein, oxidative damage, and proteasomal impairment are all hypotheses for the molecular cause of this selective neurotoxicity. Here, we describe a Saccharomyces cerevisiae model to evaluate the misfolding, aggregation, and toxicity-inducing ability of wild-type alpha-synuclein and three mutants (A30P, A53T, and A30P/A53T), and we compare regulation of these properties by dysfunctional proteasomes and by oxidative stress. We found prominent localization of wild-type and A53T alpha-synuclein near the plasma membrane, supporting known in vitro lipid-binding ability. In contrast, A30P was mostly cytoplasmic, whereas A30P/A53T displayed both types of fluorescence. Surprisingly, alpha-synuclein was not toxic to several yeast strains tested. When yeast mutants for the proteasomal barrel (doa3-1) were evaluated, delayed alpha-synuclein synthesis and membrane association were observed; yeast mutant for the proteasomal cap (sen3-1) exhibited increased accumulation and aggregation of alpha-synuclein. Both sen3-1and doa3-1 mutants exhibited synthetic lethality with alpha-synuclein. When yeasts were challenged with an oxidant (hydrogen peroxide), alpha-synuclein was extremely lethal to cells that lacked manganese superoxide dismutase Mn-SOD (sod2Delta) but not to cells that lacked copper, zinc superoxide dismutase Cu,Zn-SOD (sod1Delta). Despite the toxicity, sod2Delta cells never displayed intracellular aggregates of alpha-synuclein. We suggest that the toxic alpha-synuclein species in yeast are smaller than the visible aggregates, and toxicity might involve alpha-synuclein membrane association. Thus, yeasts have emerged effective organisms for characterizing factors and mechanisms that regulate alpha-synuclein toxicity.

Animals↗
PubMedDate not supplied

Modeling toxicity by using supervised kohonen neural networks.

Counterprogation neural network is shown to be a powerful and suitable tool for the investigation of toxicity. This study mined a data set of 568 chemicals. Two hundred eighty-two objects were used as the training set and 286 as the test set. The final model developed presents high performances on the data set R(2) = 0.83 (R(2) = 0.97 on the training set, R(2) = 0.59 on the test set). This technique distinguishes itself also for the ability to give to the expert two-dimensional maps suitable for the study of the distribution/clustering of the data and the identification of outliers.

Journal Article↗
PubMed1988

Approaches to modeling toxic responses of aquatic organisms to aromatic hydrocarbons.

Acute toxic effects on Salmo gairdneri, Poecilia reticulata, Daphnia magna, and the growth inhibition of Selenastrum capricornutum were measured for eight aromatic hydrocarbons. Toxicity measurements were carried out following the OECD standard guidelines modified as appropriate in order to prevent hydrocarbon loss by volatilization; the concentrations of the substrates in the test solutions were periodically measured by HPLC. The toxic responses were analyzed in terms of the n-octanol/water partition coefficients, by means of linear regression analysis, and in terms of five molecular properties simultaneously, by means of the partial least squares analysis in latent variables (PLS). The univariate and multivariate quantitative structure-activity relationship models obtained by the two approaches are compared and discussed.

Animals↗
PubMed2006

Deleterious role of IFNgamma in a toxic model of central nervous system demyelination.

Interferon-gamma (IFNgamma) is a pleiotropic cytokine that plays an important role in many inflammatory processes, including autoimmune diseases such as multiple sclerosis (MS). Demyelination is a hallmark of MS and a prominent pathological feature of several other inflammatory diseases of the central nervous system, including experimental autoimmune encephalomyelitis, an animal model of MS. Accordingly, in this study we followed the effect of IFNgamma in the demyelination and remyelination process by using an experimental autoimmune encephalomyelitis model of demyelination/remyelination after exposure of mice to the neurotoxic agent cuprizone. We show that demyelination in response to cuprizone is delayed in mice lacking the binding chain of IFNgamma receptor. In addition, IFNgammaR(-/-) mice exhibited an accelerated remyelination process after cuprizone was removed from the diet. Our results also indicate that the levels of IFNgamma were able to modulate the microglia/macrophage recruitment to the demyelinating areas. Moreover, the accelerated regenerative response showed by the IFNgammaR(-/-) mice was associated with a more efficient recruitment of oligodendrocyte precursor cells in the demyelinated areas. In conclusion, this study suggests that IFNgamma regulates the development and resolution of the demyelinating syndrome and may be associated with toxic effects on both mature oligodendrocytes and oligodendrocyte precursor cells.

Animals↗
PubMed1994

Modeling toxicity and response in carboplatin-based combination chemotherapy.

Data from women with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III or IV) were analyzed to evaluate the pharmacokinetic/pharmacodynamic relationships of carboplatin-based combination chemotherapy. With the equation area under the plasma concentration versus time curve (AUC) = dose/(creatinine clearance + 25), carboplatin AUC was calculated in each of up to six treatment cycles in 224 women with advanced ovarian cancer who had been randomized to receive carboplatin 300 mg/m2 plus cyclophosphamide 600 mg/m2. In addition, for each patient, the predicted nadir count (obtained by rearranging the University of Maryland single-agent carboplatin dosing formula) was compared with the actual observed nadir count, received and relative received dose intensities were calculated, and carboplatin exposure intensity was defined. Relationships were sought between these treatment indices and the clinical outcomes of time to progression and survival. When combined with cyclophosphamide 600 mg/m2, any carboplatin AUC was found to be associated with greater myelotoxicity and a higher likelihood of both leukopenia and thrombocytopenia occurring than had been determined for single-agent carboplatin. Furthermore, the platelet nadir in 83% of patients was equal to or below that predicted to result from the same dose of single-agent carboplatin. There was a relatively narrow range of received dose intensities within this patient population, but carboplatin exposure intensity was calculated as being distributed over a two-fold range within the population. Therefore, received carboplatin dose intensity underestimates the range of plasma drug exposure associated with a fixed dosing regimen of carboplatin. However, there were no consistent relationships between received dose intensity, relative received dose intensity, or carboplatin exposure intensity and the clinical outcomes of time to progression or survival. The relationships between carboplatin exposure and the pharmacodynamic measures of toxicity and response are likely to require definition in each regimen that includes carboplatin and for each tumor type treated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Evaluation of antidotes for extravasation injury produced by 6-hydroxymethylacylfulvene (MGI 114), a novel cytotoxic antitumor agent, in an intradermal toxicity model in rats.

MGI 114 (HMAF, 6-hydroxymethylacylfulvene) is a cytotoxic drug currently in phase II human clinical trials. As with other anticancer agents, inadvertent drug extravasation may result in perivascular irritation and/or necrosis. In this study the degree of soft tissue injury produced by MGI 114 after intradermal administration to rats was quantified and four potential antidotes for extravasation injuries caused by MGI 114 were evaluated. Intradermal injections of MGI 114 (0.2 ml, concentrations 0.1, 0.5 or 1.0 mg/ml) and a positive control, doxorubicin (0.2 ml, concentration 2 mg/ml) were administered to male Fischer 344 rats in an experiment designed to establish a model for antidote evaluation. Dermal lesions at the injection sites were measured and quantitated as the total area under the lesion area-time curve (AUC). Physiological saline, sodium thiosulfate, dimethylsulfoxide (DMSO) and local cooling, were then compared as potential antidotes in this model. In the initial study, dermal lesions (erythema, ulcerations and eschar formation) occurred at the MGI 114- and doxorubicin-treated sites. The lesion area resulting from MGI 114 was dose-related and was greatest at approximately 5 days, with resolution by day 7-22. Doxorubicin-induced lesions were comparable in area to those induced by the highest dose of MGI 114, but persisted approximately twice as long. In the antidote study, sodium thiosulfate administration resulted in approximately 20% diminution of lesion area and AUC value when compared to untreated controls. Normal saline caused slight reductions in maximum lesion area, but had little effect on AUC values. Local cooling also caused a modest reduction in the maximum lesion area, but actually resulted in higher AUC values by prolonging eschar duration. DMSO provided near complete tissue protection from intradermal exposure to MGI 114. In this model MGI 114 and doxorubicin were found to produce similar soft tissue injuries, but MGI 114-induced lesions tended to show a more rapid resolution. Topical DMSO treatment was found to produce the most effective protection against MGI 114-induced local tissue irritation and necrosis.

Administration, Cutaneous↗
PubMed1996

Toxic models of upper motor neuron disease.

Although neurotoxic models for progressive degeneration of both the anterior horn cell and the Betz cell do not exist, (neuro)lathyrism and neurocassavism (konzo) are examples of self limiting neurotoxic disorders that predominantly target the Betz cell. Both disorders are caused by the continuous intake of neurotoxic plant products (Lathyrus sativus and Manihot esculenta, respectively) which result in a virtually identical clinical picture of spastic paraparesis. A neurotoxic excitatory amino acid and AMPA agonist (beta-N-oxalylamino-1-alanine, BOAA) is held largely responsible for lathyrism. Epidemics of konzo are strongly associated with increased intake of the cyanide-liberating glycoside linamarin by protein-poor subjects. Whereas an animal model for neurocassavism does not exist, macaques fed Lathyrus sativus or BOAA develop central motor deficits with corticospinal tract involvement. Estimated dosages of Lathyrus sativus used to induce beginning lathyrism in well-nourished primates are 10-20 fold greater than those associated with irreversible human neurolathyrism. Major unexplained aspects of both diseases are the factors which allow the suspected toxins to target Betsz cells (blood-brain barrier, receptor distribution, cellular energy metabolism), the latency to onset in both diseases, and how two separate etiologic factors trigger clinically similar disorders.

Humans↗
PubMed2005

Dynamical coupling of PBPK/PD and AUC-based toxicity models for arsenic in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan.

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models were developed for arsenic (As) in tilapia Oreochromis mossambicus from blackfoot disease area in Taiwan. The PBPK/PD model structure consisted of muscle, gill, gut wall, alimentary canal, and liver, which were interconnected by blood circulation. We integrate the target organ concentrations and dynamic response describing uptake, metabolism, and disposition of As and the associated area-under-curve (AUC)-based toxicological dynamics following an acute exposure. The model validations were compared against the field observations from real tilapia farms and previously published uptake/depuration experimental data, indicating that predicted and measured As concentrations in major organs of tilapia were in good agreement. The model was utilized to reasonably simulate and construct a dose-dependent dynamic response between mortality effect and equilibrium target organ concentrations. Model simulations suggest that tilapia gills may serve as a surrogate sensitive biomarker of short-term exposure to As. This integrated As PBPK/PD/AUC model quantitatively estimates target organ concentration and dynamic response in tilapia and is a strong framework for future waterborne metal model development and for refining a biologically-based risk assessment for exposure of aquatic species to waterborne metals under a variety of scenarios.

Animals↗