Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Toxicity model”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed2001

The use of biomarkers in Daphnia magna toxicity testing V. In vivo alterations in the carbohydrate metabolism of Daphnia magna exposed to sublethal concentrations of mercury and lindane.

Aspects of the carbohydrate metabolism of Daphnia magna exposed for 48 and 96 h to sublethal concentrations of mercury and lindane were investigated. General as well as toxicant-specific perturbations in the intermediary metabolism were observed. Both model toxicants caused an increase in glycolytic and hexose-monophosphate shunt activity. Mercury exposure increased lactate dehydrogenase and isocitrate activity (only after 96 h), while lindane exposure, on the contrary, inhibited the cellular lactate formation and increased the Krebs' cycle activity (only after 48 h). Daphnids exposed to sublethal mercury concentrations clearly exhibited increased glycogenolytic activity, while in lindane-exposed organisms mainly glycogen phosphorylase inhibition was detected. The short-term enzyme-based effect levels (48--96 h LOEC and EC(10) values) were compared with the effects on the population dynamics. This evaluation for both model toxicants suggests that threshold levels (LOEC or EC(10) values) based on pyruvate kinase activity after 48 and 96 h of exposure could be potential early warning signals for long-term effects. A set of enzymatic endpoints, based on the intermediary metabolism, is suggested to characterize the metabolic state of the daphnids.

Animals↗
PubMed1997

Generalization of independent response model for toxic mixtures.

Interaction between toxic compounds has long been known to researchers. Attempts to model this interaction have been based on two basic paradigms--termed additivity and independence (1, 2). Previous models based on these assumptions focused on measuring the interaction between the compounds and then classifying the type of interaction as synergism, antagonism, additivity or independence (3, 4). The aim of this work is to present a generalization of the independent action hypothesis that is quantitatively capable of describing deviations regardless of the underlying single component dose response models. The mathematical framework of copulas is employed. This approach is then tested against data sets with both human health and ecological risk applications.

Animals↗
PubMed2000

Modeling the toxicity of chemicals to Tetrahymena pyriformis using molecular fragment descriptors and probabilistic neural networks.

The results of an investigation into the use of a probabilistic neural network (PNN)-based methodology to model the 48-h ICG50 (inhibitory concentration for population growth) sublethal toxicity of 825 chemicals to the ciliate Tetrahymena pyriformis are presented. The information fed into the neural networks is solely based on simple molecular descriptors as can be derived from the chemical structure. In contrast to most other toxicological models, the octanol/water partition coefficient is not used as an input parameter, and no rules of thumb or other substance selection criteria are employed. The cross-validation and external validation experiments confirmed excellent recognitive and predictive capabilities of the resulting models and recommend their future use in evaluating the potential of most organic molecules to be toxic to Tetrahymena.

Animals↗
PubMed1991

Qualitative and quantitative modelling of toxic effects of organophosphorous compounds to fish.

In this paper a QSAR analysis is applied with the intention of analyzing toxicity data of 20 organophosphorous compounds in terms of possible rate-limiting steps. Several aspects will be discussed and related to the physico-chemical properties of the test compounds. These are: bioconcentration factors, inhibition of acetylcholinesterase (AChE) and biotransformation in oxidative and glutathione-mediated in vitro systems. As expected, relatively simple relationships between toxicity data and Kow, as obtained for narcotic chemicals, were not obtained. The results of this study show that large differences can occur in the toxicity of the chemicals to fish, despite the fact that in vitro parameters for AChE inhibition and biotransformation are approximately equal. From these observations it is concluded that the application of general QSAR models for the estimation of toxicity data of reactive compounds that can be metabolized in vivo is as yet restricted due to our lack of knowledge of specific enzyme activities and of the role of possible extrahepatic biotransformation processes.

Animals↗
PubMedDate not supplied

Predictive models for aquatic toxicity of aldehydes designed for various model chemistries.

Predictive models for the aquatic toxicity of aldehydes were designed for a set of 50 aromatic or aliphatic compounds containing at least one aldehyde group, for which the acute toxicity data for the fathead minnow (Pimephales promelas) are available (96 h test assessing 50% lethal waterborne concentration). The molecular descriptors were based on calculations with various semiempirical or ab initio model chemistries. The resulting four-parameter models were evaluated according to the correlation coefficients R(2). The best predictive model was obtained with the HF/STO-3G model chemistry (R(2) = 0.868), while the models designed for descriptors based on ab initio calculations of higher level showed a slightly worse predictivity (the HF/3-21G(d) based model R(2) = 0.800, the HF/6-31G(d) based model R(2) = 0.808, the B3LYP/6-31G(d,p) based model R(2) = 0.812). With the semiempirical methods a good predictivity was observed with the PM3 based model (R(2) = 0.811) and the AM1 based model (R(2) = 0.791), but the MNDO based model showed the worst predictivity (R(2) = 0.760). In all ab initio models and the PM3 model very similar descriptors were involved. The importance of the descriptor logarithm of the partition coefficient logP for toxicity prediction was confirmed. Additionally, the descriptors encoding the negatively charged molecular surface area, hydrogen bonding molecular surface area, and reactivity of aldehyde group were identified as essential for the toxicity prediction of aldehydes.

Aldehydes↗
PubMed1991

QSAR modelling of the ERL-D fathead minnow acute toxicity database.

1. Regression analysis has been applied to examine the structure-activity relationships regarding the acute fish toxicity (96 h LC50 fathead minnow) of organic chemicals. The log P dependent baseline toxicity model has been confirmed for a data set composed of 618 compounds from 24 chemical classes associated with a putative common mode of action. 2. Covariance analysis of the discrete by class regression functions resulted in the combination of chemicals to subsets associated with their mode of action. Separate models were derived for nonpolar (Class I) and polar (Class II and III) compounds. Chemicals which are more toxic than estimated from the baseline model are identified.

Animals↗
PubMed2006

Screening for reactive intermediates and toxicity assessment in drug discovery.

Moving forward in the 21st century, toxicity remains a significant cause for failures during drug development, and limited correlations exist between preclinical in vitro cellular toxicity and/or in vivo animal toxicity models, and human toxicity. This is due, in part, to the fact that drug candidates generally target multiple tissues rather than single organs, and result in a series of inter-related biochemical events. Drug-induced toxicities, such as idiosyncratic drug reactions, represent a serious complication of drug therapy that needs to be addressed at the drug discovery stage. Many robust toxicity screening methods, however, have been developed, and are described in the literature. Although biochemical mechanisms of drug-induced toxicities are complex, by combining these screening methods into a panel of assays, a risk assessment profile/decision-making guide can be obtained for each drug candidate. The panel of assays covered by this review broadly includes in silico prediction of reactive intermediates, detection and structural characterization of reactive intermediates, covalent binding of reactive intermediates to macromolecules, and the impact of reactive intermediates on cellular functions. Current and future strategies for the proper sequencing of these assays in a drug discovery environment are also discussed.

Animals↗
PubMed1996

Interleukins 6 and 11 protect mice from mortality in a staphylococcal enterotoxin-induced toxic shock model.

BALB/By mice given doses of D-galactosamine plus Staphylococcus aureus enterotoxin B die within 48 h of administration. The cause of death is a syndrome much like toxic shock syndrome in humans. We used this model to investigate the role of two cytokines, interleukin 6 and interleukin 11, which share the signal transducing subunit, gp130, of their respective receptors. We observed that pretreatment of mice with antibody to interleukin 6 increased mortality from 55% to nearly 90% (P < 0.001), while pretreatment with either cytokine reduced death. The protection was dose dependent; however, interleukin 6 was about 10-fold more potent that interleukin 11. These data indicate that endogenous interleukin 6 plays a protective role in attenuating acute inflammatory responses; furthermore, interleukin 6 and interleukin 11 can abrogate T-cell activation due to triggering by superantigen. A possible clinical role for these cytokines in the treatment of toxic shock merits further investigation.

Animals↗
PubMed2003

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease.

Experimental models of dopaminergic neurodegeneration play a critical role in our quest to elucidate the cause of Parkinson's disease (PD). Despite the recent development of "genetic models" that have followed upon the discovery of mutations causing rare forms of familial PD, toxic models remain at the forefront when it comes to exploring the pathogenesis of sporadic PD. Among these, the model produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has a competitive advantage over all other toxic models because once this neurotoxin causes intoxication, it induces in humans a syndrome virtually identical to PD. For the past two decades, the complex pharmacology of MPTP and the key steps in the MPTP neurotoxic process have been identified. These molecular events can be classified into three groups: First, those implicated in the initiation of toxicity, which include energy failure due to ATP depletion and oxidative stress mediated by superoxide and nitric oxide; second, those recruited subsequently in response to the initial neuronal perturbations, which include elements of the molecular pathways of apoptosis such as Bax; and, third, those amplifying the neurodegenerative insult, which include various proinflammatory factors such as prostaglandins. Herein, these different contributing factors are reviewed, as is the sequence in which it is believed these factors are acting within the cascade of events responsible for the death of dopaminergic neurons in the MPTP model and in PD. How to target these factors to devise effective neuroprotective therapies for PD is also discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Alternative models for toxicity testing of xenobiotics.

The alternatives to whole-animal testing include endpoint assays, cell and tissue cultures, use of tissue slices, toxicokinetic modelling, and structure-activity relationships and databases. The use of in vitro systems (subcellular fractions, cell lines, primary cell cultures, tissue slices, organ cultures, etc.) as research tools in toxicology is widespread. In the past few years, the apoptosis phenomena were followed by very precise intracellular changes where, through programmed cell death, a cell can be removed from a population. The in vitro systems are ideally suited for investigations of the molecular, cellular and physiological mechanisms of chemically induced toxicity, which cannot readily be studied in vivo for known target organ and target species toxicity studies and for answering specific questions about toxic effects. The main justification for developing in vitro toxicity tests is that they will make toxicology a more scientifically based practice. It is increasingly apparent that the development and incorporation of stepwise testing strategies, combining experimental data from a range of alternative methods (physicochemical techniques, quantitative structure-activity relationships--QSAR, metabolic and kinetic modelling and in vitro tests), provide the most advanced way to predict toxicity, reducing at the same time the number of laboratory animals used for testing.

Animal Testing Alternatives↗
PubMed2000

Chemometric models for toxicity classification based on NMR spectra of biofluids.

1H NMR spectroscopic and pattern recognition (PR)-based methods were used to investigate the biochemical variability in urine obtained from control rats and from rats treated with a hydrazine (a model hepatotoxin) or HgCl(2) (a model renal cortical toxin). The 600 MHz (1)H NMR spectra of urine samples obtained from vehicle- or toxin-treated Han-Wistar (HW) and Sprague-Dawley (SD) rats were acquired, and principal components analysis (PCA) and soft independent modeling of class analogy (SIMCA) analysis were used to investigate the (1)H NMR spectral data. Variation and strain differences in the biochemical composition of control urine samples were assessed. Control urine (1)H NMR spectra obtained from the two rat strains appeared visually similar. However, chemometric analysis of the control urine spectra indicated that HW rat urine contained relatively higher concentrations of lactate, acetate, and taurine and lower concentrations of hippurate than SD rat urine. Having established the extent of biochemical variation in the two populations of control rats, PCA was used to evaluate the metabolic effects of hydrazine and HgCl(2) toxicity. Urinary biomarkers of each class of toxicity were elucidated from the PC loadings and included organic acids, amino acids, and sugars in the case of mercury, while levels of taurine, beta-alanine, creatine, and 2-aminoadipate were elevated after hydrazine treatment. SIMCA analysis of the data was used to build predictive models (from a training set of 416 samples) for the classification of toxicity type and strain of rat, and the models were tested using an independent set of urine samples (n = 124). Using models constructed from the first three PCs, 98% of the test samples were correctly classified as originating from control, hydrazine-treated, or HgCl(2)-treated rats. Furthermore, this method was sensitive enough to predict the correct strain of the control samples for 79% of the data, based upon the class of best fit. Incorporation of these chemometric methods into automated NMR-based metabonomics analysis will enable on-line toxicological assessment of biofluids and will provide a tool for probing the mechanistic basis of organ toxicity.

Animals↗
PubMed2002

Extension of the biotic ligand model of acute toxicity to a physiologically-based model of the survival time of rainbow trout (Oncorhynchus mykiss) exposed to silver.

Chemical speciation controls the bioavailability and toxicity of metals in aquatic systems and regulatory agencies are recognizing this as they develop updated water quality criteria (WQC) for metals. The factors that affect bioavailability may be quantitatively evaluated with the biotic ligand model (BLM). Within the context of the BLM framework, the 'biotic ligand' is the site where metal binding results in the manifestation of a toxic effect. While the BLM does account for the speciation and complexation of dissolved metal in solution, and competition among the free metal ion and other cations for binding sites at the biotic ligand, it does not explicitly consider either the physiological effects of metals on aquatic organisms, or the direct effect of water chemistry parameters such as pH, Ca(2+)and Na(+) on the physiological state of the organism. Here, a physiologically-based model of survival time is described. In addition to incorporating the effects of water chemistry on metal availability to the organism, via the BLM, it also considers the interaction of water chemistry on the physiological condition of the organism, independent of its effect on metal availability. At the same time it explicitly considers the degree of interaction of these factors with the organism and how this affects the rate at which cumulative damage occurs. An example application of the model to toxicity data for rainbow trout exposed to silver is presented to illustrate how this framework may be used to predict survival time for alternative exposure durations. The sodium balance model (SBM) that is described herein, a specific application of a more generic ion balance model (IBM) framework, adds a new physiological dimension to the previously developed BLM. As such it also necessarily adds another layer of complexity to this already useful predictive framework. While the demonstrated capability of the SBM to predict effects in relation to exposure duration is a useful feature of this mechanistically-based framework, it is envisioned that, with suitable refinements, it may also have utility in other areas of toxicological and regulatory interest. Such areas include the analysis of time variable exposure conditions, residual after-effects of exposure to metals, acclimation, chronic toxicity and species and genus sensitivity. Each of these is of potential utility to longer-term ongoing efforts to develop and refine WQC for metals.

Animals↗
PubMed2005

Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds.

Novel ruthenium(II) organo-metallic compounds are active in ovarian cancer models [Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE, Chen H, et al. In vitro and in vivo activity and cross resistance profiles of novel ruthenium(II) organometallic arene complexes in human ovarian cancer. Br J Cancer 2002;86(10):1652-7]. [(eta6-C6H5C6H5)Ru(en)Cl]+ (as a PF6 salt, where en=ethylenediamine (RM175)) has been evaluated in a 13-cell line panel. Particular sensitivity (approximately 10-fold lower than mean IC50) was noted in breast cancer and non-small cell lung cancer cell lines. In addition, IC50 in the A549 was 2 microM and RM175 (25 mg kg-1, days 1 and 5, i.p.) caused a significant (p=0.004) growth delay in a xenograft model. HC11 [(eta6-tetrahydroanthracene)Ru(en)Cl]PF6 was more potent in the A549 cell line (IC50 0.5 microM). HC11 (25 mg kg-1, days 1, 8 and 15, i.p.) was also active in vivo. Following RM175 25 mg kg-1, days 1 and 5, and 15 mg kg-1, days 1-5, HC11 25 and 40 mg kg-1, day 1, elevated alanine transaminase levels were detected, suggesting hepatotoxicity. No changes were observed in kidney or haematological parameters. In liver sections, multi-focal hepatic necrosis was seen, becoming confluent at high doses of HC11. In vitro studies confirmed that HC11 was more toxic than RM175 to fresh human hepatocytes and equitoxic to mithramycin. Liver toxicity may be related to the arene ligand and modification may reduce the potential for hepatic toxicity, while maintaining the anti-tumour activity seen.

Alanine Transaminase↗
PubMed2005

Establishment of a germ-somatic cell coculture model for toxicity assessment of environmental endocrine disrupters.

The objective of this study was to evaluate the effect of environmental endocrine disrupting chemicals by a germ--somatic cell coculture model in vitro. Testicular cells of 18-day-old chicken embryos were dispersed and cultured in different media. Results showed that somatic cells formed a monolayer to which germ cells adhered in the medium supplemented with insulin (Ins), transferrin (Tf), and selenite (Se) (ITS medium). However, the medium without ITS or single subtraction of Ins, Tf, or Se could not maintain cell survival in culture because many germ cells manifested apoptosis. Three known endocrine disrupters were selected to test the feasibility of this model. Aroclor 1254 (A1254, 10 microg/mL) induced condensed nuclei and vacuolated cytoplasm in germ cells, which was further confirmed by a cell proliferation assay. However, after culture for 48 h, the number of germ cells displayed a significant augment stimulated by A1254 (0.1-10 microg/mL) (P < 0.05). Similarly, 2,4-dichlorophenoxyacetic acid and busulfan displayed notable toxic effects on germ cells, and germ cell number and cell viability were significantly decreased in a dose-dependent manner (P < 0.05). The above results indicate that the chicken testicular germ-somatic cell coculture model is a simple, rapid, and veracious in vitro tool for evaluating the effect of environmental endocrine disrupters on functional basis of the cultured cells.

Animals↗
PubMed1985

On the development of skin models for toxicity testing.

The extrapolation of the results of measurements of skin penetration or skin damage with current in vitro and in vivo animal models to humans is of questionable value. Therefore, the usefulness of two other models is being evaluated: human skin grafts on congenitally athymic mice and cultures of human epidermal cells. The results show that histologically and immunologically the human skin grafts retain their "human" characteristics for at least 6 months. In contrast to animal skin these grafts also form blisters in response to heat and microblisters in response to sulfur mustard. By comparing blood cholinesterase (CHE) activity after epicutaneous, subcutaneous, and intravenous administration of soman in intact and (auto- or homo-) grafted mice it appears that the transplantation process itself does not influence penetration speed, nor does it affect the total amount of soman that ultimately reaches the blood. When applied on the human skin graft, soman penetration is slower and CHE inhibition in blood has not reached a plateau value after 2 1/2 hr. Substantial amounts of soman are metabolized in the skin. With epidermal cell cultures the different mechanisms of action of the mycotoxin T2 and that of tributyltin (TBT) can be demonstrated. In a young growing culture, 10(-8) M T2 completely blocks the increase in the number of epidermal cells, whereas the same concentration of TBT has no effect. In a fullgrown culture, however, 5 X 10(-5) M TBT causes membrane damage, detectable by the leakage of lactate dehydrogenase (LDH) into the medium, whereas the same concentration of T2 has no effect. Moreover the differential effects of TBT on cytoplasmic and lysosomal membranes can be demonstrated by measuring the rates at which the cytoplasmic marker enzyme LDH and the lysosomal marker enzyme N-acetyl-beta-glucosaminidase appear in the medium. From the results obtained so far it is concluded that these two models have quite a number of promising features for dermatotoxicity testing.

Animals↗
PubMed1987

The fish gill: site of action and model for toxic effects of environmental pollutants.

The gill epithelium is the site of gas exchange, ionic regulation, acid-base balance, and nitrogenous waste excretion by fishes. The last three processes are controlled by passive and active transport of various solutes across the epithelium. Various environmental pollutants (e.g., heavy metals, acid rain, and organic xenobiotics) have been found to affect the morphology of the gill epithelium. Associated with these morphological pathologies, one finds alterations in blood ionic levels, as well as gill Na,K-activated ATPase activity and ionic fluxes. Such physiological disturbances may underly the toxicities of these pollutants. In addition, the epithelial transport steps which are affected in the fish gill model resemble those described in the human gut and kidney, sites of action of a variety of environmental toxins.

Animals↗