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At least 379 records · Page 21Linked to original sources
PubMed2006

Comparative ecotoxicological hazard assessment of beta-blockers and their human metabolites using a mode-of-action-based test battery and a QSAR approach.

We analyzed nontarget effects of the beta-blockers propranolol, metoprolol, and atenolol with a screening test battery encompassing nonspecific, receptor-mediated, and reactive modes of toxic action. All beta-blockers were baseline toxicants and showed no specific effects on energy transduction nor endocrine activity in the yeast estrogen and androgen screen, and no reactive toxicity toward proteins and DNA. However, in a phytotoxicity assay based on the inhibition of the photosynthesis efficiency in green algae, all beta-blockers were 10 times more toxic than their modeled baseline toxicity. Baseline- and phytotoxicity effects increased with hydrophobicity. The beta-blockers showed concentration addition in mixture experiments, indicating a mutual specific nontarget effect on algae. Using literature data and quantitative structure-activity relationships (QSAR), we modeled the total toxic potential of mixtures of the beta-blockers and their associated human metabolites for the phytotoxicity endpoint with two scenarios. The realistic scenario (I) assumes that the metabolites lose their specific activity and act as baseline toxicants. In the worst-case scenario (II) the metabolites exhibitthe same specific mode of action as their parent drug. For scenario (II), metabolism hardly affected the overall toxicity of atenolol and metoprolol, whereas propranolol's hazard potential decreased significantly. In scenario (I), metabolism reduced the apparent EC50 of the mixture of parent drug and metabolite even further. The proposed method is a simple approach to initial hazard assessment of pharmaceuticals and can guide higher tier testing. It can be applied to other classes of pollutants, e.g., biocides, as well as to environmental transformation products of pollutants.

Adrenergic beta-Antagonists↗
PubMed1992

A probability model for assessing exposure among respirator wearers: Part II-Overexposure to chronic versus acute toxicants.

A model describing the lognormal total distribution of contaminant levels inside a respirator (CI) is applied to assessing the probability of toxicant overexposure among a population of respirator wearers; the model accounts for between-wearer and within-wearer variability in ambient exposure levels (CO) and decimal fraction respirator penetration (P) values. The three exceedance probabilities are defined as PrI, the proportion of all CI levels over the permissible exposure limit (PEL); PrII, the proportion of wearers with an arithmetic mean CI level over the PEL; and PrIII, the proportion of wearers with a 95th percentile CI value over the PEL. PrII is considered that fraction of the population overexposed to a chronic toxicant; PrIII is considered that fraction overexposed to an acute toxicant. The behavior of PrII and PrIII over a range of exposure parameters is explored. An important observation is that a respirator-wearing population can have a substantial fraction of toxicant overexposure even though two conditions are met: (1) the P values for the population satisfy the criterion for the assigned protection factor (APF); and (2) the population arithmetic mean CO level is at or below the maximum use concentration (MUC), defined as APF x PEL. The authors recommend that the current MUCs for air-purifying respirators be reduced by one-half to reduce the potential respirator-wearing population fraction of overexposure and that appropriate exposure surveillance programs for all wearers be mandated.

Acute Disease↗
PubMed2002

Probabilistic neural network modeling of the toxicity of chemicals to Tetrahymena pyriformis with molecular fragment descriptors.

We present the results of an investigation into the use of a probabilistic neural network (PNN) based methodology to model the 48-60-h ICG50 (inhibitory concentration for population growth) sublethal toxicity to the ciliate Tetrahymena pyriformis. The information fed into the neural network 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 involved. The model was trained on a 1,000 substances data set and validated using an 84 substances external test set. The associated analysis of errors confirms the excellent recognitive and predictive capabilities of the model.

Animals↗
PubMed1996

Mass-transport models to predict toxicity of inhaled gases in the upper respiratory tract.

Mass transport (the movement of a chemical species) plays an important role in determining toxic responses of the upper respiratory tract (URT) to inhaled chemicals. Mathematical dosimetry models incorporate physical characteristics of mass transport and are used to predict quantitative uptake (absorption rate) and distribution of inhaled gases and vapors in the respiratory tract. Because knowledge of dose is an essential component of quantitative risk assessment, dosimetry modeling plays an important role in extrapolation of animal study results to humans. A survey of existing mathematical dosimetry models for the URT is presented, limitations of current models are discussed, and adaptations of existing models to produce a generally applicable model are suggested. Reviewed URT dosimetry models are categorized as early, lumped-parameter, and distributed- parameter models. Specific examples of other relevant modeling work are also presented.

Administration, Inhalation↗
PubMed2004

Re-evaluation of metal bioaccumulation and chronic toxicity in Hyalella azteca using saturation curves and the biotic ligand model.

Bioaccumulation by Hyalella of all metals studied so far in our laboratory was re-evaluated to determine if the data could be explained satisfactorily using saturation models. Saturation kinetics are predicted by the biotic ligand model (BLM), now widely used in modelling acute toxicity, and are a pre-requisite if the BLM is to be applied to chronic toxicity. Saturation models provided a good fit to all the data. Since these are mechanistically based, they provide additional insights into metal accumulation mechanisms not immediately apparent when using allometric models. For example, maximum Cd accumulation is dependent on the hardness of the water to which Hyalella are acclimated. The BLM may need to be modified when applied to chronic toxicity. Use of saturation models for bioaccumulation, however, also necessitates the need for using saturation models for dose-response relationships in order to produce unambiguous estimates of LC50 values based on water and body concentrations. This affects predictions of toxicity at very low metal concentrations and results in lower predicted toxicity of mixtures when many metals are present at low concentrations.

Amphipoda↗
PubMed1984

Accelerated accumulation of aluminum by osteoid matrix in vitamin D deficiency. An animal model of aluminum toxicity.

To investigate the possibility that aluminum (Al) salts might associate specifically with osteoid matrix in bone, an animal model was developed in which hyperosteoidosis was controlled independently by the vitamin D status. Nonuremic rats were weaned on a vitamin D-free diet (D-) and half were given intraperitoneal AlCl3 (9.25 mg Al over 33 days). At sacrifice, serum calcium was significantly higher in Al-treated D- rats compared to D- controls (9.4 +/- 0.3 vs. 6.9 +/- 0.8 mg/dl, p less than 0.01). Serum and bone Al content were measured by flameless atomic absorption spectroscopy; Al content was 318 +/- 38 micrograms/l in serum, and 248 +/- 11 mg/kg dry bone weight in Al-treated rats, compared to almost undetectable levels in D- controls. Al was identified histochemically in Al-treated rats by its heavy deposition in subepiphyseal trabecular bone; where it occupied almost 50% of the linear trabecular bone surface, usually sandwiched between bone and osteoid seams. Both groups of animals had severe osteomalacia, but there was no evidence that Al induced a more severe lesion in addition to vitamin D deficiency. Parenteral Al was also given to rats fed a similar diet, but supplemented with vitamin D3 (D+) (cumulative dose of Al, 37.25 mg over 70 days). At sacrifice, serum Al was 671 +/- 50 micrograms/l, but bone Al was only 142 +/- 10 mg/kg, significantly less than bone Al in D- Al-treated rats. There was no evidence of osteomalacia in D+ Al-treated rats in which histochemical staining for Al was essentially negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗
PubMedDate not supplied

Prediction of mammalian toxicity of organophosphorus pesticides from QSTR modeling.

Quantitative structure-toxicity relationship (QSTR) models were derived for estimating the acute oral toxicity of organophosphorus pesticides to male and female rats. The 51 chemicals of the training set and the nine compounds of the external testing set were described by means of autocorrelation vectors encoding lipophilicity, molar refractivity, H-bonding acceptor ability (HBA) and H-bonding donor ability (HBD) of the molecules. A feature selection was employed for selecting the most relevant autocorrelation descriptors. A PLS regression analysis and an artificial neural network (ANN) were used for deriving models accounting for the sex of the organisms in the estimation of the toxicity of pesticides. The best results were obtained with an 8/4/1 ANN model trained with theback-propagation and conjugate gradient descent algorithms. The root mean square residual (RMSR) values for the training set and the external testing set equaled 0.29 and 0.26, respectively.

Animals↗
PubMed2004

An examination of quinone toxicity using the yeast Saccharomyces cerevisiae model system.

The toxicity of quinones is generally thought to occur by two mechanisms: the formation of covalent bonds with biological molecules by Michael addition chemistry and the catalytic reduction of oxygen to superoxide and other reactive oxygen species (ROS) (redox cycling). In an effort to distinguish between these general mechanisms of toxicity, we have examined the toxicity of five quinones to yeast cells as measured by their ability to reduce growth rate. Yeast cells can grow in the presence and absence of oxygen and this feature was used to evaluate the role of redox cycling in the toxicity of each quinone. Furthermore, yeast mutants deficient in superoxide dismutase (SOD) activity were used to assess the role of this antioxidant enzyme in protecting cells against quinone-induced reactive oxygen toxicity. The effects of different quinones under different conditions of exposure were compared using IC50 values (the concentration of quinone required to inhibit growth rate by 50%). For the most part, the results are consistent with the chemical properties of each quinone with the exception of 9,10-phenanthrenequinone (9,10-PQ). This quinone, which is not an electrophile, exhibited an unexpected toxicity under anaerobic conditions. Further examination revealed a potent induction of cell viability loss which poorly correlated with decreases in the GSH/2GSSG ratio but highly correlated (r2 > 0.7) with inhibition of the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), suggesting disruption of glycolysis by this quinone. Together, these observations suggest an unexpected oxygen-independent mechanism in the toxicity of 9,10-phenanthrenequinone.

Cell Survival↗
PubMed1991

Effects of alpha-1-acid glycoprotein on the cardiovascular toxicity of nortriptyline in a swine model.

Tricyclic antidepressant toxicity is a frequently encountered and life-threatening problem in emergency medicine. This trial investigated the effect of alpha-1-acid glycoprotein (AAG), an acute phase reactant with a high affinity for basic drugs, on the clinical and pharmacological manifestations of nortriptyline (NT) toxicity. Fourteen pentobarbital-anesthetized swine (10-13 kg) were given a 10-min loading dose followed by a 45-min maintenance infusion of NT to achieve a plasma level of approximately 1000 ng/ml. At the end of the infusion, 7 control (C) animals were given 50 ml of 0.9% saline and 7 AAG animals were given 50 ml of 10% AAG, both over 15 min. Heart rate, QRS duration, QTc interval, blood pressure, temperature, arterial blood gases, albumin, and plasma-free and plasma-bound NT levels were measured at baseline and at every hour for 4 h. One death was noted in the AAG group and none in the C group (p = NS). Mean total NT levels after infusion in the C group was 1240 +/- 1118 ng/ml and in the AAG group 804 +/- 194 ng/ml (p = NS). No significant differences were found in the plasma-free fractions between groups at any time interval. However, significantly shorter QTc intervals were found during treatment with AAG compared to controls (P = 0.02). A trend toward increased systolic blood pressure (p = 0.09) and shorter QRS duration (p = 0.09) was noted during AAG treatment. No significant changes were shown between groups with respect to heart rate, arterial blood gases, or albumin measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Radiation induced secretion of surfactant from cell cultures of type II pneumocytes: an in vitro model of radiation toxicity.

The pathogenesis of pneumonitis and fibrosis secondary to lung irradiation is incompletely understood. The role of the type II alveolar epithelial pneumocyte in these processes has been under investigation. The type II pneumocyte has been shown in vivo to respond to radiation induced injury with release of pulmonary surfactant. The effect of irradiation on cell cultures of type II pneumocytes was studied to determine if this could be reproduced in vitro. Type II pneumocytes were found to release surfactant material with a threshold of radiation dose between 1000 and 1500 rad. This is similar to the dosage range over which the same effect has been demonstrated in vivo. Experimental results support the concept that the release of surfactant is not due to either cell disruption or non-specific release of phospholipid from cell membranes. Irradiation appears to trigger membrane receptor mediated surfactant release. In addition, irradiation abolishes the ability of cells to subsequently respond to a physiologic agonist, suggesting radiation induced damage to the secretory mechanism. These studies establish that surfactant release in response to irradiation in vivo is a direct effect on type II pneumocytes. Cell cultures of type II pneumocytes can serve as a laboratory model of lung cell radiation toxicity.

Animals↗
PubMed2005

Elevation of the Hsp70 chaperone does not effect toxicity in mouse models of familial amyotrophic lateral sclerosis.

Mutations in copper/zinc superoxide dismutase (SOD1) account for 10-20% of a familial form of amyotrophic lateral sclerosis (ALS). A common feature of SOD1 mutants is abnormal aggregation of the aberrant SOD1 in neurons and glia. We now report that in ALS transgenic mouse models the constitutively expressed heat shock protein 70 (Hsp70) is mislocalized into aggregates together with mutant SOD1 and ubiquitin. Forcing increased synthesis of Hsp70 ameliorates both aggregate formation and toxicity in primary motor neurons in culture. However, chronic increase in an inducible form of Hsp70 to about 10-fold its normal level is shown here not to affect disease course or pathology developed in mice from accumulation of any of three familial ALS causing SOD1 mutants with different underlying biochemical characteristics. Therefore, increasing Hsp70 to a level that is protective in mouse models of acute ischemic insult and selected neurodegenerative disorders is not sufficient to ameliorate mutant SOD1-mediated toxicity.

Age Factors↗
PubMed1997

A model for light toxicity of cultured human retinal pigment epithelium.

BACKGROUND: The effect of visible light on human retinal pigment epithelial (HRPE) cells has not been characterized under conditions that provide strict thermal control. METHODS: HRPE cells were isolated and grown to confluence. Cells were exposed to light in an incubator in which the cell temperature was controlled in response to a temperature sensor maintained in the tissue culture medium. Cells were exposed: (A) for 24, 36, and 48 h; and using a 24-h exposure followed by 24 h darkness; (B) at varying intensities of light using neutral density filters; (C) under a yellow filter; and (D) with a 12-h on-off cyclic light. RESULTS: (A) Light exposure of 36 and 48 h resulted in significant cytotoxicity, while the initial 24-h exposure did not induce subsequent cytotoxicity. (B) Light irradiance levels from 43 to 54 mW/cm2 were required to demonstrate cytotoxicity. (C) Use of a yellow filter did not eliminate the observed cytotoxicity. (D) Cyclic exposure did not result in significant cytotoxicity. CONCLUSION: This study establishes a model and basic parameters of light toxicity to HRPE cells in vitro using strict temperature control that may be used to evaluate photochemical injury to HRPE cells.

Adolescent↗
PubMed2005

Cell signalling during sea urchin development: a model for assessing toxicity of environmental contaminants.

The early development of sea urchins has been thoroughly studied since the beginning of the 20th century thanks to the particular features of the model involving cell signalling, making it easy to follow the complex cell-to-cell interactions that lead to development. In this chapter, the prominent role of cell-to-cell communication in developmental events is discussed, as well as the role of intracellular ion changes that are in turn regulated by signal molecules belonging to the cholinergic system. The results seem to indicate that the zygote stage is the most suitable to study the role of the cholinergic system, as at this stage, a calcium spike can be evoked by exposure to acetylcholine (ACh) or to muscarinic drugs, at any time before the nuclear breakdown. The described outcomes also open a path to a new way of considering biomarkers. In fact, most environmental factors have the capacity to interfere with the cholinergic system: stress, wounds, inflammation and pollution in general. In particular, this offers a way to investigate the presence in the environment and the degree of aggressiveness of neurotoxic contaminants, such as organophosphate and carbamate pesticides, largely used in European countries for many purposes, including agricultural pest control and medical treatment. These drugs exert their function by interfering with the regulation of the cholinergic system and the consequent electrical events. Thus, the sea urchin zygote could represent a reliable model to be used in biosensors with the capacity to translate the effect of neurotoxic pesticides, and generally of stress-inducing contaminants, in living cell responses, such as electrical responses.

Acetylcholine↗