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PubMed1996

Exposure-response functions in Air Force toxic risk modeling.

A new methodology for estimating the probabilistic risk from acute toxic exposures is planned as a support tool for the Air Force at the Eastern and Western Ranges. Two such methodologies are programs entitled the Launch Area Toxic Analysis program (LATRA) and the Cold Spill Toxic Risk Analysis program (COSTRA). These programs combine probabilistic models of an accident (when applicable), release cloud formation and dispersion (appropriate to the toxic substance and accounting for meteorological conditions), and new exposure-response functions (ERFs) for sensitive and normal exposed populations. These ERFs, anchored on specific exposure standards, estimate the probability of a given severity of health effect in a particular population as a function of the concentration or dose to which it is exposed. The further development and acceptance of these ERFs by the toxicology community, especially for different sensitivities, are key concerns addressed in this paper.

Accidents, Aviation↗
PubMed2004

Organ-specific toxicokinetics and dose-response of arsenic in tilapia Oreochromis mossambicus.

We appraised organ-specific toxicokinetics and dose responses of arsenic burdens in tilapia Oreochromis mossambicus. We kinetically linked an Area-under-the-curve (AUC)-based acute toxicity model and a pharmacodynamic model to derive dose-response relationships between equilibrium organ-specific arsenic concentrations and mortality effects. The AUC-based acute toxicity model was also used to derive organ-specific internal effect concentration (IEC)-time-response relationships, which can also be applied to predict a time-mortality profile. We conducted a 7-day exposure experiment to obtain toxicokinetic parameters, whereas the AUC-based acute toxicity model was verified with LC50(t) data obtained from a 7-day acute toxicity bioassay. Our results demonstrated that 96-hour LC50 and incipient LC50 for tilapia exposed to arsenic are 28.68 (95% confidence interval to 24.92 to 32.44) and 25.55 mg L(-1), respectively. Dose-response relationships followed the Hill equation, which could be expressed as organ-specific bioconcentration factors and incipient LC50. Organ-specific dose-response relationships showed that muscle, gill, and liver have a relatively steep sigmoid dose-response profile in that IEC50 were 26.6, 62.5, and 78.5 microg g(-1) dry wt (dw), respectively. Organ-specific arsenic internal lethal burdens were the highest in the gill and the lowest in the muscle in waterborne-exposed tilapia. The IEC and target-organ concentrations derived in this study can be used in site-specific risk assessment.

Animals↗
PubMed2001

Modeling acute toxicity of chemicals to Daphnia magna: a probabilistic neural network approach.

A methodology based on probabilistic neural networks (PNNs) is applied to model the acute toxicity (48-h LC50) of a set of 700 highly diverse chemicals to Daphnia magna. First, cross-validation experiments confirming the potential use of the PNN as modeling tool for the problem at hand were performed. Next, various approaches to construct-improved models are presented. The resulting four models are then validated using an external test set of 76 additional compounds. Input to the PNNs is derived solely from simple molecular descriptors and structural fragments and excludes bulk property parameters, such as the water solubility or the octanol/water partition coefficient.

Animals↗
PubMedDate not supplied

Tracheal epithelium in culture: a model for toxicity testing of inhaled molecules.

Rabbit trachea primary cultures have been developed as a model to evaluate the toxicity of noxious airborne pollutants. A mucociliary epithelium has been restored in vitro on collagen gel. Several general cytotoxicity assays (viability and growth inhibition) permit a first assessment for the acute toxicity of the tested molecules. More specific criteria such as measurement of the integrity of the epithelial barrier and inhibition of ciliary beat frequency allow to determine a specific impact of xenobiotics on the mucociliary epithelium in culture.

Acrolein↗
PubMed1988

Protection of rabbits in an infection model of toxic shock syndrome (TSS) by a TSS toxin-1-specific monoclonal antibody.

An anti-TSST-1-specific monoclonal antibody (MAb 8-5-7) was tested for its protective capacity in a rabbit infection model to toxic shock syndrome (TSS). The challenge strain of Staphylococcus aureus (RN4710), which contained a plasmid encoding TSS toxin-1, was introduced into previously implanted chambers. Purified monoclonal antibody (1.25 mg of immunoglobulin G) administered parenterally 1 day before and 1 day after initiation of infection provided complete protection against the TSS-like syndrome and the mortality which occurred in unprotected rabbits.

Animals↗
PubMed1999

Using probabilistic neural networks to model the toxicity of chemicals to the fathead minnow (Pimephales promelas): a study based on 865 compounds.

We investigate the use of probabilistic neural networks (PNN) to model the acute toxicity (96-hr LC50) to the fathead minnow (Pimephales promelas) based on a 865 chemicals data set. In contrast to most other toxicological models, the octanol/water partition coefficient is not used as input parameter. The information fed into the neural network is solely based on simple molecular descriptors as can be derived from the chemicals' structures and indicates the potential of this approach as general methodology for the estimation of toxicological effects of chemicals.

Animals↗
PubMed1987

The use of the ionization constant (pKa) in selecting models of toxicity in phenols.

Phenols elicit a toxic response by one of two mechanisms: polar narcosis or uncoupling of oxidative phosphorylation, and pKa values appear to be useful in predicting the mechanism of toxic action of a given phenol. The relative biological response (log BR) of 21 selected phenols in the static Tetrahymena pyriformis population growth test was determined. Seven derivatives, including dinitro- and polyhalogen-substituted phenols, were selected for testing because they were potential uncoupling agents. The other 14 derivatives were all suspected polar narcotics. 1-octanol/water partition coefficient (log Kow)-dependent regression analysis of the two subsets of derivatives results in two linear equations. The polar narcosis model is log BR = 0.6128 (log Kow) - 1.1297; r2 = 0.958, s = 0.187. The uncoupling of oxidative phosphorylation model is log BR = 0.4485 (log Kow) + 0.3007; r2 = 0.985, s = 0.209. Polar narcotic chemicals have pKa values greater than 8.00, while uncoupling agents have pKa values less than 6.50. Combining descriptors and modeling across mechanisms of toxicity in the model log BR = 0.5671 (log Kow) - 0.1885 pKa + 0.8190; r2 = 0.958, s = 0.225.

Animals↗
PubMed1993

A Gompertz age-specific mortality rate model of toxicity from short-term whole-body exposure to fission neutrons in rats.

A Gompertz age-specific mortality rate model was developed for toxicity resulting from a single dose of a toxicant resulting in nonrepaired injury that summates with natural (aging) injury. The model was applied to mortality data for male Sprague-Dawley rats subjected to short-term whole-body exposure to fission neutrons (D. Chmelevsky et al., Radiat. Res. 98, 519-535, 1984; J. LaFuma et al., Radiat. Res. 118, 230-245, 1989). The logarithmic-logistic function was used to relate the displacement of the Gompertz function with dose. Analysis of the age-specific mortality rate provides a measure of total injury over time from combined neoplastic and non-neoplastic causes and can be used to calculate the relative biological effectiveness (RBE) of different radiation sources. It is a useful adjunct to conventional risk assessment paradigms, particularly for those toxicants such as fission neutrons which result in a large number of competing causes of death other than cancer.

Age Factors↗
PubMed1993

A risk-assessment model for toxic exposure of small mammalian carnivores to cadmium in contaminated natural environments.

A model is presented to assess the risk of cadmium toxicity in mammalian wildlife in contaminated environments. The target-organ load was used as a hazard indicator and animals were considered to be at risk when a critical value, i.e. the lowest-observed-adverse-effect level (LOAEL), was attained or exceeded. The model was developed for Sorex araneus, a small mammalian predator with a high potential of attaining the critical target-organ load. Model parameter values were estimated from both explicit analysis of original field data and from theoretical considerations. A submodel was derived from linear regression of data concerning 36 field sites to predict the bioconcentration of cadmium in earthworms, an important food item of small mammalian carnivores. In addition to soil cadmium concentration several soil factors affecting cadmium bioavailability were included in the submodel. A second submodel was developed to predict target-organ load from a non-linear age-dependent regression of data on 63 predators from two different field sites. A separate theoretical model was constructed for the prediction of target-organ load as a function of pollutant ingestion, assimilation rates, and internal partitioning. The risk of cadmium exposure was assessed by estimating the EC50 value, the environmental effect concentration of a toxic substance in soil at which 50% of an adult population of predators would attain a target-organ load equal to or higher than the LOAEL. The model allows one to establish availability-differentiated soil quality standards with regard to cadmium pollution in natural environments. It predicts an exponential increase of the risk of hazardous exposure of terrestrial wildlife in areas sensitive to increasing levels of soil acidification ('chemical time bomb effect').

Animals↗
PubMedDate not supplied

Modeling the toxicity of aromatic compounds to tetrahymena pyriformis: the response surface methodology with nonlinear methods.

Response surface models based on multiple linear regression had previously been developed for the toxicity of aromatic chemicals to Tetrahymena pyriformis. However, a nonlinear relationship between toxicity and one of the molecular descriptors in the response surface model was observed. In this study, response surface models were established using six nonlinear modeling methods to handle the nonlinearity exhibited in the aromatic chemicals data set. All models were validated using the method of cross-validation, and prediction accuracy was tested on an external data set. Results showed that response surface models based on locally weighted regression scatter plot smoothing (LOESS), multivariate adaptive regression splines (MARS), neural networks (NN), and projection pursuit regression (PPR) provided satisfactory power of model fitting and prediction and had similar applicabilities. The response surface models based on nonlinear methods were difficult to interpret and conservative in discriminating toxicity mechanisms.

Animals↗
PubMed1998

Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice.

Pretreatment of mice with clofibrate (CFB) has been shown to protect against acetaminophen (APAP) hepatotoxicity. To determine if pretreatment with CFB prevents the toxicity of other model hepatotoxicants, male C57BL6J or CD-1 mice received 500 mg CFB/kg, i.p., daily for 10 days, and then were challenged with either 250 mg bromobenzene (BrB)/kg, 0.025 ml carbon tetrachloride (CCl4)/kg or 0.5 ml chloroform (CHCl3)/kg. Liver and kidney injury was assessed by plasma sorbitol dehydrogenase activity (SDH) and blood urea nitrogen (BUN), respectively and histopathology. Challenge with BrB significantly elevated plasma SDH activity in C57Bl6J mice. This was prevented in CFB pretreated mice receiving the same dose of BrB. Changes in BUN were not detected in either group of BrB treated mice. Similarly, pretreatment of male CD-1 mice with CFB significantly reduced CCl4-induced elevation in plasma SDH activity, with no BUN elevation detected in either group. CFB pretreatment also diminished elevation in plasma SDH activity produced by CHCl3 in CD-1 mice, while BUN was significantly elevated in both groups, indicating that CFB did not protect against CHCl3-induced nephrotoxicity. Histopathological examination of liver and kidney sections confirmed these results. This study shows that mice pretreated with CFB were protected from toxicity at 24 h after challenge with other model hepatotoxic agents besides APAP.

Administration, Oral↗
PubMedDate not supplied

Statistically validated QSARs, based on theoretical descriptors, for modeling aquatic toxicity of organic chemicals in Pimephales promelas (fathead minnow).

The use of Quantitative Structure-Activity Relationships in assessing the potential negative effects of chemicals plays an important role in ecotoxicology. (LC50)(96h) in Pimephales promelas (Duluth database) is widely modeled as an aquatic toxicity end-point. The object of this study was to compare different molecular descriptors in the development of new statistically validated QSAR models to predict the aquatic toxicity of chemicals classified according to their MOA and in a unique general model. The applied multiple linear regression approach (ordinary least squares) is based on theoretical molecular descriptor variety (1D, 2D, and 3D, from DRAGON package, and some calculated logP). The best combination of modeling descriptors was selected by the Genetic Algorithm-Variable Subset Selection procedure. The robustness and the predictive performance of the proposed models was verified using both internal (cross-validation by LOO, bootstrap, Y-scrambling) and external statistical validations (by splitting the original data set into training and validation sets by Kohonen-artificial neural networks (K-ANN)). The model applicability domain (AD) was checked by the leverage approach to verify prediction reliability.

Animals↗
PubMed2002

Development and application of an oil toxicity and exposure model, OilToxEx.

An oil toxicity and exposure model (OilToxEx) was developed and validated for estimation of impacts to aquatic organisms resulting from acute exposure to spilled oil. Because oil exposure is shorter than the time required for equilibrium between the organism and the water to be reached, the time and temperature dependence of toxicity is addressed. Oil toxicity is a function of aromatic composition and the toxicity of individual aromatics in the mixture. Lethal concentration to 50% of exposed organisms (LC50), as a function of octanol-water partition coefficient (Kow), and an additive model are used to estimate the toxicity of monoaromatic and polycyclic aromatic hydrocarbon mixtures in water-soluble fractions (WSF) and oil-in-water dispersions (OWD) of oil. The toxicity model was verified by comparison with oil bioassay data where the exposure concentrations of aromatics were measured. The observed toxicity in the bioassays could be accounted for by the additive narcotic effects of the dissolved aromatics in the exposure media. Predicted LC50s were compared to those calculated from measured concentrations after spills to verify the exposure model for field conditions. These results indicate that the additive toxicity and exposure model may be used to estimate toxicity of untested oils and spill conditions.

Environmental Exposure↗
PubMed1992

Safety aspects of non-ionic surfactant vesicles: a toxicity study related to the physicochemical characteristics of non-ionic surfactants.

Two different toxicity models were used to assess the relationship between the physicochemical properties of non-ionic surfactant vesicles (NSVs), and the safety of these vesicles for topical drug administration. The vesicles used in this study consisted of polyoxyethylene alkyl ethers (CnEOm) in which the number of C atoms (n) varied between 12 and 18 and the number of oxyethylene units (m) between 3 and 7. The physicochemical properties of the vesicles are described in terms of hydrophilic-lipophilic balance (HLB) values, and critical micelle concentrations (CMC), and the rigidity of the bilayers as determined by the gel-liquid transition temperatures and the cholesterol content of the bilayers. The first toxicity model, comprising the measurement of the ciliary beat frequency, is a tool to assess the safety of intranasally applied formulations. Studies using this ciliotoxicity model revealed that by increasing the length of the alkyl chain of the surfactant, a decrease in toxicity was observed. The opposite correlation was found if the length of the polyoxyethylene headgroup was increased. Furthermore, it was observed that gel-state vesicles produce less of an effect on the ciliary beat frequency than liquid state vesicles. The second toxicity model, comprising the determination of cell proliferation of human keratinocytes, is a method to assess skin irritancy. In contrast to the ciliotoxicity model the length of the polyoxyethylene headgroup and of the alkyl chains did not seem to have an effect on the safety of the vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1999

Staphylococcus aureus isogenic mutant, deficient in toxic shock syndrome toxin-1 but not staphylococcal enterotoxin A production, exhibits attenuated virulence in a tampon-associated vaginal infection model of toxic shock syndrome.

Since menstrual toxic shock syndrome (MTSS) is associated with a predominant clone of Staphylococcus aureus which produces both toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin A (SEA), we sought to clarify the role of TSST-1 in a tampon-associated vaginal infection model in New Zealand White (NZW) rabbits, using isogenic tst+/sea+ S. aureus mutants in which tst was inactivated by allelic replacement. Rabbits infected with the tst-/sea+ strain became ill within 3 days, with fever, weight loss, conjunctival hyperemia, and lethargy. Mortality was significantly higher with the tst+/sea+ strain compared to its tst-/sea+ isogenic derivative (4/13 vs. 0/14; p < 0.05, Fisher's exact test, 2-tailed). Mean fever index was higher (p < 0.005; t test, 2-tailed) and weight loss more sustained among survivors in the tst+/sea+ group. Furthermore, culture filtrates from the tst+/sea+ strain induced a significantly greater response in mitogenesis and TNF alpha secretion from rabbit splenocytes in vitro compared to the tst-/sea+ isogenic derivative. Thus, regardless of the role of SEA, TSST-1 significantly contributed to both morbidity and mortality in this tampon-associated vaginal infection model in NZW rabbits. This is the first demonstration of the potential role of TSST-1 and SEA in the pathogenesis of MTSS with a MTSS-associated clinical S. aureus strain in a relevant animal model.

Animals↗
PubMed1997

Effects of lazaroids and a peroxynitrite scavenger in a cell model of peroxynitrite toxicity.

We developed a cerebellar granule cell model of peroxynitrite toxicity and showed that certain sulfhydryl-containing compounds (e.g., penicillamine) present as concurrent treatments could inhibit this toxicity. In the present study, 21-aminosteroid and pyrrolopyrimidine lazaroids were tested for cytoprotection in this peroxynitrite toxicity model. In addition, we tested for added protection using a peroxynitrite scavenger concurrent treatment combined with a lazaroid post-treatment. The toxicity assay utilized cells that were previously exposed to 100 microM L-buthionine (S,R)-sulfoximine (BSO), an inhibitor of gamma-glutamyl-cysteine synthetase, for 24 h. This sublethal concentration of BSO shifted the peroxynitrite (1-1000 microM) toxicity curve to the left by more than one-half of a log unit. The half-maximal toxicity concentration (TC50) of peroxynitrite in cells treated with BSO was 50 microM. The 21-aminosteroids, U-74006F and U-74500A, and the pyrrolopyrimidines, U-91736B and U-101033E, were tested as post-treatments. U-74006F and U-74500A had EC50 values of approximately 100 microM (concentrations which blocked 50% of the toxicity). U-91736B and U-101033E had EC50 values of 1 microM and showed 100% protection at 3-10 microM. Treatment with either 100 microM U-74006F or 1 microM U-101033E resulted in a right-hand shift (protection) in the peroxynitrite toxicity curve. Further, combination treatment of lazaroids with 1 mM penicillamine resulted in additive protection compared to either treatment alone.

Animals↗
PubMedDate not supplied

Vaginal tampon model for toxic shock syndrome.

The effects of tampon composition, inoculum size, and simulated menses on production of toxic shock syndrome toxin 1 (TSST-1) and toxic shock syndrome (TSS) were evaluated in a rabbit model that simulates tampon use in humans. Three small generic compressed-fiber tampons were successively inserted vaginally (remained in place 4.5 hours x 2; overnight x 1). Tampon no. 1 was inoculated with live TSST-1-positive staphylococci plus 5 mL of saline or simulated menses (defibrinated rabbit blood plus 2.5 g of bovine serum albumin/dL) immediately after insertion; saline or simulated menses alone were used with tampons no. 2 and 3. The vagina was washed after removal of tampon no. 3. TSS-like illness was produced consistently in animals with carboxymethyl cellulose/polyester foam tampons, which supported higher organism counts and greater TSST-1 production in association with subsequent tampons. Cotton and rayon tampons were not associated with as much clinical illness, organism growth, or TSST-1 production. Simulated menses supported toxin production and clinical illness when the inoculum was one-tenth that required for controls. Sham tampon insertion was associated with TSS-like illness in two of 10 rabbits; thus, other factors may promote TSS in the absence of vaginal tampons. This model reliability reproduces menstrual TSS, since one-time vaginal inoculation with TSST-1-positive staphylococci in the presence of blood and certain tampons leads to TSS, and may be useful in evaluating catamenial products and in understanding other factors important in TSST-1 production in vivo and the development of TSS.

Animals↗
PubMed1985

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) as a potent and persistent thyroxine agonist: a mechanistic model for toxicity based on molecular reactivity.

TCDD and thyroxine have common molecular reactivity properties which enable them to present a planar face and lateral halogens in interactions with proteins. These molecular properties are consistent with the structure-toxicity relationship for TCDD and related compounds. Biological evidence is discussed including preliminary studies on the effects of TCDD exposure on tadpole growth and development which is consistent with the possible thyroxine-like activity of TCDD. The work suggests the possibility that toxicity is at least in part the expression of potent and persistent thyroid hormone activity (responses induced by TCDD which qualitatively correspond to those mediated by thyroid hormones). A mechanism for toxicity is proposed which involves receptor proteins; the planar aromatic system controls binding to cytosolic proteins and halogen substituents regulate binding to nuclear proteins. This simple model based on molecular reactivity sheds light on the diversified effects of TCDD and related compound toxicity and on certain thyroid hormone action. The model also permits predictions to be made with regard to the toxicity and thyroid hormone activity of untested compounds. In addition, the model suggests a general mechanism for hormone action based on metabolically regulated differential and cooperative protein receptor binding events in cellular compartments which can explain agonism, antagonism and potentiation within the framework of receptor occupancy theory.

Animals↗