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PubMed2005

An integrated addition and interaction model for assessing toxicity of chemical mixtures.

The high propensity for simultaneous exposure to multiple environmental chemicals necessitates the development and use of models that provide insight into the toxicity of chemical mixtures. In this study, we developed a mathematical model that combines concepts of concentration addition, response addition, and toxicokinetic chemical interaction to assess toxicity of chemical mixtures. A ternary mixture of acetylcholinesterase inhibiting organophosphates (malathion and parathion) and the P450 inhibitor piperonyl butoxide was used to model toxicity. Concentration-response curves were generated for individual chemicals as well as for mixtures of the chemicals using acute toxicity tests with Daphnia magna. The toxicity of binary combinations of malathion and parathion adhered to the principles of concentration addition. The contribution of piperonyl butoxide to mixture toxicity was integrated using a model for response addition. Piperonyl butoxide also modified the toxicity of the organophosphates by inhibiting their metabolic activation. The antagonistic effects of piperonyl butoxide towards the organophosphates were quantified as coefficients of interactions (K-functions) and incorporated into the mixture model. Finally, toxicity of the ternary mixture was modeled at 30 different mixture formulations using three additive models that assumed no interaction (concentration addition, response addition, and integrated addition) and using the integrated addition and interaction (IAI) model. Toxicity of the 30 mixtures was then experimentally determined and compared to model results. Only the IAI model accurately predicted the toxicity of the mixtures. The IAI model holds promise as a means for assessing hazard of complex chemical mixtures.

Acetylcholinesterase↗
PubMed2005

Greater than the sum of its parts: combining models for useful ADMET prediction.

In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) models are important tools in combating late-stage attrition in the drug discovery process. This work shows how ADMET models can be combined to tailor predictions depending on one's needs. We demonstrate how the judicious use of data and considered combination of predictions can produce models that provide truly useful answers. This approach is illustrated with the prediction of hERG channel blocking and cytochrome P450 2D6 inhibition, where combination of two predictive models (with >80% of compounds correctly predicted) resulted in models with even better predictive values (with >90% of compounds correctly predicted for those classes of interest).

Bayes Theorem↗
PubMed2003

E-state modeling of fish toxicity independent of 3D structure information.

Topological structure methods are used to model fish toxicity against three classes of organic chemicals. The models were obtained independent of 3D structure information. Further, no mechanism of partitioning was assumed, thus avoiding the problems associated with selection of partitioning system for computation of log P. QSAR models were developed for a set of 92 compounds, including phenols, anilines and substituted aromatic hydrocarbons, yielding excellent statistics: r2 = 0.87, s = 0.25 and q2 = 0.85 leave-one-out (LOO), that are better than those reported in the literature. The model is based on molecular connectivity valence chi-1 index [1chiv], the atom type E-State indices for chlorine [ST(-Cl)] and for ether oxygen [ST(-O-)], and the maximum hydrogen E-State atom value in a molecule [Hmax]. Each of the subgroups was also separately well modeled. The model for the full set is validated through use of external validation test sets and ten-fold cross-validation (repeated three times). The quality of the validation statistics supports the claim that the model may be used for estimation of pLC50 values for similar molecules. Detailed structure interpretation is given for the descriptors in the model. These four structure descriptors encode influence of molecular context of groups as well as counts of those groups, in addition to molecular skeletal structure.

Aniline Compounds↗
PubMed1998

Quantitative structure-based modeling applied to characterization and prediction of chemical toxicity.

Quantitative modeling methods, relating aspects of chemical structure to biological activity, have long been applied to the prediction and characterization of chemical toxicity. The early linear free-energy approaches of Hansch and Free Wilson provided a fundamental scientific framework for the quantitative correlation of chemical structure with biological activity and spurred many developments in the field of quantitative structure-activity relationships (QSARs). In addition to modeling of chemical toxicity, these methods have been extensively applied to modeling of medicinal properties of chemicals. However, there are important differences in the nature and objectives of these two applications, which have led to the evolution of different modeling approaches (namely, the need for treating sets of noncongeneric toxic compounds). In this paper are discussed those approaches to chemical toxicity that have taken a more "personalized" configuration and have undergone implementation into software programs able to perform the various steps of the assessment of the hazard posed by the chemicals. These models focus both on a variety of toxicological endpoints and on key elements of toxicity mechanisms, such as metabolism.

Automation↗
PubMed1976

Triethyltin toxicity as a model for degenerative disorders.

Triethyltin (TET) toxicity in mice was examined as a model for certain degenerative disorders. Spontaneous and elicited behavioral tests, electrophysiological measures and nervous system protein characterizations were used to study anomalies resulting from TET treatments. TET animals exhibited lowered spontaneous locomotor activity levels, increased sciatic nerve excitation threshold and conduction velocities, and increased power levels in the slower frequency components of their electroencephalograms. Performance in an active avoidance task suggest that the gross ultrastructural changes commonly seen in TET intoxication are not primarily responsible for the observed neurophysiological changes. Possible sites of action of TET, in both the peripheral and central nervous systems, that would produce these neurophysiological changes and the relationship of these changes to the behavioral symptoms are discussed.

Animals↗
PubMedDate not supplied

Creation of predictive models of aquatic toxicity of environmental pollutants with different mechanisms of action on the basis of molecular similarity and HYBOT descriptors.

Over half of known industrial pollutants have minimal toxic effect, in line with the concept of "baseline toxicity"; such toxicity usually correlates well with lipophilicity. The remainder require additional descriptors in order to model their toxicity by the QSAR approach. Hence, it has not been possible, to date, to develop common stable QSAR models for the toxicity of diverse chemicals with various modes of action on the basis of simple regression relationships. Any new methodology has to take such different modes of action into account. In our work, we used for this purpose an original combination of the similarity concept and physicochemical descriptors calculated by HYBOT, in order to construct stable QSAR models of guppy toxicity. The training set comprised 293 diverse chemicals. Experimental value(s) of one or more nearest related chemicals were used to take structural features and possible modes of toxic action into account. In addition, molecular polarisability and hydrogen bond descriptors for the chemicals of interest and related compounds were used to calculate any additional contribution in toxicity by means of linear regression relationships. Final comparison of calculated and experimental toxicity values gave good results, with standard deviation close to the experimental error.

Animals↗
PubMed2004

Assessment and modeling of the toxicity of organic chemicals to Chlorella vulgaris: development of a novel database.

This study reports a database of toxicity values for 91 compounds assessed in a novel, rapid, and economical 15 min algal toxicity test. The toxicity data were measured using the unicellular green alga Chlorella vulgaris in an assay that determined the disappearance of fluorescein diacetate. The chemicals tested covered a wide range of physicochemical properties and mechanisms of action. Quantitative activity-activity relationships with the toxicity of the chemicals to other species (Tetrahymena pyriformis, Vibrio fischeri, and Pimephales promelas) showed strong relationships, although some differences resulting from different protocols were established. Quantitative structure-activity relationships (QSARs) were determined using linear [multiple linear regression (MLR)] and nonlinear [k-nearest neighbors (KNN)] methods. Three descriptors, accounting for hydrophobicity, electrophilicity, and a function of molecular size corrected for the presence of heteroatoms, were found to be important to model toxicity. The predictivity of MLR was compared to KNN using leave-one-out cross-validation and the simulation of an external test set. MLR demonstrated greater stability in validation. The results of this study showed that method selection in QSAR is task-dependent and it is inappropriate to resort to more complicated but less transparent methods, unless there are clear indications (e.g., inability of MLR to deal with the data set) for the need of such methods.

Chemical Phenomena↗
PubMed1986

A new experimental model to study oxygen toxicity.

An experimental model was developed in order to study the protective effect of antioxidant molecules. Human diploid WI-38 fibroblasts were cultivated under 2 atm of 95% O2. Antioxidants like alpha-tocopherol or superoxide dismutase (SOD) were added respectively in the culture medium or directly inside the cell through a microinjection technique. With both antioxidant molecules a protection was observed. In the control experiment, cells died within 6 or 8 days depending on the confluency and the malonaldehyde content increased sharply. This model represents a new tool in order to test other antioxidant systems towards an oxidative stress.

Antioxidants↗
PubMedDate not supplied

[Highly-sensitive method of studying the toxicity of lipid peroxides].

A highly sensitive and simple method is developed for study of lipid peroxides toxicity with the use of quail developing embryos as a model. Toxicity of linolenic acid hydroperoxides, obtained by the lipoxygenase catalysis, was distinctly higher than the toxicity of the peroxides, produced alter autooxidation (LD50 = 0.12 and 0.38 mc-eq/embryo, respectively). Occurrence of toxic properties was observed in lipids, isolated from tissues of mice subjected to the oxygen stress. The advantages of the method described are discussed as compared with the published data.

Animals↗
PubMed1980

Experimental model of doxorubicin extravasation in the mouse.

Doxorubicin (Adriamycin), a widely used antitumor agent, can occasionally cause severe and protracted local tissue damage if inadvertently extravasated during intravenous injection. An animal model was developed in adult BALB/c mice to experimentally duplicate such human skin toxicity, Intradermal (ID) doxorubicin injections of 0.5, 0.05 and 0.005 mg (per 0.05 ml) provided reproducible, dose-related skin lesions, quantitated with daily measurement of perpendicular diameters of induration, erythema, and ulceration. Maximal lesions developed rapidly (within 3-5 days) and slowly resolved over 30-40 days. There were dose-related increments in peak toxicity levels, total toxicity, and the duration of damage for each parameter (0.5 > 0.05 > 0.005 mg). Subcutaneous (ie, subpannicular) injections, and ID saline control injections did not cause local skin toxicity. A local intervention with ID hydrocortisone (2.5 mg) substantially reduced erythema and induration, and eliminated ulceration only in animals receiving the lower dose (0.05 mg) doxorubicin challenge (p < 0.05). This direct skin toxicity method is compared to reported animal skin toxicity models, and the intervention results are discussed in reference to current toxicity observations in man.

Animals↗
PubMed2001

A field-based population model for the sediment toxicity test organism Leptocheirus plumulosus: II. Model application.

A stage-structured population model has been developed for the estuarine amphipod Leptocheirus plumulosus to provide interpretive guidance for sediment toxicity tests with this species. This time-varying, field-based model includes several matrices to reflect seasonal changes in demographics. In this paper, we conduct sensitivity analysis of the model to identify which life history parameters have the greatest potential impact on population growth rate (lambda). Results indicate seasonal variability in the relative demographic importance of vital rates. Over winter, annual population growth is most sensitive to the persistence of juveniles and adults and growth from the juvenile to the adult stage. In spring and fall, changes in fecundity are likely to have large effects on population dynamics. In addition, we demonstrate the applicability of the model by using it to interpret toxicological data from an assessment of sediment contamination in Baltimore Harbor, MD. The model was parameterized with survival data from acute toxicity tests with L. plumulosus to project effects on population growth rate (lambda). Results of these model simulations indicate that relatively small changes in survival can result in large changes in lambda, indicating high risk to benthic populations. Furthermore, population projections mirror observed abundances of L. plumulosus at the test sites. These analyses provide a first indication of the usefulness of the Leptocheirus population model as a tool for exploring ecological effects of sediment contamination.

Animals↗
PubMed1994

Permanence of populations in a polluted environment.

Studies of several population-toxicant models are discussed. Under the hypothesis that the exogenous input of toxicant into the environment is periodic in time, the conditions for permanence of populations are obtained.

Animals↗
PubMed2004

Pharmacokinetic-pharmacodynamic models for categorical toxicity data.

We propose a pharmacokinetic-pharmacodynamic (PK/PD) model (with possibly different choices for the PD link) for categorical toxicity data analysis. This is extension of the one-comportment model that applies to toxic endpoints categorised by grades (e.g., benign, mild, severe, and very severe). The model assumes that the area under the curve (AUC) of the internal quantity of the chemical substance is the critical dose-metric that drives the acute toxic phenomenon. That model handles time-varying concentrations and takes into account follow-up time, i.e., time at which effects are observed. Moreover the model bridges mechanistically based dose-response models and standard dose-response models, retaining the advantages of both. We use Markov chain-Monte Carlo (MCMC) simulations to fit the model to mortality data for mice exposed to chlorine, rats exposed to ammonia, and categorical data (different severity levels) from acute exposures of rats and humans to hydrogen sulfide.

Air Pollutants↗
PubMed2000

CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation.

Machado-Joseph disease (MJD) is one of several disorders caused by the expansion of a coding CAG repeat (exp-CAG). The presence of intranuclear inclusions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyngeal muscular dystrophy, which is caused by a short expansion of an alanine-encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity. We show evidence that supports our hypothesis in lymphoblast cells from MJD patients, as well as in pontine neurons of MJD brain and in in vitro cell culture models of the disease. We also provide evidence that alanine polymers alone are harmful to cells and predict that a similar pathogenic mechanism may occur in the other CAG repeat disorders.

Amino Acid Sequence↗
PubMed1991

The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorobiphenyls (Aroclor 1254 and PCB-77) compared in Ah-responsive and Ah-nonresponsive mice.

The toxicity of the PCB substitute Ugilec 141, a mixture of tetrachlorobenzyltoluenes (TCBTs), is compared with the toxicity of a commercial mixture of polychlorobiphenyls (Aroclor 1254) and with the model toxic PCB-congener 3,3',4,4',-tetrachlorobiphenyl (PCB-77) as a positive control. Alterations in liver weight, hepatic cytochrome P450 content and EROD and PROD activity, plasma thyroxin and retinol level, hepatic retinoid level and liver and thyroid pathology, have been studied in Ah-responsive and Ah-nonresponsive mice. Ugilec 141 proved to induce similar toxicological changes, qualitatively and quantitatively, to Aroclor 1254. Therefore Ugilec may pose a similar environmental and health risk as PCBs. The criteria for acceptance of new substances, like Ugilec 141, on the European market are discussed.

Journal Article↗
PubMed2002

Synergistic bone marrow toxicity of pyrimethamine and zidovudine in murine in vivo and in vitro models: mechanism of toxicity.

Pyrimethamine (Pyr) is commonly used for treatment of toxoplasmic encephalitis in AIDS patients; however, in two clinical studies, an increased number of deaths were observed when Pyr was coadministered with zidovudine (ZDV). The BALB/c mouse was chosen as a model to study the mechanism underlying the unexpected toxicity from coadministration of these drugs. Daily administration by oral gavage of 60 mg/kg Pyr and 240 mg/kg ZDV resulted in 100% lethality after 30 days. These dose levels produced no effect when the drugs were given individually for the same period. Administration of combinations of Pyr and ZDV resulted in macrocytic anemia and leukopenia with synergistic decreases in lymphocyte and neutrophil numbers. To examine the mechanism of this hematotoxicity at the cellular level, mouse bone marrow colony-forming unit (mCFU) assays were employed. A combination of ZDV with various concentrations of Pyr resulted in synergistic decreases in numbers of erythroid and granulocyte-macrophage precursors (mCFU-E and mCFU-GM). mCFU-GM precursors appeared more sensitive than erythroid precursors to combinations of Pyr and ZDV. Incorporation of (14)C-ZDV into cellular DNA was increased in a dose-dependent manner in the presence of increasing concentrations of Pyr in the mCFU-GM assay. This suggested that inhibition of dihydrofolate reductase by Pyr and accompanying inhibition of dTTP synthesis allows preferential incorporation of ZDV into DNA, with resulting strand breakage and cell death. (14)C-ZDV incorporation was also observed when human GM cultures were analyzed, however, incorporation was less and required higher concentrations of Pyr.

Administration, Oral↗
PubMed1982

Toxicity, efficacy, and clearance of intravitreally injected of cefazolin.

The intravitreal injection of cefazolin sodium was evaluated with respect to its potential toxicity, efficacy, and clearance in the treatment of bacterial endophthalmitis in the rabbit model. Toxicity evaluation included indirect ophthalmoscopy, scotopic electroretinogram, and light microscopy of histopathologic specimens. Rabbits given doses up to and including 2.25 mg of cefazolin sodium showed no evidence of toxic reaction by these criteria after two weeks of observation. When injected within 24 hours of inoculation, 2.25 mg of cefazolin sodium sterilized five of six rabbit eyes infected with Staphylococcus aureus. Following intravitreal injection of 2.25 mg of cefazolin sodium, vitreous concentrations in excess of the minimum inhibitory concentration for S aureus were maintained for five days. A 2.25-mg dose of cefazolin sodium appears to be nontoxic, effective, and biologically active against susceptible organisms during a prolonged period, when injected into the vitreous cavity of the pigmented rabbit in vivo.

Animals↗
PubMed2005

Flexible Bayesian methods for cancer phase I clinical trials. Dose escalation with overdose control.

We examine a large class of prior distributions to model the dose-response relationship in cancer phase I clinical trials. We parameterize the dose-toxicity model in terms of the maximum tolerated dose (MTD) gamma and the probability of dose limiting toxicity (DLT) at the initial dose rho(0). The MTD is estimated using the EWOC (escalation with overdose control) method of Babb et al. We show through simulations that a candidate joint prior for (rho0,gamma) with negative a priori correlation structure results in a safer trial than the one that assumes independent priors for these two parameters while keeping the efficiency of the estimate of the MTD essentially unchanged.

Antimetabolites, Antineoplastic↗