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PubMed2006

Resolving neighborhood scale in air toxics modeling: a case study in Wilmington, CA.

Air quality modeling is useful for characterizing exposures to air pollutants. Whereas models typically provide results on regional scales, new concerns regarding the potential for differential exposures among racial/ethnic populations and income strata within communities are driving the need for increasingly refined modeling approaches. These approaches need to be capable of resolving concentrations on the scale of tens of meters, across modeling domains 10-100 km2 in size. One approach for refined air quality modeling is to combine Gaussian and regional photochemical grid models. In this paper, the authors demonstrate this approach on a case study of Wilmington, CA, focused on diesel exhaust particulate matter. Modeling results suggest that pollutant concentrations in the vicinity of emission sources are elevated, and, therefore, an understanding of local emission sources is necessary to generate credible modeling results. A probabilistic evaluation of the Gaussian model application indicated that spatial allocation, emission rates, and meteorological data are important contributors to input and parameter uncertainty in the model results. This uncertainty can be substantially reduced through the collection and integration of site-specific information about the location of emission sources and the activity and emission rates of key sources affecting model concentrations.

Air Pollutants↗
PubMedDate not supplied

Effects of Gd-DTPA after osmotic BBB disruption in a rodent model: toxicity and MR findings.

OBJECTIVE: This experiment was done to evaluate the gross neurotoxicity of intravenous Gd-DTPA administered in conjunction with osmotic blood-brain barrier (BBB) disruption and to image a human small cell lung carcinoma intracerebral tumor xenograft before and after osmotic BBB disruption. MATERIALS AND METHODS: Neurotoxicity studies were performed in normal Sprague-Dawley rats following osmotic BBB disruption by the injection of 25% mannitol in the right internal carotid artery and intravenous administration of Gd-DTPA (n = 10). Animals were observed for major neurologic changes such as seizure or substantial motor defects, and after death neuropathologic examination was performed. Human small cell lung carcinoma cells were implanted intracerebrally in athymic nude rats (n = 4). Gadopentetate dimeglumine was injected intravenously and serial T1-weighted images were obtained. Blood-brain barrier disruption was produced in each animal, followed by a second dose of intravenous Gd-DTPA, and imaging studies were repeated. RESULTS: No gross neurologic toxicity was observed. Tumors showed dense enhancement in a small area, and BBB disruption resulted in marked enhancement in most of the gray matter of the right cerebral hemisphere. CONCLUSION: Gadopentetate dimeglumine appears to be safe in doses up to 21 mmol/m2 in conjunction with barrier disruption in rats. A human small cell lung carcinoma intracerebral xenograft provides a useful method to study brain tumors.

Animals↗
PubMed1996

Tetrodotoxin infusion: nonventilatory effects and role in toxicity models.

OBJECTIVES: To determine the cardiovascular, autonomic, and neuromuscular effects of an IV infusion of tetrodotoxin (TTX) when ventilation is supported. METHODS: TTX was infused in 18 anesthetized beagles during conventional mechanical ventilation. TTX infusion continued at a rate of 9.3 micrograms/kg/hr until apnea occurred with 1 minute of ventilator disconnection. Measurements included intravascular pressures, heart rate (HR), cardiac output, blood gases, displacements of the rib cage and abdomen, O2 delivery, and responses to train-of-four and tetanic peripheral nerve stimulation. Results are expressed as mean +/- SD. RESULTS: During TTX infusion, all the dogs had discoordinate movements of the rib cage, abdomen, and limbs. Vomiting, urination, defecation, and increased salivation occurred. Nicotinic and muscarinic effects, neuromuscular blockade, and cardiovascular depression were produced by TTX. Apnea occurred in 72.0 +/- 17.0 minutes when a total of 119.0 +/- 17.4 micrograms of TTX was infused. At apnea, decreases in arterial pressure, cardiac index, HR, O2 delivery, and systemic vascular resistance occurred, while pulmonary artery pressure and pulmonary vascular resistance increased. Loss of response to tetanic stimulation was closely correlated with the dose of TTX that produced apnea. CONCLUSION: The clinical symptoms and signs of TTX poisoning are similar to those of anticholinesterase poisons, and TTX dosing as described by this model may serve as a surrogate for organophosphorus poisoning. The model may be useful to determine optimum therapies for TTX poisoning and, since TTX prevents sodium influx into cells, to investigate enhanced survival in animals suffering from ischemia.

Animals↗
PubMed2001

QSAR approach for the selection of congeneric compounds with a similar toxicological mode of action.

The selection of compounds with a similar toxicological mode of action is a key problem in the study of chemical mixtures. In this paper, an approach for the selection of chemicals with similar mode of action, based on the analysis of structural similarities by means of QSAR and chemometric methods, is described. As a first step, a complete representation of chemical structures for examined chemicals (phenylureas and triazines) by different sets of molecular descriptors allows a preliminary exploration of similarity using multi-dimensional scaling (MDS). The use of genetic algorithm (GA) to select the most relevant molecular descriptors in modeling toxicity data makes it possible to develop predictive toxicity models. The final step is a similarity analysis, based again on MDS, using selected molecular descriptors, really relevant in describing the toxicological effect.

Humans↗
PubMedDate not supplied

[Enzymatic activity of the pancreas and small intestinal mucosa in modelling of toxic hepatitis by administration of heliotrine].

The activity of pancreatic (alpha-amylase, protease, and lipase) and enteral (maltase, glycyl-L-leucine dipeptidase, monoglyceride lipase) was studied in the experiments on adult male Wistar rats weighting 350 +/- 35 g 1-3, 7, 10, 30, 60, and 90 days after injection of a single dose of 25 mg per 100 g body weight. Acute heliotrine intoxication (in a toxic hepatitis model) was shown to lead to a marked decrease in the activities of both pancreatic and intestinal enzymes. It is suggested that the changes may be associated with the direct action of heliotrine on the pancreas and small intestinal mucosa or with hepatic failure.

Animals↗
PubMed1997

New approaches to toxicity: a seven-gas predictive model and toxicant suppressants.

Two new research approaches in combustion toxicology are: 1. the prediction of smoke toxicity from mathematical equations, which are empirically derived from, experiments on the toxicological interactions of complex fire gas mixtures and 2. the use of toxicant suppressants in materials or products to prevent the formation of toxic combustion products. The predictive approach consists of burning materials using a bench-scale method that simulates realistic fire conditions, measuring the concentrations of the primary fire gases--CO, CO2, low O2, HCN, HCl, HBr, and NO2--and predicting the toxicity of the smoke using either the 6- or 7-gas N-Gas Model. These models are based on the results of toxicological studies of these primary gases as individual gases and as complex mixtures. The predicted toxic potency is checked with a small number of animal (Fischer 344 male rats) tests to assure that an unanticipated toxic gas is not generated or an unexpected synergistic or antagonistic effect has not occurred. The results indicate if the smoke from a material or product is extremely toxic (based on mass consumed at the predicted toxic level) or unusually toxic (based on the gases deemed responsible). The predictions based on bench-scale laboratory tests have been validated with full-scale room burns of a limited number of materials of widely differing characteristics chosen to challenge the system. The advantages of this new approach are 1. the number of test animals is minimized by predicting the toxic potency from the chemical analysis of the smoke, 2. smoke may be produced under conditions that simulate the fire scenario of concern, 3. fewer tests are needed, thereby reducing the overall cost of the testing and 4, information is obtained on both the toxic potency of the smoke and the responsible gases. The N-Gas Models have been developed into the N-Gas Method (described in this paper) and these results have been used in computations of fire hazard. The 6-Gas Model is now part of the international standard ISO 13344 approved by 16 member countries of the International Standards Organization (ISO) and is also included in the U.S. national standard ASTM E1678 approved by the American Society for Testing and Materials (ASTM). In addition, the 6-Gas Model is used in the American National Standard--NFPA 269--approved by the National Fire Protection Association (Quincy, MA). The second new research approach, toxicant suppressants, examines the potential of chemical compounds, which when added to a material, to inhibit or reduce the concentration of a specific toxic gas normally generated during the material's thermal decomposition. The effectiveness of this approach was demonstrated at the National Institute of Standards and Technology (NIST) when HCN generation was reduced by 90% and the resultant toxicity of the combustion products was lowered by 50% when a flexible polyurethane foam (FPU) was treated with 0.1% (by weight) cuprous oxide (Cu2O). Copper and cupric oxide (CuO) also reduced the HCN generation but were not as efficient as Cu2O. Although melamine-treated FPU foams are being promoted as more fire safe than standard foams, a melamine-treated foam generated 10 times more HCN than a foam without melamine. The addition of Cu2O to this melamine foam also reduced the HCN generation by 90%.

Animal Testing Alternatives↗
PubMed2004

Development and field validation of a biotic ligand model predicting chronic copper toxicity to Daphnia magna.

In this study, we developed a toxicity model predicting the long-term effects of copper on the reproduction of the cladoceran Daphnia magna that is based on previously reported toxicity tests in 35 exposure media with different water chemistries. First, it was demonstrated that the acute copper biotic ligand model (BLM) for D. magna could not serve as a reliable basis for predicting chronic copper toxicity. Consequently, BLM constants for chronic exposures were derived by multiple regression analysis of 21-d median effective concentrations (EC50s; expressed as Cu2+ activity) versus physicochemistry from a large toxicity dataset and the results of an additional experiment in which the individual effect of sodium on copper toxicity was investigated. The effect of sodium on chronic toxicity (log K NaBL = 2.91) seemed to be similar to its effect on acute toxicity (log K NaBL = 3.19). However, in contrast to the acute BLM, no significant calcium, magnesium, or combined competition effect was observed, and an increase in proton competition and bioavailability of CuOH+ and CuCO3 complexes was noted. Some indirect evidence was also found for some limited toxicity of complexes of copper with two of three tested types of dissolved organic matter. Because the latter was only a minor effect, this factor was not included in the chronic Cu BLM. The newly developed model performed well in predicting 21-d EC50s and no-observed-effect concentrations in natural water samples: 79% of the toxicity threshold values were predicted within a factor of two of the observed values. It is clear, however, that more research is needed to provide information on the exact mechanisms that have resulted in different BLM constants for chronic exposures (as opposed to acute exposures). It is suggested that the developed model can contribute to the improvement of risk assessment procedures of copper by incorporating bioavailability of copper in these regulatory exercises.

Animals↗
PubMed1995

Assessment of developmental toxicity potential of chemicals by quantitative structure-toxicity relationship models.

Statistically significant quantitative structure-toxicity relationship (QSTR) models have been developed for assessing developmental toxicity potential (DTP) of chemicals. Three submodels, one each for aliphatic, heteroaromatic and carboaromatic compounds, have been cross-validated to ascertain their robustness. The specificities of the models range from 86% to 97%, and their sensitivities between 86% and 89%. For convenient computer-assisted application, the models are installed in a toxicity assessment software package, TOPKAT, which has been recently enhanced with algorithms to identify whether or not a query structure is inside the optimum prediction space (OPS) of a QSTR model. Different functionalities of the TOPKAT program have been explained by assessing the DTP of a number of compounds not used in the model training sets. The DTP of 18 existing drugs was assessed using these models; the DT assay results were available for 5 of these. Three of these 5 molecules were identified to be inside the OPS and their TOPKAT assessment matched their experimental assignment.

Algorithms↗
PubMed2006

QSAR models of quail dietary toxicity based on the graph of atomic orbitals.

Graphs of atomic orbitals (GAOs) have been used to represent molecular structures. We describe rules to convert the labelled hydrogen-filled graphs (LHFGs) into GAOs. The GAO is one possible way of taking account of the structure of atoms (i.e., atomic orbitals, such as 1s(1), 2p(2) and 3d(10)) for QSPR/QSAR analyses. Optimization of correlation weights of local invariants (OCWLI) of the LHFGs and the GAOs was used to obtain a method of quail dietary toxicity modelling. Statistical characteristics of the models based on the OCWLI of GAO are better than those based on the OCWLI of the LHFGs.

Animals↗
PubMed1985

Expression of the cloned toxic shock syndrome toxin 1 gene (tst) in vivo with a rabbit uterine model.

Toxic shock syndrome (TSS) toxin 1 (TSST1) is produced by strains of Staphylococcus aureus associated with TSS. Purified TSST1 induces in rabbits a shock-like illness with many features similar to TSS in humans. These symptoms were also induced by TSST1-producing bacteria in diffusion chambers implanted in the rabbit uterus. Naturally occurring TSST1+ strains and a TSST1- strain harboring a pE194-derived plasmid carrying the cloned TSST1 determinant tst gave the same symptoms. TSST1- strains and a TSST1- strain carrying a pE194-tst plasmid with a deletion of the tst gene had no effect in rabbits. The results with the plasmid-carrying TSST1+ and TSST1- strains, which were isogenic apart from tst, show that the toxin is responsible for the illness in rabbits and suggest that it is a major factor in the pathogenesis of TSS.

Animals↗
PubMed2002

Derivation of a toxicity-based model to predict how water chemistry influences silver toxicity to invertebrates.

The effect of altering water chemistry on acute silver toxicity to three invertebrate species, two Daphnids, Daphnia magna and Daphnia pulex, as well as an amphipod Gammarus pulex was assessed. In addition, the physiological basis of Ag(I) toxicity to G. pulex was examined. Daphnia magna and D. pulex were more sensitive than G. pulex and 48 h LC(50) values in synthetic ion poor water were 0.47, 0.65 and 2.1 microg Ag(I) l(-1), respectively. Increasing water [Cl(-)] reduced Ag(I) toxicity in all species, and increasing water [Ca(2+)] from 50 to 1,500 microM reduced Ag(I) toxicity in G. pulex. Whole body Na(+) content, but not K(+) or Ca(2+) was significantly reduced in G. pulex exposed to 6 microg Ag(I) l(-1) for 24 h, but there was no inhibition of whole body Na(+)/K(+)-ATPase activity. Both increasing water [Cl(-)] and [Ca(2+)] reduced this Ag(I)-induced Na(+) loss. For D. magna, the presence of 10 mg l(-1) humic acid or 0.5 microM 3-mercaptoproprionic acid (3-MPA) increased the 48 h LC(50) values by 5.9 and 58.5-fold, respectively, and for D. pulex the presence of 1 microM thiosulfate increased the 48 h LC(50) value by four-fold. The D. magna toxicity data generated from this study were used to derive a Daphnia biotic ligand model (BLM). Analysis of the measured LC(50) values vs. the predicted LC(50) values for toxicity data from the present and published results where water Cl(-), Ca(2+), Na(+) or humic acid were varied showed that 91% of the measured toxicity data fell within a factor of two of the predicted LC(50) values. However, the daphnid BLM could not accurately predict G. pulex toxicity. Additionally, the Daphnia BLM was under-protective in the presence of the organic thiols 3-MPA or thiosulphate and predicted an increase in the LC(50) value of 114- and 74-fold, respectively. The Daphnia toxicity based BLM derived from the present data set is successful in predicting Daphnia toxicity in laboratory data sets in the absence of sulfur containing compounds, but shows its limitations when applied to waters containing organic thiols or thiosulphate.

Amphipoda↗
PubMedDate not supplied

A toxicity estimation model.

A statistical model has been developed for estimation of acute toxicity. The model, currently operational for rat oral LD50, permits the estimation of rat oral LD50 for untested chemical compounds. Only the chemical structure, partition coefficient, and molecular weight for a compound are needed for estimation purposes. The chemical structure is partitioned into substructural fragments using the CIDS fragment keys. A regression model is developed on the basis of 425 compounds. A test of the regression equation with 100 compounds not used in its design shows that 56 percent of the compounds are predicted with less than 0.4 log unit deviation between extimated and measured LD50. This toxicity estimation model can be readily adapted to other species and to other measures of toxicity by the use of suitable design data bases. The model also identifies the contribution to toxicity of the fragments and physical characteristics. The use of this model can materially reduce the amount of toxicological testing for new compounds. It also permits the ranking of potentially toxic compounds to allow the most likely candidates to be tested. The method may also prove applicable to the determination of optimum dosages for new drugs.

Animals↗
PubMedDate not supplied

Prediction of aquatic toxicity: use of optimization of correlation weights of local graph invariants.

Quantitative structure-activity relationships (QSARs) were developed for three sets of toxicity data. Chemicals in each set represented a number of narcoses and electrophilic mechanisms of toxic action. A series of quantitative structure-toxicity models correlating toxic potency with a number of optimization of correlation weights of local graph invariants were developed. In the case of the toxicity of a heterogeneous set of benzene derivatives to Tetrahymena pyriformis, the QSARs were based on the Descriptor of Correlation Weights (DCW) using atoms and extended connectivity (EC) graph invariants. The model [log (IGC(50)(-1)) = 0.0813 DCW(a(k),(3)EC(k)) + 2.636; n = 157, r(2) = 0.883, s = 0.27, F = 1170, Pr > F = 0.0001] based on third-order EC of 89 descriptors was observed to be best for the benzene data. However, fits for these data of > 0.800 were achieved ECs with as few as 23 variables. The relationship between the toxicity predicted by this model and experimental toxicity values for the test set [obs. log(IGC(50)(-1))) = 0.991 (pred. (log(IGC(50)(-1))) - 0.012; n = 60, r(2) = 0.863, s = 0.28, F = 372, Pr > F = 0.0001] is excellent. The utility of the approach was demonstrated by the model [log (IGC(50)(-1)) = 0.1744(DCW (a(k), (2)EC) - 3.505; n = 39, r(2) = 0.900, s = 0.35, F = 333, Pr > F = 0.0001] for the toxicity data for T. pyriformis exposed to halo-substituted aliphatic compounds and the model [log (IC(50)(-1)) = 0.1699(DCW (a(k), (2)EC)) - 2.610; n = 66, r(2) = 0.901, s = 0.31, F = 583, Pr > F = 0.0001] for the Vibrio fischeri toxicity data.

Animals↗
PubMed2004

[Current situation of substance abuse/dependence in psychiatric hospital settings].

Over the last several years, Japan has been facing its third epidemic of methamphetamine abuse. Methamphetamine and MDMA are categorized as Amphetamine Type Stimulants (ATS), and abuse of these substances has become a worldwide problem. A nationwide mental hospital survey on substance-related psychiatric disorders in Japan has been conducted since 1987 to clarify the current situation of Japan's substance abuse and dependence. Recent surveys show that methamphetamine and organic solvents are the most common substances of abuse in hospital settings. Fifty-five percent of all the patients included in the latest study in 2002 had psychiatric disorders due to methamphetamine abuse. Forty-five percent of them were diagnosed as having a psychotic disorder, and twenty-five percent had psychotic episodes lasting over six months. According to the psychotic disorder criteria in ICD-10 (F1x.5), the duration of a psychotic episode must not exceed six months. If the criteria are strictly applied to the abusers, they should not be diagnosed as having a psychotic disorder due to methamphetamine use, but as having schizophrenia or some other delusional disorder. However, the study demonstrates that many psychiatrists in Japan recognize methamphetamine user patients with persistent episodes of psychosis as having psychosis due to the substance use. This may reflect differences of diagnostic viewpoint between operational criterion in English-speaking countries and clinical observation of Japanese psychiatrists. In other words, it may reflect the difference between the acute toxic model and chronic toxic model of substance-induced psychiatric disorders. Reconsidering this point further will be productive and interesting. The latest survey also indicated gender differences in psychiatric disorders related to substance use. It revealed that female patients were likely to have more severe dependence syndromes, co-morbid psychiatric disorders, and a history of traumatic life events. It suggests that the substance-related psychiatric problems in female patients are possibly more complex and harder to treat. Treatment programs that focus more on gender differences in these disorders should be developed.

Adolescent↗
PubMed2002

Coupling toxicokinetics and pharmacodynamics for predicting survival of abalone (Haliotis diversicolor supertexta) exposed to waterborne zinc.

We developed a mortality model, by coupling an acute toxicity model and a pharmacodynamic model, to predict survival of abalone (Haliotis diversicolor supertexta) exposed to waterborne zinc (Zn). We conducted a laboratory 14-day exposure experiment to obtain biokinetic parameters of depuration rate constant (k(2)) and bioconcentration factor (BCF). A one-compartment uptake-depuration model was used to fit the exposure data to estimate BCF and k(2) values. The acute toxicity model was developed based on the receptor theory and was verified with LC(50)(t) data obtained from a 7-day acute toxicity test. A highly significant correlation (r(2) = 0.98) was found between predictions and LC(50)(t) data for the acute toxicity model, indicating a successful description of 7-day LC(50)(t) data of Zn in abalone. The predicted time course of lethal body burden of Zn in abalone was compared with measured data, showing that the average percent error was 14.04 +/- 3.02%. A refined pharmacodynamic model was expressed as the Hill equation, which in terms of waterborne Zn and LC(50)(t) data was used to fit observed mortality percentages to determine the Hill coefficient (r(2) = 0.98). The proposed mortality model in terms of whole body burden and lethal body burden at site of action was then employed to predict the time-varying mortality of abalone exposed to various Zn concentrations in pond water. Our results demonstrate that 96-h LC(50) and incipient LC(50) for H. diversicolor supertexta exposed to Zn are 1.1 and 1.05 mg L(-1), respectively. Our predictions also demonstrate that equilibrium lethal body burden at site of action is about 198 microg g(-1), whereas the mortalities never reach 50% when H. diversicolor supertexta exposed to Zn is < or = 1 mg L(-1).

Animals↗
PubMed2003

Effects of total body irradiation and cyclosporin a on the lethality of toxic shock syndrome toxin-1 in a rabbit model of toxic shock syndrome.

Toxic shock syndrome (TSS) may be mediated by superantigen-activated T cells, a theory we tested in rabbits, which are more susceptible to the lethal effects of superantigens, such as TSS toxin-1 (TSST-1), than are mice. Rabbits exposed to 10 cGy of total body irradiation exhibited T cell deficiency, with profound depletion of splenic lymphocytes and circulating CD4(+) lymphocytes, as well as an inability to manifest delayed-type hypersensitivity. Nevertheless, these rabbits remained completely susceptible to TSST-1, indicating that TSS can occur in the setting of marked immunosuppression.

Animals↗
PubMed2004

Topological estimation of electronic absorption bands of arene absorption spectra as a tool for modeling their toxicity and environmental pollution.

A novel application of distance-based topological indices : Wiener (W)-, Szeged (Sz)-, Padmakar-Ivan (PI)-, and Sadhana (Sd)-indices in modeling electronic absorption bands of arene absorption spectra has been described. It is demonstrated that all these indices correlate linearly with the logarithm of beta and para electronic absorption bands in several series of arene systems. The results have shown that our methodology is best suited for the estimation--lnlambda(beta), while comparatively less significant results are obtained in case of the estimation of lnlambda(p). The statistical analysis of the data have shown that PI index gives better results for modeling lnlambda(beta); while Sz index proved better for modeling lnlambda(p). The results are critically discussed on the basis of regression parameters and quality of correlation. Such a study will be useful as a tool for modeling toxicity of arene system as well as their environmental pollution.

Electrochemistry↗