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PubMed2004

Application of high-throughput Fourier-transform infrared spectroscopy in toxicology studies: contribution to a study on the development of an animal model for idiosyncratic toxicity.

An evaluation of high-throughput Fourier-transform infrared spectroscopy (FT-IR) as a technology that could support a "metabonomics" component in toxicological studies of drug candidates is presented. The hypothesis tested in this study was that FT-IR had sufficient resolving power to discriminate between urine collected from control rat populations and rats subjected to treatment with a potent inflammatory agent, bacterial lipopolysaccharide (LPS). It was also hypothesized that co-administration of LPS with ranitidine, a drug associated with reports of idiosyncratic susceptibility, would induce hepatotoxicity in rats and that this could be detected non-invasively by an FT-IR-based metabonomics approach. The co-administration of LPS with "idiosyncratic" drugs represents an attempt to develop a predictive model of idiosyncratic toxicity and FT-IR is used herein to support characterization of this model. FT-IR spectra are high dimensional and the use of genetic programming to identify spectral sub-regions that most contribute to discrimination is demonstrated. FT-IR is rapid, reagentless, highly reproducible and inexpensive. Results from this pilot study indicate it could be extended to routine applications in toxicology and to supporting characterization of a new animal model for idiosyncratic susceptibility.

Animals↗
PubMed2005

Diminution of toxic copper accumulation in toxic milk mice modeling Wilson disease by embryonic hepatocyte intrasplenic transplantation.

AIM: To observe the therapeutic effect of intrasplenic transplantation with embryonic hepatocytes on amelioration of hereditary copper accumulation in toxic milk (TX) mouse modeling Wilson disease. METHODS: Donor hepatocytes were harvested from 14-d fetal liver of a pregnant homogeneous DL mouse. These cells were successively cultured, labeled with fluorescein dye Hoechst 33342 for 24 h, and sequentially infused into the spleen parenchyma of the recipient TX mice. No host immunosuppression measures were taken. Two and four weeks after transplantation, the recipients were killed for routine histologic investigation and immunohistochemistry study up to 4 wk after transplantation. The serum copper and ceruloplasmin concentrations of the recipient mice were determined by graphite furnace atomic absorption spectroscopy. RESULTS: In the following 2nd and 4th wk after transplantation, the donor hepatocytes could be visualized in the livers of 47.3% recipients. The serum ceruloplasmin and copper concentrations increased by 1.6-fold after 2 wk and 2.0-fold times after 4 wk respectively, which ultimately rose from about 30% of the normal level to nearly 60% (P<0.01). The hepatic copper concentration decreased 7.2%, 4 wk after transplantation. Pathologic examination showed that there were many actively proliferative hepatocyte precursor cells with specific embryonic hepatocyte marker AFP migrated into hepatic sinusoids of the recipients. A large number of cells carrying hepatocytes marker and albumin were observed in the recipient spleen tissues. CONCLUSION: Embryonic hepatocytes are capable of differentiating into mature hepatocytes in vivo. After transplantation, the hereditary abnormalities of copper metabolism in TX mice could be corrected partially by intrasplenic transplantation of homogeneous embryonic hepatocytes.

Animals↗
PubMed2003

FK506 is neuroprotective in a model of antiretroviral toxic neuropathy.

Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus-infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced "neuritic pruning," neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy.

Animals↗
PubMed2005

QSAR models for Daphnia toxicity of pesticides based on combinations of topological parameters of molecular structures.

A topological parameter is defined as an integer value of a given local or global invariant of a molecular graph. We examined three types of local graph invariants, the vertex degrees (0EC), the extended connectivity of first order (1EC), and the numbers of paths of length two (P2), as elementary invariants for construction of quantitative structure-activity relationships (QSAR). We also examined combined invariants, obtained by multiplying one of these three elementary types with another (i.e., [0EC.1EC], [0EC.P2], and [1EC.P2]), as graph invariants. Finally, global invariants were used in the QSAR analyses, codifying the presence and nature of cycles in the molecular structures under consideration. We used the correlation weights of these invariants to obtain optimal descriptors. These descriptors have been used in one-variable models to predict toxicity toward Daphnia magna for a set of pesticides. Statistical characteristics of the best model, based on the correlation weight of local topological parameters (the [0EC.P2]) together with the global topological parameters, are the following: n=220, r2=0.7822, s=0.849, F=783 (training set); n=42, r2=0.7388, s=0.941, F=113 (test set). The role of these topological parameters is discussed.

Animals↗
PubMed2004

Challenges in constructing statistically based structure-activity relationship models for developmental toxicity.

Regulatory agencies are increasingly called upon to review large numbers of environmental contaminants that have not been characterized for their potential to pose a health risk. Additionally, there is special interest in protecting potentially sensitive subpopulations and identifying developmental toxicants that may be present in the environment. Thus, there is an urgent need for efficient methods to screen large numbers of chemicals for their potential to pose a developmental hazard. One potential screening method involves the use of statistically based structure-activity relationship (SAR) tools to predict activity of untested chemicals. Such systems rely on statistical analyses to discern relationships between structure and activity for a training set of substances. Predictions can then be made for an untested substance as long as its structural features are encompassed by chemicals of the training set. In theory, such systems could assist regulatory agencies in their screening efforts; however, to date, there has been little independent evaluation of these tools for this use. To contribute to such an evaluation, the International Life Sciences Institute Risk Science Institute (ILSI RSI) convened a Working Group to examine methodology used to construct statistically based SAR systems for developmental toxicity. This document reports on the deliberations of the Working Group, which concluded that an improved process is needed for utilizing developmental toxicity data in the construction of statistically based SAR models. The process must be objective, reproducible, rational and transparent. Moreover, it must be informed by the expertise of developmental toxicologists and biologists and must be subject to peer review.

Congenital Abnormalities↗
PubMed1996

Differentiated HL-60 cells as model system for toxicity studies of inhalable dusts.

For the assessment of the toxicity of inhalable dusts, generally either in vivo investigations or tests with cultures of freshly isolated macrophages are used. In the present study, a calcitriol-treated HL-60 tumor cell line was investigated as an alternative model and compared with bovine alveolar macrophages. In both systems, upon exposure to two different quartz fractions, the amount and reaction pattern of superoxide anion release (O2.-) were determined by lucigenin-enhanced chemiluminescence; viability of cells was determined using the fluorescein diacetate-ethidium bromide assay. Nearly equal results were obtained in both systems, recommending the differentiated HL-60 cell line as an easily manageable model system for toxicity studies of particulate bronchopulmonary noxious agents, especially with regard to the lower experimental expenditure.

Animals↗
PubMedDate not supplied

Use of the microorganism Bacillus stearothermophilus as a model to evaluate toxicity of the lipophilic environmental pollutant endosulfan.

Microorganisms are very powerful tools for the supply of information about the toxic effects of lipophilic compounds, since an impairment of cell growth usually occurs as a result of perturbations related, in most cases, with the partition of toxicants in membranes. The thermophilic eubacterium Bacillus stearothermophilus has been used as a model system to identify alpha- and beta-endosulfan interactions with the membrane possibly related with the insecticide toxicity. Two approaches have been pursued: (a) bacterial growth is followed and the effects of endosulfan isomers determined; (b) biophysical studies with the fluorescent fluidity probe 1,6-diphenyl-1,3,5-hexatriene (DPH) were performed to assess the effects of alpha- and beta-endosulfan on the organization of the membrane lipid bilayer. The effects on growth were quantitatively evaluated by determination of growth parameters, namely the lag phase, the specific growth rate and the cell density reached by cultures in the stationary phase. Growth inhibition by alpha and beta-endosulfan dependent on the concentration is diminished or removed by the addition of 2.5 mM Ca2+ to bacterial cultures. Fluorescence DPH polarization consistently showed opposite effects of Ca2+ and alpha- and beta-endosulfan on the physical state of bacterial polar lipid dispersions.

Animal Testing Alternatives↗
PubMed1992

Stochastic models for toxicant-stressed populations.

We obtain conditions for the existence of an invariant distribution on (0, infinity) for stochastic growth models of Ito type. We interpret the results in the case where the intrinsic growth rate is adjusted to account for the impact of a toxicant on the population. Comparisons with related results for ODE models by Hallam et al. are given, and consequences of taking the Stratonovich interpretation for the stochastic models are mentioned.

Environmental Pollution↗
PubMed2004

Linear versus nonlinear QSAR modeling of the toxicity of phenol derivatives to Tetrahymena pyriformis.

Quantitative structure-activity relationship (QSAR) models were derived from a structurally heterogeneous set of 200 phenol derivatives for which the 50% growth inhibition concentration (IGC(50)) values to the ciliated protozoan Tetrahymena pyriformis were available. Each molecule was described by means of physicochemical descriptors and structural features. Partial least squares (PLS) regression analysis and a three-layer perceptron were used as statistical engine. The performances of the linear and nonlinear models were estimated from an external testing set of 50 chemicals. Despite hard constraints voluntarily imposed in the design of the neural network models, they provided better simulation results than the PLS models.

Animals↗
PubMed2002

Defining the molecular and cellular basis of toxicity using comparative models.

A critical element of any experimental design is the selection of the model that will be used to test the hypothesis. As Claude Bernard proposed over 100 years ago "the solution of a physiological or pathological problem often depends solely on the appropriate choice of the animal for the experiment so as to make the result clear and searching." Likewise, the Danish physiologist August Krogh in 1929 wrote that "For a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied." This scientific principle has been validated repeatedly in the intervening years as investigators have described unique models that exploit natural differences in chemical and molecular structure, biochemical function, or physiological response between different cells, tissues, and organisms to address specific hypotheses. Despite the power of this comparative approach, investigators have generally been reluctant to utilize nonmammalian or nonclassical experimental models to address questions of human biology. The perception has been that studies in relatively simple or evolutionarily ancient organisms would provide little insight into "complex" human biology. This perception, although always somewhat misguided, is now even less tenable given the results of the genome sequencing projects, which demonstrate that the human genome is remarkably similar to that of evolutionarily ancient organisms. Thus, the various life forms on Earth share much more in common then anyone had previously envisioned. This realization provides additional rationale for the use of nonclassical experimental models and provides perhaps the strongest validation of Bernard's and Krogh's assertions. This overview emphasizes some of the special attributes of alternative animal models that may be exploited to define the molecular and cellular basis of toxicity. For each attribute, selected examples of animal models and experimental approaches are presented. It focuses on the areas of neurotoxicology, reproductive and developmental toxicology, organ systems toxicology, carcinogenesis, and functional genomics/toxicogenomics and highlights the use of fish, avian, Drosophila, Caenorhabditis elegans, and yeast models in such studies.

Animals↗
PubMed2005

Ranking of aquatic toxicity of esters modelled by QSAR.

Alternative methods like predictions based on Quantitative Structure-Activity Relationships (QSARs) are now accepted to fill data gaps and define priority lists for more expensive and time consuming assessments. A heterogeneous data set of 74 esters was studied for their aquatic toxicity, and available experimental toxicity data on algae, Daphnia and fish were used to develop statistically validated QSAR models, obtained using multiple linear regression (MLR) by the OLS (Ordinary Least Squares) method and GA-VSS (Variable Subset Selection by Genetic Algorithms) to predict missing values. An ESter Aquatic Toxicity INdex (ESATIN) was then obtained by combining, by PCA, experimental and predicted toxicity data, from which model outliers and esters highly influential due to their structure had been eliminated. Finally this integrated aquatic toxicity index, defined by the PC1 score, was modelled using only a few theoretical molecular descriptors. This last QSAR model, statistically validated for its predictive power, could be proposed as a preliminary evaluative method for screening/prioritising esters according to their integrated aquatic toxicity, just starting from their molecular structure.

Esters↗
PubMed2006

Screening for genetic modifiers of amyloid toxicity in yeast.

In recent years the facile, yet powerful, genetics of the baker's yeast Saccharomyces cerevisiae has been appropriated for the study of amyloid toxicity. Several models of amyloid toxicity using this simple eukaryotic organism have been developed that faithfully recapitulate many disease-relevant phenotypes. Furthermore, these models have been exploited in genetic screens that have provided insight into conserved mechanisms of amyloid toxicity and identified potential therapeutic targets for disease. In this chapter, we discuss the strengths and weaknesses of yeast models of amyloid toxicity and how experiments with these models may be relevant to amyloid disorders. We suggest approaches for development of new yeast models of amyloid toxicity and provide an overview of screening protocols for genetic modifiers of amyloid toxicity by both random and systematic approaches.

Amyloid↗
PubMed2004

Development of a two-dimensional analytical model for predicting toxic sediment plumes due to environmental dredging operations.

A two-dimensional analytical transport model is developed to predict the dredge induced plume concentration in the horizontal plane under steady-state for simple hydraulic conditions. The derivation of the analytical solution is based on the solution to the advection-diffusion equation. The application of this analytical model is limited to mechanical dredge operations, bucket dredge, which has continuous point source in the water column. The analytical model developed herein is used to simulate sediment concentration distributions from a hypothetical dredging site and compared to results from a similar model using Stokes' settling. The result shows that Stokes' settling underestimates settling in the near-field and overestimates settling in the far-field plume. In summary, the model provides the ability to account for the rapid settling of larger particles in the suspended sediment near the dredging operations while simulating the slower settling and diffusive transport of smaller particles moving away from the dredging sites.

Environment Design↗
PubMed1996

Logistic regression model of fotemustine toxicity combining independent phase II studies.

BACKGROUND: To optimize fotemustine chemotherapy, the authors considered how to combine independent Phase II trials to predict the risk of first occurrence of severe toxicity as a function of initial patient characteristics. METHODS: Clinical data from six Phase II trials were collected. Of the 478 patients enrolled 442 (male/female, 259/183; age range, 15-81 years) were evaluable for toxicity (1384 cycles of chemotherapy), including 221 with malignant malignant melanomas, 138 with primary brain tumors, 29 with lung carcinomas, 8 with head and neck carcinomas, and 46 with miscellaneous cancers. The influence of age, sex, performance status, type of tumor, number and location of metastases, and previous treatment by chemotherapy and/or radiotherapy was studied. The logistic regression method was applied to predict occurrence of leukopenia, thrombocytopenia, anemia, digestive tract, and/or hepatic toxicity. RESULTS: Univariate analysis showed that predictive factors for hematologic toxicity were age (> 50 years), type of tumor (brain < melanoma < others), number of metastatic sites (> 3), location of metastases (nonvisceral), and previous chemotherapy. Performance status and previous radiotherapy did not affect the toxicity of fotemustine Nausea and vomiting were predictable based on the type of tumor (head and neck < lung < brain < melanoma < others), the number of metastatic sites (> three) and visceral metastases. Hepatic disorders occurred preferentially in patients with hepatic metastases and more than three metastatic sites. Individual risk of hematologic and hepatic toxicity for patients with melanoma and primary brain tumors was predicted using logistic regression models. CONCLUSIONS: By combining clinical data from independent Phase II trials, the logistic model developed could predict the probability of fotemustine hematologic and hepatic toxicity.

Adolescent↗
PubMed1995

Biologically based dose response model for hepatic toxicity: a mechanistically based replacement for traditional estimates of noncancer risk.

Uncertainty in risk assessment can be reduced by increasing the use of relevant data specific to the particular xenobiotic and exposed organism. We describe the development of a preliminary, mechanism-based exposure response model for chloroform hepatotoxicity consistig of toxicokinetic (TK) and toxicodynamic (TD) submodels. The TK submodel is based on an existing physiologically based toxicokinetic (PBTK) model for chloroform. The TD submodel consists of an empirical function linking tissue dose, defined by the PBTK model, with hepatocyte killing and subsequent regenerative cellular replication. Chloroform-induced cell killing was inferred quantitatively from dose-response hepatic labelling index studies conducted in female B6C3F1 mice and male F344 rats. The overall model was scaled to humans by conventional scaling of the TK submodel and by using the TD submodel as is, i.e. as developed from the rodent data. The resulting human model was used to analyze a case of human poisoning which developed after repeated ingestion of large doses of cough syrup containing chloroform and alcohol. The model predicted the observed toxic response after the capacity for chloroform metabolism was increased by a factor of 3 from the value estimated using human liver microsomes. This is an acceptable adjustment of this parameter, given the uncertainty associated with the extrapolation from microsomes and the coexposure to alcohol. This preliminary result is encouraging, suggesting that the model, at its current stage of development, is able to approximate actual human risks of hepatotoxicity from chloroform exposure. The extensive use of data on chloroform TK and cytolethality-induced regenerative cellular replication for model development suggests that the model has reduced uncertainty relative to the current U.S. EPA oral reference dose (RfD) calculation for chloroform, which does not use any mechanistic or dose-response data.

Animals↗
PubMed1984

Acetylation pharmacogenetics: experimental models for human toxicity.

Hereditary acetylation polymorphisms well-suited to experimental pharmacogenetic investigation are now known in three laboratory animal species (rabbit, mouse, and hamster). These animal models provide new evidence for the profound influence of this trait on the metabolic fate of arylamines and hydrazines, and on their pharmacological and toxicological profiles. The rabbit polymorphism most closely resembles that in humans. For the rabbit model, studies have shown that 1) monoacetylhydrazine is a polymorphic substrate for liver N-acetyltransferase in rapid and slow acetylators. This observation, in conjunction with human epidemiological data of others, opposes the commonly held view that rapid acetylators are predisposed to isoniazid (INH)-induced hepatotoxicity. 2) Slow acetylators are much more sensitive than rapid acetylators to the lethal central nervous system toxicity of INH. 3) In hepatocytes in short-term culture and exposed to arylamines and hydrazines, DNA damage is produced by hydralazine in slow acetylator hepatocytes but not in rapid acetylator hepatocytes, whereas hepatocytes from rapid acetylators are more sensitive to toxicity and DNA damage from 2-aminofluorene and benzidine. These investigations in animal models of the acetylation polymorphism provide new insights into human toxicity resulting from environmental arylamines and hydrazines.

Acetylation↗
PubMedDate not supplied

Caenorhabditis elegans as model system for rapid toxicity assessment of pharmaceutical compounds.

INTRODUCTION: The model organism Caenorhabditis elegans is widely used for genetic studies as well as a living biomonitor in ecotoxicology. In this study, we investigated whether C. elegans may represent a suitable model for rapid preliminary toxicity studies of pharmaceutical compounds. METHODS: For this purpose, we used the EGFR kinase inhibitors BIBU1361, BIBX1382, and an inactive chemical analogue BIBU1476. As a first parameter to score for toxicity, we determined lethality of the wild-type C. elegans strain N2 (Bristol) in the presence of the compounds. The transgenic C. elegans strain PC72 (lacZ, heat shock protein-16 [hsp-16] construct) was used as a report organism for toxic effects. PC72 expresses beta-Galactosidase which is induced by hsp-16 in direct response when exposed to toxic compounds. The expression of beta-Galactosidase in cells was subsequently visualized by histochemical staining with X-Gal. RESULTS: A rank order of potency with respect to lethality was established: BIBU1361>BIBX1382>>BIB1476. The induction of beta-Galactosidase was concentration-dependent for each compound and demonstrated the same order of potency as observed for lethality. Furthermore, these compounds showed the same order for lethality in rodents, the first requirement of validation. DISCUSSION: These results indicate that wild-type C. elegans and the transgenic strain PC72 are both suitable models to determine the toxicity of pharmaceutical compounds. This approach allows for an easy and fast ranking of compound toxicity, which may lead to a more rational choice for further in vivo tests.

Animal Use Alternatives↗
PubMed2002

Development and validation of models predicting the toxicity of major seawater ions to the mysid shrimp, Americamysis bahia.

The concentration and balance of major ions that comprise total dissolved solids (TDS) can influence the toxicity of effluents discharged to freshwater and marine environments. An additional complicating factor in waters released to saltwater systems is the effluent salinity since the toxicity of major ions changes with the salinity of the test solution. A study was conducted to evaluate the toxicity of six major seawater ions (bicarbonate, borate, calcium, magnesium, potassium, and sulfate) to the mysid shrimp, Americamysis bahia, at salinities of 10 and 20/1000. Logistic regression models were developed to predict organism survival at deficient and excess concentrations of the ions. Calcium and potassium caused significant mortality to mysid shrimp in both excess and deficient (relative to artificial seawater) solutions. Bicarbonate, borate, and magnesium displayed significant toxicity only in excess concentrations, while sulfate had no adverse impacts at any of the concentrations tested. As the salinity of the test solutions decreased, mysid shrimp tolerated increasingly lower calcium and potassium concentrations. Similarly, as salinity increased, the upper tolerance levels of calcium, potassium, and magnesium also increased. The models developed during these studies, and similar models developed by other researchers, were used to evaluate 11 actual effluents with unexplained toxicity that might be associated with TDS ions. The models correctly identified calcium as the primary toxicant in 9 of the 11 effluents. These results indicate the models can be used as an important tool to identify toxicity associated with major seawater ions.

Animals↗