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PubMed1989

2-Bromohydroquinone-induced toxicity to rabbit renal proximal tubules: the role of biotransformation, glutathione, and covalent binding.

2-Bromohydroquinone (BHQ) is a model toxic hydroquinone and plays an important role in bromobenzene-induced nephrotoxicity. Proximal tubules isolated to contain decreased glutathione (GSH) levels were at least twice as sensitive to the GSH depleting effects of BHQ and BHQ-induced mitochondrial dysfunction as were tubules with "normal" (i.e., in vivo) GSH content. The decrease in tubular GSH content resulted from BHQ-GSH conjugate formation. A mono-GSH conjugate (2-bromo-3-(glutathion-S-yl)hydroquinone) and a di-GSH conjugate (2-bromo-3,5- or 6-(diglutathion-S-yl)hydroquinone) were identified. In addition, a glucuronide conjugate was identified (2-bromo-1- or 4-O-glucuronylhydroquinone). BHQ-GSH conjugates were not responsible for BHQ-induced toxicity since (1) tubules with normal levels of GSH were more resistant to BHQ-induced toxicity even though they formed more BHQ-GSH conjugates than tubules with decreased GSH levels and (2) inhibition of gamma-glutamyltranspeptidase did not prevent BHQ-induced toxicity. BHQ-equivalents bound covalently to tubular protein in a concentration-, time-, and temperature-dependent manner with the majority of the binding (61%) occurring during the first 15 min after exposure to 0.2 mM BHQ. Tubules pretreated with GSH underwent less BHQ-protein alkylation and mitochondrial dysfunction, and the amount of BHQ recovered and BHQ-di-GSH conjugate formed increased. These data suggest that BHQ is biotransformed to a reactive intermediate (2-bromoquinone and/or 2-bromosemiquinone) and that this intermediate can react with GSH to form BHQ-GSH conjugates and/or bind covalently to tubular protein which may result in mitochondrial dysfunction and tubular death.

Animals↗
PubMed2001

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

We describe the development of a stage-structured population matrix model for the estuarine amphipod Leptocheirus plumulosus, a sediment toxicity test organism, based on regular sampling of a natural population for approximately 2 years. Annual population dynamics were characterized by abundance peaks in the spring and fall, and low densities in the summer and winter. We use a sequence of seasonal projection matrices to capture these qualitative patterns in population dynamics. We compare two methods for estimating transition probabilities: multiple regression and truncated singular value decomposition (SVD). Overall, SVD gave more realistic parameter estimates than regression, although fecundity estimation was problematic. There were predictable trends in growth, survival and fecundity within years. The SVD-derived model provides a framework for assessing the population-level effects of contaminants on Leptocheirus.

Animals↗
PubMed1975

Cell models in the study of mechanisms of toxicity.

Cell models, particularly in vitro systems, allow studies of toxicological mechanisms to be made under controlled conditions. One way that such mechanisms can be studied is by determining the reproducible changes that toxins induce, at the electron microscopic level, in the structure of cultured cells. A detailed description of such a study is given and includes preparation of the cell model, treatment of the cells, assessment of toxin-induced changes, and some general conclusions derived from experiments with this cell model. Other models which have been used for toxicological studies are also discussed with reference to advantages, limitations and potential applications.

Adult↗
PubMed1987

Mitochondrial toxicity of 2-bromohydroquinone in rabbit renal proximal tubules.

2-Bromohydroquinone (BHQ) is a nephrotoxic metabolite of bromobenzene and a model toxic hydroquinone. The primary goal of these studies was to determine whether BHQ produces toxicity in rabbit renal proximal tubules by inhibiting mitochondrial function. BHQ induces a specific sequence of cellular events. Initially there was decrease in tubular glutathione content followed by a decrease in nystatin-stimulated ouabain-sensitive respiration. A decrease in cell viability, as measured by a decrease in lactate dehydrogenase retention, was late event. Associated with the decrease in respiration was a decrease in intracellular ATP content. Probing of mitochondrial function in the tubule revealed that BHQ did inhibit mitochondrial function in a somewhat selective manner. State 3 respiration was inhibited prior to changes in the rate of electron flow through cytochrome c-cytochrome oxidase. It is postulated that BHQ may initially inhibit state 3 respiration by inhibiting the adenine nucleotide translocator and/or the F1-ATPase.

Adenosine Monophosphate↗
PubMed1993

Relationships between descriptors for hydrophobicity and soft electrophilicity in predicting toxicity.

The toxicity of chemicals is orthogonal with individual molecular descriptors used to quantify hydrophobicity and soft electrophilicity when considering large data sets. Estimating the toxicity of reactive chemicals requires descriptors of both passive transport and the stereoelectronic interaction, which are largely independent processes. QSARs using either log P or an electronic parameter alone are only significant for sets of chemicals that represent special, albeit some important, cases in QSAR. Chemicals were clustered according to their reactivity as soft electrophiles by defining isoelectrophilic windows along the toxicity response surface. Within these narrow windows of reactivity, the variation of toxicity was explained by the variation of log P. We observed that the dependence of toxicity on log P in different isoelectrophilic windows decreased as reactivity increased. The data are consistent with toxicity models where competing nucleophilic interaction sites are distributed along the transport route of the chemicals.

Animals↗
PubMedDate not supplied

The effect of haloperidol in cocaine and amphetamine intoxication.

The effectiveness of haloperidol pretreatment in preventing the toxic effects of high doses of amphetamine and cocaine was studied in rats. In this model, toxic effects were induced by intraperitoneal (i.p.) injection of amphetamine 75 mg/kg (100% death rate) or cocaine 70 mg/kg (82% death rate). Haloperidol failed to prevent amphetamine-induced seizures, but did lower the mortality rate at most doses tested. Haloperidol decreased the incidence of cocaine-induced seizures at the two highest doses, but the lowering of the mortality rate did not reach statistical significance at any dose. These data suggest a protective role for the central dopamine blocker haloperidol against death from high-dose amphetamine exposure without reducing the incidence of seizures. In contrast, haloperidol demonstrated an ability to reduce cocaine-induced seizures without significantly reducing mortality.

Amphetamines↗
PubMed2001

Quantitative structure--toxicity relationships using TOPS-MODE. 1. Nitrobenzene toxicity to Tetrahymena pyriformis.

The TOPological Sub-Structural MOlecular DEsign (TOPS-MODE) approach (Estrada, E. SAR QSAR Environ. Res. 2000, 11, 55-73) has been introduced to the study of toxicological properties. The toxicity of 42 nitrobenzenes was studied with this approach obtaining a good quantitative structure--toxicity model. For the first time we compare the use of eight different weights in the diagonal entries of the bond matrix for selecting the best TOPS-MODE model. TOPS-MODE was used to derive the contribution of different fragments to the toxicity of studied compounds. These contributions were applied to calculate toxicity substituent constants for the groups present in the nitrobenzenes studied.

Animals↗
PubMed1988

Increased intrapulmonary retention of radiolabeled neutrophils in early oxygen toxicity.

Sequential lung injuries, such as oxygen toxicity followed by septicemia, are common during the adult respiratory distress syndrome (ARDS). As these forms of vascular injury may be mediated in part by polymorphonuclear leukocytes (PMN), aberrant interactions between PMN and previously injured pulmonary endothelium are of both theoretical interest and clinical importance. The present study was undertaken to test the hypothesis that early oxygen toxicity at a dose that injuries pulmonary endothelium relatively selectively alters intrapulmonary neutrophil kinetics. Unanesthetized rats breathing 1.0 atmospheres oxygen for 36 h showed ultrastructural endothelial damage but no edema, injury, or neutrophilic inflammation by histologic criteria. However, in these oxygen-toxic animals, whereas initial accumulation of radiolabeled PMN in lungs was normal, washout of PMN was abnormal at 120 min after infusion, at which point the pulmonary retention of radiolabeled PMN in the lungs of oxygen-treated animals was significantly higher than in control animals (139% of control, p less than 0.0096). Features of our methodology, including avoidance of osmotic stress and use of paired control animals, appear to have greatly enhanced the sensitivity of radiolabeled neutrophils for detecting a subtle abnormality of neutrophil-endothelial interactions. Our studies in the oxygen toxicity model provide the first demonstration in vivo of abnormal intrapulmonary neutrophil kinetics in early oxygen toxicity prior to the onset of histologic evidence of lung injury or inflammation.

Animals↗
PubMed2005

Development of an information-intensive structure-activity relationship model and its application to human respiratory chemical sensitizers.

Structure-activity relationship (SAR) models are recognized as powerful tools to predict the toxicologic potential of new or untested chemicals and also provide insight into possible mechanisms of toxicity. Models have been based on physicochemical attributes and structural features of chemicals. We describe herein the development of a new SAR modeling algorithm called cat-SAR that is capable of analyzing and predicting chemical activity from divergent biological response data. The cat-SAR program develops chemical fragment-based SAR models from categorical biological response data (e.g. toxicologically active and inactive compounds). The database selected for model development was a published set of chemicals documented to cause respiratory hypersensitivity in humans. Two models were generated that differed only in that one model included explicate hydrogen containing fragments. The predictive abilities of the models were tested using leave-one-out cross-validation tests. One model had a sensitivity of 0.94 and specificity of 0.87 yielding an overall correct prediction of 91%. The second model had a sensitivity of 0.89, specificity of 0.95 and overall correct prediction of 92%. The demonstrated predictive capabilities of the cat-SAR approach, together with its modeling flexibility and design transparency, suggest the potential for its widespread applicability to toxicity prediction and for deriving mechanistic insight into toxicologic effects.

Allergens↗
PubMed1994

Dose-response assessment for developmental toxicity. III. Statistical models.

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.

Animals↗
PubMed2003

Extended rat liver slice survival and stability monitored using clinical biomarkers.

Precision-cut liver slices are reportedly limited as toxicity models by their short half-life in culture. We used traditional clinical chemistry biomarkers and histology to assess a newer procedure for improved liver slice maintenance. Slices from Sprague-Dawley rat livers were well maintained in a roller culture system for up to 10 days based on protein content (60-70% or higher of initial values) and biomarker retention and verified by histological examination of the tissues showing morphological integrity and viability of hepatocyte and biliary regions. Exposure of the slices to geldanamycin (GEL) resulted in loss of slice LDH and transaminase content, with associated depression in ALP and GGT levels and elevated bilirubin, indicating that GEL affects both cell types as occurs in vivo with this hepatobiliary toxicant. Thus, we conclude that liver slices merit further investigation as a general model for chronic as well as acute toxicity studies.

Alanine Transaminase↗
PubMed2005

Effect of varying physicochemistry of European surface waters on the copper toxicity to the green alga Pseudokirchneriella subcapitata.

Most standard toxicity test results, used in present environmental risk assessment and water quality criteria (WQC) setting procedures are obtained with standard test media that are not representative for natural surface waters when metal toxicity modifying factors like pH, water hardness and dissolved organic carbon (DOC) are considered. The aim of this study was, using the green alga Pseudokirchneriella subcapitata, (1) to investigate the individual effects of Ca, Mg (the hardness cations) and pH on the toxicity of copper in reconstituted artificial test waters and (2) to study the copper toxicity in 13 spiked surface waters originating from different European eco-regions. Surface waters were selected such that a broad range of DOC (1.55-20.4 mg/l), pH (5.52-8.30) and water hardness (7-238 mg CaCO(3)/l) was covered. Tests in reconstituted artificial waters demonstrated that the 72 h-E(b)C50 (expressed as dissolved Cu) increased by about a factor of 3 when the Ca and Mg concentrations increased from 0.25 to 2.5 mM. When pH was increased from 5.8 to 8.0, dissolved 72 h-E(b)C50 decreased by a factor of 3. It is suggested that competition between Cu2+, Ca2+, Mg2+ and H+ ions at the cell surface are the most likely explanation for these observations. Dissolved 72 h-E(b)C50s in the natural surface waters varied between 32.0 and 245 mug Cu/l and were up to a factor 15 higher than the 72 h-E(b)C50 in standard artificial medium (16.5+/-4.8 mug Cu/l). Consequently, Water Effect Ratio's (WER, the ratio between the EC50 in natural water to the EC50 in standard test water) ranged from 1.9 to 14.8. Linear regression analysis revealed that higher E(b)C50 were significantly related to higher DOC-concentration of the natural waters (R2 = 0.69), but that water hardness and pH did not show a significant relation with copper toxicity in these surface waters. In European surface waters, a positive correlation is observed between water hardness and pH. As a result, hardness and pH effects on copper toxicity are counteractive in European surface waters, resulting in the highly significant relation between the 72 h-E(b)C50 and DOC-concentration. Normalisation of the obtained effect concentrations using a Biotic Ligand based predictive Cu-toxicity model revealed that variation in DOC and pH are mainly responsible for the observed differences of Cu-toxicity in natural waters.

Calcium↗
PubMed1989

Current problems associated with toxicity evaluation of medical device materials and future research needs.

The application of toxicology to the evaluation of medical device materials is reviewed. Strengths and weaknesses of systemic and local toxicity models are described. Developments needed to improve the methodology and predictability of assays for immunotoxicity and particulate toxicity are identified. Emerging methods are introduced for assessing adhesion, fibrosis, and blood compatibility.

Animals↗
PubMed2004

Progress in applying genomics in drug development.

Genomics has had an impact on two areas of drug development, "predictive" toxicology and mechanism-based risk assessment. Predictive toxicology studies are aimed at identifying the potential for a compound to be toxic. By developing databases of expression profiles for a wide variety of toxic compounds and toxic models it has been possible to create statistical and computational methods which provide an indication of the toxic potential of a drug from the pattern of gene expression changes it elicits in in vitro or in vivo systems. Because gene expression is central to many responses to xenobiotics, genomic approaches lend themselves very readily to mechanistic toxicology studies. By examining changes in gene expression in cells and tissues in response to drugs it is possible to generate hypotheses as to the underlying mechanism and in some cases it is possible to evaluate hypotheses of toxic mechanism. Some concerns remain about the use of the technology but toxicogenomics can no longer be regarded as "new" technology in drug development. The investments made in applying the technology are maturing and there is a determined effort to bring the full power of the technology into drug development.

Animals↗
PubMed2000

Feasibility study of an online toxicological sensor based on the optical waveguide technique.

Morphological properties of the cells often change as an early response to the presence of a pharmacologically acting toxic substance [Etcheverry, S.B., Crans, D.C., Keramidas, A.D., Cortizo, A.M., Arch. Biochem. Biophys. 338 (1997) 7-14]. Recently it has been shown that living animal cell adhesion and spreading can be monitored online and quantitatively via the interaction of the cells with the evanescent electromagnetic field present at the surface of an optical waveguide [Ramsden, J.J., Li, S.Y., Heinzle, E., Prinosil, J.E. Cytometry 19 (1995) 97-102]. In the present study, optical waveguide lightmode spectroscopy (OWLS) and confocal laser scanning microscopy (CLSM), which provides information about the shape of the cells at the surface, were compared under identical experimental conditions. This allowed for the correlation between the cell-shape information from CLSM and the cell-surface interaction measurements from OWLS. The proposed design of the microsystem sensor involves the establishment of a cell layer on the surface of the waveguide and the subsequent online measurement of the morphological response of the cells to various toxic substances. In the present study, the setup was evaluated using cells from an osteoblastic MC 3T3-E1 cell line, and sodium hypochlorite was used as model toxic substance. Comparing the OWLS signal to the morphological response measured by CLSM reveals that OWLS is effective in monitoring not only cell attachment and spreading but also the cellular response to toxic compounds (i.e. by means of change in cell morphology). For the model toxin, the OWLS measurements indicate that, at concentrations above 0.01%, the cells exhibit a clearly discernable morphological effect (i.e. a decrease in average cell contact area). Thus, the potential of an on-line sensor based on OWLS to applications in toxicology, pharmacy and biocompatibility was demonstrated.

3T3 Cells↗
PubMed1989

2-Bromohydroquinone-induced toxicity to rabbit renal proximal tubules: evidence against oxidative stress.

2-Bromohydroquinone (BHQ) plays an important role in bromobenzene-induced nephrotoxicity and is a model toxic hydroquinone. Since BHQ has a quinone nucleus and various quinones have been shown to produce cytotoxicity via oxidative stress, the goal of this study was to determine whether BHQ produced cytotoxicity in a suspension of rabbit renal proximal tubules via oxidative stress. t-Butyl hydroperoxide (TBHP), an agent known to produce cytotoxicity via oxidative stress in this preparation, was used as a positive control. BHQ decreased tubular glutathione disulfide content whether glutathione reductase was inhibited or not. Inhibition of glutathione reductase did not result in the potentiation of BHQ-induced mitochondrial dysfunction or cell death. In contrast, TBHP increased tubular glutathione disulfide content. TBHP-induced increases in glutathione disulfide content, mitochondrial dysfunction, and cell death were potentiated when glutathione reductase was inhibited. Unlike TBHP, BHQ did not initiate lipid peroxidation nor was the antioxidant butylated hydroxytoluene protective. However, BHQ and TBHP both increased sodium cyanide-insensitive oxygen consumption. These results suggest that BHQ may undergo "redox cycling," but BHQ-induced mitochondrial dysfunction and cell death are not due to oxidative stress.

Animals↗
PubMed2006

A novel RBF neural network training methodology to predict toxicity to Vibrio fischeri.

This work introduces a neural network methodology for developing QSTR predictors of toxicity to Vibrio fischeri. The method adopts the Radial Basis Function (RBF) architecture and the fuzzy means training strategy, which is fast and repetitive, in contrast to most traditional training techniques. The data set that was utilized consisted of 39 organic compounds and their corresponding toxicity values to Vibrio fischeri, while lipophilicity, equalized electronegativity and one topological index were used to provide input information to the models. The performance and predictive ability of the RBF model were illustrated through external validation and various statistical tests. The proposed methodology can be used to successfully model toxicity to Vibrio fischeri for a heterogeneous set of compounds.

Aliivibrio fischeri↗
PubMed2006

A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity.

Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point for modeling reactive toxicity is the applicability of the general rules of organic chemical reactions and the association of these reactions to cellular targets of importance in toxicology. The identification of plausible "molecular initiating events" based on covalent reactions with nucleophiles in proteins and DNA provides the unifying concept for a framework for reactive toxicity. This paper outlines the proposed framework for reactive toxicity. Empirical measures of the chemical reactivity of xenobiotics with a model nucleophile (thiol) are used to simulate the relative rates at which a reactive chemical is likely to bind irreversibly to cellular targets. These measures of intrinsic reactivity serve as correlates to a variety of toxic effects; what's more they appear to be more appropriate endpoints for QSAR modeling than the toxicity endpoints themselves.

Amino Acids↗