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PubMed2006

Bioavailability models for predicting copper toxicity to freshwater green microalgae as a function of water chemistry.

We investigated whether an earlier-developed bioavailability model for predicting copper toxicity to growth rate of the freshwater alga Pseudokirchneriella subcapitata could be extrapolated to other species and toxicological effects (endpoints). Hardness and dissolved organic carbon did not significantly affect the toxicity of the free Cu2+ ion to P. subcapitata (earlier study) and Chlorella vulgaris(this study), but a higher pH resulted in an increased toxicity for both species. Regression analysis showed significant linear relationships between ECxpCu (= "effect concentration" that produces x% adverse effect, expressed as pCu = -log of the Cu2+ activity) and pH. By linking these regression models with a geochemical metal speciation model, dissolved copper concentrations that elicit a given adverse effect (EC(X)dissolved) can be predicted. Within the pH range investigated (5.5-8.7), slopes of the linear EC(X)pCu vs pH regression models varied between 1.301 and 1.472 depending on the species and the effect level (10% or 50%) considered. In a statistical sense these slopes were all significantly different from one another (p < 0.05), suggesting that this empirical regression model does not yet capture the full complexity of toxicological copper bioavailability to algae. However, we demonstrated that regression models with an "average" slope of 1.354 had predictive power very similar to those of regression models with species and effect-specific slopes. Additionally, the "average" regression model was further successfully validated for other species (Chlamydomonas reinhardtii and Scenedesmus quadricauda) and for different toxicological effects/endpoints (growth rate, biomass yield, and phosphorus uptake rate). For all these toxicity datasets effect concentrations of copper could be predicted with this "average" model by errors of less than a factor of 2 in 94-100% of the cases. The success of this "average" model suggests the possibility that the pH-based linear regression model may form a sound conceptual basis for modeling the toxicological bioavailability of copper to green algae in regulatory assessments, although a full mechanistic understanding is lacking and should be the focus of future studies.

Biological Availability↗
PubMed2000

A quantitative structure--activity relationships model for the acute toxicity of substituted benzenes to Tetrahymena pyriformis using Bayesian-regularized neural networks.

We have used a new, robust structure-activity mapping technique, a Bayesian-regularized neural network, to develop a quantitative structure-activity relationships (QSAR) model for the toxicity of 278 substituted benzenes toward Tetrahymena pyriformis. The independent variables used in the modeling were derived solely from the molecular structure, and the model was tested on 20% of the data set selected from the whole set by cluster analysis and which had not been used in training the network. The results show that the method is robust and reliable and give results for mixed class compounds which are comparable to earlier QSAR work on single-chemical class subsets of the 278 compounds and which employed measured physicochemical parameters as independent variables. Comparisons of Bayesian neural net models with those derived by classical PLS analysis showed the superiority of our method. The method appears to be able to model more diverse chemical classes and more than one mechanism of toxicity.

Animals↗
PubMed1997

Estimating relative potency for receptor-mediated toxicity: reevaluating the toxicity equivalence factor (TEF) model.

Once considered and interim procedure for use with mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans, use of the toxicity equivalence factor (TEF) model has been proposed for other groups of structurally similar chemicals. Data from polychlorinated dibenzo p-dioxins and polychlorinated dibenzofurans as well as theoretical analyses of the biological basis for receptor-mediated toxicity demonstrate the limitations of this model and indicate that estimation of equivalent doses for such chemicals is more likely to require a function than a point estimate such as a TEF. Relatively small changes in the TEFs can result in both significant changes in the estimated dose for the mixture and the percentage of the estimated risk that is attributable to the most potent or reference compound. Estimates of equivalent doses are likely to become less accurate when extrapolated to lower responses which frequently serve as the basis for regulatory decisions. Existing models allow the relative potency to be a function rather than a point estimate as well as interaction at the receptor among the chemicals.

Benzofurans↗
PubMed1994

Modelling of human acute toxicity from physicochemical properties and non-vertebrate acute toxicity of the 38 organic chemicals of the MEIC priority list by PLS regression and neural network.

Linear and non-linear modelling of human acute toxicity (as human lethal concentrations; HLCs) of the 38 organic chemicals from the 50 priority compounds of the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme was investigated. The models obtained were derived either from a set of 23 physicochemical properties of the compounds or from their acute toxicities to five aquatic non-vertebrates together with the physicochemical properties. For the linear type, modelling was performed using a partial least square projection to latent structures (PLS) regression method; for the non-linear models, both PLS regression and neural network were utilized. A neural network using a combination of backpropagation and cascade-correlation algorithms was applied in this study. The results generally reveal a slightly better predictive performance of the models obtained from PLS regression than those obtained from neural networks. However, the model composed of physicochemical properties (PC-model) from the trained neural network using a back propagation algorithm with pruning technique proved superior to that trained with a combination of backpropagation and cascade-correlation algorithms after leave-one-out cross-validation. The predictive power of the PC-models, whether linear or non-linear, was comparable with that of the corresponding models consisting of both structural descriptors and the ecotoxicological tests (ECOPC-models), except for the battery (ECOPC-model) from the neural network. The composition of the 'best' PLS and neural network models points to the importance of the combination of physicochemical properties reflecting lipophilicity, size, volume, intermolecular binding forces and electronic properties of the molecule. All the aquatic non-vertebrate tests are shown to be essential in explaining human acute toxicity. However, the degree of contribution differed, with the crustacean (Artemia salina) and the bacterial (Microtox) bioassays being more important to the linear and non-linear PLS models, whereas the crustacean (Artemia salina and Streptocephalus proboscideus) tests, and the rotifer (Brachionus calyciflorus) assay were important to the neural network models. The organochlorine (lindane) and bipyridinium (paraquat) pesticides were common outliers in all the models. Moreover, the latter two compounds and the organophosphate (malathion) pesticide were also common outliers in all ECOPC-models. Other types of pesticides, however, fit the models. The predicted HLCs of a number of non-pesticides, including some chlorinated compounds, also deviated from the observed HLCs by more than one order of magnitude.

Algorithms↗
PubMed2002

Application of the biotic ligand model to predicting zinc toxicity to rainbow trout, fathead minnow, and Daphnia magna.

The Biotic Ligand Model has been previously developed to explain and predict the effects of water chemistry on the toxicity of copper, silver, and cadmium. In this paper, we describe the development and application of a biotic ligand model for zinc (Zn BLM). The data used in the development of the Zn BLM includes acute zinc LC50 data for several aquatic organisms including rainbow trout, fathead minnow, and Daphnia magna. Important chemical effects were observed that influenced the measured zinc toxicity for these organisms including the effects of hardness and pH. A significant amount of the historical toxicity data for zinc includes concentrations that exceeded zinc solubility. These data exhibited very different responses to chemical adjustment than data that were within solubility limits. Toxicity data that were within solubility limits showed evidence of both zinc complexation, and zinc-proton competition and could be well described by a chemical equilibrium approach such as that used by the Zn BLM.

Animals↗
PubMedDate not supplied

Chemical models for the lethality curves of toxic metal ions.

Several equilibrium models are presented for the calculation of the lethality curves due to toxic metal ions. In the first, a generalized Langmuir model is used to examine the occupancy of linear arrays of 1, 2, ..., 6 interacting adsorption sites on a macromolecular species. This model permits one to take into account cooperative or anticooperative interaction of occupied adjacent sites. In the second model, a variety of nonlinear distributions of interacting sites (in triangular, square, tetrahedral, and octahedral array) are analyzed, and the corresponding adsorption isotherms are calculated. The third model treated, the Ising model, represents a linear infinite array of sites with nearest-neighbor interactions. The fourth and fifth models examined are the Bragg-Williams model and the quasi-chemical model, both of which permit approximate treatment of infinite arrays of adsorption sites having arbitrary numbers of interacting nearest neighbors. These models are then combined with the assumption that the differential distribution of mortality is a known function of the fraction of sites occupied by the toxic metal ion to generate lethality curves. Results are computed for the special case in which the differential mortality distribution is Gaussian, and it is shown that all of the models are capable of generating lethality curves of the sort found experimentally when plots are made of percentage lethality versus log dosage. The models can also be used for situations in which toxic effects other than lethality arise from the interaction of a toxic molecule or ion with more than one site on a linear macromolecule or for reactions involving certain other arrays of specified configuration.

Binding Sites↗
PubMed2005

Development of a biotic ligand model and a regression model predicting acute copper toxicity to the earthworm Aporrectodea caliginosa.

The purpose of this study was to develop a terrestrial biotic ligand model (BLM) for predicting acute copper toxicity to the earthworm Aporrectodea caliginosa. To overcome the basic problems hampering development of BLMs for terrestrial organisms, an artificial flow-through exposure system was developed consisting of an inert quartz sand matrix and a nutrient solution, of which the composition was univariately modified. A. caliginosa was exposed for 7 days under varying concentrations of copper and the major cations modifying toxicity: H+, Ca2+, Mg2+, and Na+. In addition copper speciation was modulated by means of EDTA or dissolved organic carbon (DOC). An increase in pH or pNa resulted in a linear decrease of 7-days median lethal concentrations. Increasing Ca2+ and Mg2+ activities had inconsistent effects. EDTA addition decreased toxicity when the total copper concentration in the pore water was kept the same. This is attributed to the strong complexation capacity of EDTA and shows that total copper is not the toxic species. DOC was more protective than could be explained by its metal complexing properties. The BLM developed incorporates the effects of H+ and Na+. This BLM was validated with the results of a set of bioassays with artificial pore water in quartz sand and by a set of bioassays in spiked field soils. Prediction error was within a factor of 2, but some predictions were not within the 95% confidence interval. Therefore a more widely applicable regression type model was developed that was able to explain >95% of the (lack of) toxicity observed. To our knowledge this is the first report of the successful development of a terrestrial BLM.

Animals↗
PubMed2003

Partial least squares modelling of the acute toxicity of aliphatic compounds to Tetrahymena pyriformis.

The aim of this study was to evaluate a multivariate statistical model, utilising Partial Least Squares (PLS) analysis, for the prediction of the acute toxicity of aliphatic chemicals to the ciliate Tetrahymena pyriformis. A model was developed that was capable of making a prediction regardless the mechanism of toxic action. The toxicity of 476 compounds, possessing different mechanisms of toxic action was considered. A set of 74 descriptors, including the octanol-water partition coefficient, molecular-orbital descriptors, geometrical, topological and connectivity indices, was generated. A three-component, eight-descriptor PLS model was developed. It was validated by a Y-permutation test and by simulation of external prediction for complementary subsets. A comparison with existing class or mechanism-based models, derived on the same data set, was made.

Animals↗
PubMed2002

Antitumor activity of a new orally active organotin compound: a preliminary study in murine tumor models.

The toxicity and antitumor activity of the novel organotin compound triethyltin(IV)lupinylsulfide hydrochloride (IST-FS 29), administered by the oral route, have been evaluated against three transplantable murine tumor models: P388 lymphocytic leukemia, B16F10 melanoma and 3LL Lewis lung carcinoma. Mild and reversible signs of acute toxicity such as behavioral symptoms, weight loss and histological alterations were mainly reported at the highest single dose of 28 mg/kg. Conversely, lower concentrations of compound ranging from 7 to 21 mg/kg did not result in major toxic effects, even after repeated dosing. The antitumor activity studies showed that fractionation dosing, rather than single bolus administration, over 1 week, might prove more active and better tolerated by allowing the achievement of the highest therapeutic total dose of IST-FS 29 (42 mg/kg). Indeed, repeated administrations of IST-FS 29 resulted in marked significant improvement of antitumor activity against B16F10 (50% of tumor volume inhibition, p = 0.0003) and, to a greater extent, 3LL (90% of tumor volume inhibition, p = 0.0001) tumors. These results indicate that IST-FS 29 might be a suitable candidate as an orally administrable anticancer drug and support its further development in human tumor xenografts.

Animals↗
PubMed2000

Hypertonic sodium bicarbonate is effective in the acute management of verapamil toxicity in a swine model.

STUDY OBJECTIVE: This study was conducted to determine whether hypertonic sodium bicarbonate would improve the hypotension associated with severe verapamil toxicity compared with volume expansion. METHODS: The study design used a nonblinded acute animal preparation. Twenty-four anesthetized and instrumented swine were poisoned with verapamil delivered at a rate of 1 mg/kg per hour for 10 minutes followed by incremental increases of 1 mg/kg per hour every 10 minutes until the endpoint of a mean arterial blood pressure of 45% of baseline was achieved. Animals alternately received either 4 mEq/kg of hypertonic sodium bicarbonate intravenously over 4 minutes or similar volumes of 0.6% sodium chloride in 10% mannitol (control). The main outcome parameter followed was mean arterial pressure. In addition, physiologic parameters including cardiac output, heart rate, pH, PCO (2), PO (2), plasma ionized calcium, sodium, and potassium were monitored. RESULTS: Verapamil toxicity, as defined by a mean arterial pressure of 45% of baseline, was produced in all animals following an average verapamil infusion dose of 0.6+/-0.12 mg/kg. This dose produced an average plasma verapamil concentration of 728.1+/-155.4 microgram/L, with no significant difference between groups. Swine treated with hypertonic sodium bicarbonate experienced a significant increase in mean arterial pressure (>50%) and cardiac output (>30%) over the first 20 minutes that slowly equilibrated with the control group over the remainder of the experiment. As expected, plasma sodium concentrations were elevated significantly in the sodium bicarbonate group while plasma potassium concentrations were decreased significantly. Finally, there was a significant decrease in plasma ionized calcium concentration in the sodium bicarbonate-treated group compared with controls. CONCLUSION: Hypertonic sodium bicarbonate reversed the hypotension and cardiac output depression of severe verapamil toxicity in a swine model.

Animals↗
PubMed2005

Pressure-immobilization bandages delay toxicity in a porcine model of eastern coral snake (Micrurus fulvius fulvius) envenomation.

STUDY OBJECTIVES: Pressure-immobilization bandages are used in countries where neurotoxic snake envenomations are common. They impede lymphatic egress from the bite site and delay systemic venom toxicity. The effectiveness of these devices has not been evaluated in coral snake envenomations. We investigated the efficacy of pressure-immobilization bandages in delaying the onset of systemic toxicity in a porcine model of coral snake envenomation. METHODS: A randomized controlled trial of pressure-immobilization bandages was conducted in a university animal care center. Subjects were 12 anesthetized, spontaneously breathing pigs, ranging from 9.1 to 11.4 kg. After injection with 10 mg of Micrurus fulvius fulvius venom in the subcutaneous tissue of the distal foreleg, subjects were randomized to receive no treatment or application of a pressure-immobilization bandage at 1 minute after injection. Treated animals had elastic bandages applied to the extremity and splinting for immobilization. Vital signs and quality of respirations were recorded. Outcome was the onset of respiratory failure or survival to 8 hours. Necropsies and histologic analysis of the envenomation site was performed. RESULTS: One animal from each group was removed because of the discovery of pre-existing respiratory pathology. Four of 5 pigs in the treatment group survived to 8 hours, but none in the control group survived. Mean time to onset of respiratory compromise was 170.4 +/- 33.3 minutes in the control group. None of the pigs had histologic changes at the envenomation site consistent with ischemia or pressure-related injury. CONCLUSION: Pressure-immobilization bandages delayed the onset of systemic toxicity in our porcine model of M fulvius envenomation.

Animals↗
PubMedDate not supplied

Hazard assessment of chemical carcinogens: the impact of hormesis.

The recent report of reductions in the number and area of preneoplastic hepatic lesions in response to low doses of the tumor promoter phenobarbital provides important new support for the existence of hormetic responses to carcinogens. The presence of hormetic responses to carcinogenic agents and the corollary that beneficial doses of these compounds can be determined have several implications for the bioassay and hazard assessment of carcinogens as well as for public policy regulating exposure to these agents. To be adequately sensitive to detect and quantify hormetic or other non-linear dose-response functions, current study designs must be modified to include lower doses and sufficiently large numbers of animals. Short- or medium-term animal studies are a cost-effective means of addressing these needs and have been used recently to describe a classical hormetic response to the non-genotoxic carcinogen phenobarbital. These basic changes should be supported by a continuing emphasis on mechanistic research and the development of biologically based quantitative models of toxicant action. Linking these models with physiologically based pharmacokinetic model descriptions of target dose holds the greatest promise for improving the description of the dose-response curve at low doses. These approaches are generally encouraged by the USEPA in the form of The 1996 Proposed Carcinogen Risk Assessment Guidelines. However, there remain substantial questions regarding integration of the concept of hormesis into hazard testing and public policy that require careful consideration. Herein, we explore the issues that surround testing for hormetic responses and the implications for public policy.

Animals↗
PubMed1997

Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines.

Certain bacterial immunostimulatory (i.s.) DNA sequences containing unmethylated CpG motifs stimulate antigen-presenting cells (APC) to express a full complement of costimulatory molecules and to produce cytokines including interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. While IL-12 is key to their T helper cell (Th)1-promoting adjuvant activity, secretion of toxic levels of TNF-alpha is harmful in that it promotes toxic shock. Given the beneficial as well as harmful consequences of i.s. DNA, we investigated the possibility of identifying DNA sequences, i.e. CpG oligodeoxynucleotides (ODN) which differentially activate IL-12 versus TNF-alpha cytokine production in APC. Here, we describe an i.s. DNA sequence with these characteristics. While its potential to induce IL-12 is preserved, its ability to trigger TNF-alpha release is strongly curtailed both in vitro and in vivo. I.s. DNA could be segregated into lethal and non-lethal in a mouse toxic shock model. The non-toxic i.s. DNA was useful as an adjuvant, thus allowing cytotoxic T cell responses to the soluble protein ovalbumin and conferring a resistant Th 1 phenotype to BALB/c mice lethally infected with Leishmania major. This i.s. CpG motif may thus be prototypic for a useful immunostimulating DNA sequence that lacks harmful side effects.

Adjuvants, Immunologic↗
PubMed2000

Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis.

Evidence is increasing that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by selective motoneuron death. To study the role of mitochondrial dysfunction in the pathways leading to motoneuron death, we developed an in vitro model of chronic motoneuron toxicity, based on malonate-induced inhibition of complex II in the mitochondrial electron transport chain. Treatment with malonate resulted in a dose-dependent decrease in cellular ATP levels. We observed that motoneurons were significantly more vulnerable to mitochondrial inhibition than control neurons in the dorsal horn. We could reproduce this dose-dependent phenomenon with the complex IV inhibitor sodium azide. The free radical scavenger alpha-phenyl-N-tert-butylnitrone, the AMPA/kainate receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione, and riluzole, a drug that is currently used for the treatment of amyotrophic lateral sclerosis, were protective against malonate-induced motoneuron death. Furthermore, the caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and z-Asp-Glu-Val-Asp-fluoromethyl ketone were both protective against malonate toxicity. Our model shows that chronic mitochondrial inhibition leads to selective motoneuron death, which is most likely apoptotic.

Adenosine Triphosphate↗
PubMed1991

Digoxin-specific Fab fragments in the treatment of oleander toxicity in a canine model.

STUDY OBJECTIVE: To examine the efficacy of digoxin-specific Fab fragments (dsFab) in the treatment of experimentally induced Nerium oleander cardiac glycoside toxicity in a dog model. DESIGN: A nonblined, placebo-controlled experiment. SUBJECTS: Ten adult greyhound dogs of either sex divided into treatment and control groups of five dogs each. INTERVENTIONS: A tincture of oleander was prepared and administered intravenously to each animal. After the onset of cardiotoxicity, the treatment group received 60 mg/kg dsFab IV. MEASUREMENTS AND MAIN RESULTS: All dogs exhibited dysrhythmias meeting our criteria for cardiac glycoside cardiotoxicity within 27 minutes of beginning the infusion. Three of five control dogs had lethal dysrhythmias during the three-hour observation period. The remaining two control dogs exhibited dysrhythmias throughout the three-hour experiment. All five of the dsFab-treated dogs survived and converted to normal sinus rhythm within eight minutes of dsFab infusion. Three treatment animals reverted back to nonlethal and hemodynamically stable dysrhythmias after a mean of 107 minutes. CONCLUSION: Large doses of dsFab are efficacious in the treatment of dysrhythmias in this canine model of N oleander cardiac glycoside poisoning.

Animals↗
PubMed2006

A dose-based modeling approach for accumulation and toxicity of arsenic in tilapia Oreochromis mossambicus.

We proposed an approach to relate metal toxicity to the concentrations of arsenic (As) in specific target organs of tilapia Oreochromis mossambicus. The relationships among As exposure, uptake, accumulation, and toxicity of tilapia were investigated using kinetic and dynamic modeling. The biouptake rate of waterborne As through the gills of fish was dependent on exposure concentrations, in that the relationship was well described by incorporating Michaelis-Menten type uptake kinetics. The fitted bioaffinity parameter and limiting uptake flux were 3.07 +/- 2.21 microg/mL(-1) (mean +/- SD) and 2.17 +/- 0.38 microg/mL(-1)/d(-1), respectively, suggesting that a low As binding affinity of tilapia gills, yet a relatively high binding capacity was obtained. The toxicity of As was analyzed by determining the lethal exposure concentration associated with a mortality of 50% (LC50) at different integration times. Our results demonstrate that 96-h and incipient LC50s for tilapia are 28.68 (95% CI: 15.98-47.38) and 25.55 microg/mL(-1), respectively. The organ-specific internal residue associated with 50% mortality was estimated by combining the model-predicted toxicokinetic parameters and the area-under-curve (AUC)-based time-integrated concentration toxicity model. A physiologically based toxicokinetic model was constructed to elucidate the principle mechanisms that account for the observed data and to predict the kinetics of As in tilapia under different water exposure scenarios. We employed the Hill equation model to predict the organ-specific dose-response relationships. We used the liver as a surrogate of target sites to assess the As toxicity to tilapia because of its higher sensitivity to As toxic effects. The predicted mortalities never reach 50% when the tilapia were exposed to waterborne As <2 microg/mL(-1). The predicted mortality is, however, slightly higher than the observed values before the 10th day in that the profile reached the 70% maximum mortality, which is comparable to the observed data when the tilapia were exposed to 4 microg/mL(-1). Our results show that a dose-based toxicokinetic and toxicodynamic modeling approach successfully links metal exposure to bioavailability, bioaccumulation, and toxicity, under variable exposure scenarios.

Algorithms↗
PubMed1991

Essential roles for animal models in understanding human toxicities.

Strong cases have been made that there are no viable alternatives to the use of animal models in toxicology and, indeed, that virtually every major advance in the biomedical sciences and technologies stems in whole or in part from research performed with animals. Basic to these assertions is the assumption that information gained from such research can be extrapolated to "analogous" human conditions. Analogies may involve modeling at levels of bio-organization from molecules to the behaviour of the total, integrated organism: toxicity of exposure to a chemical varies with the structure(s) or function(s) modeled. Important decisions by regulators are always influenced by trade-offs between biological limitations and social cost-benefits, much information about the former coming from research on animals. This places great importance on the validities of extrapolations from the animal data, which may be expected to satisfy a hierarchy of five criteria. These range from evidence of superficial similarity ("face validity") to demonstration that knowledge obtained from the model is related to predictable outcomes in humans ("predictive validity"). Given the nature of the problems to be solved, which drastically limits the use of humans as subjects, animal models play essential roles in the biomedical sciences and technologies provided that due precautions are taken in creating models and in generalizing from them.

Animals↗