Two new rodent models for actinide toxicity studies.
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Americium↗
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Rat heart cells in culture: a model of iron toxicity and chelation.
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Animals↗
Contribution of TNF/TNF receptor and of Fas ligand to toxicity in murine models of endotoxemia and bacterial peritonitis.
Fas/Fas ligand and TNF/TNF receptors are involved in apoptosis. Whether both systems are involved in septic shock has not been determined so far. We investigated the role of TNF/TNFR and Fas/Fas ligand in models of endotoxemia and of speticemia in mice. Upon LPS challenge, TNF and TNFR p55 were involved in the process inducing lethality. FasL did not contribute to enhance lethality, as evidenced in gld mice, lacing FasL. Following an intraperitoneal injection of live E. coli, TNF and TNFR p55 were necessary to combat infection. Disruption of either gene was associated with enhanced lethality and failure to clear the bacteria. No effect observed in gld mice in this peritonitis model. Thus, these observations confirmed the pathogenic role of TNF/TNFR in endotoxemia and its beneficial role in local bacterial infections. In addition the data ruled out a major role for Fas/FasL in septic shock in mice.
Animals↗
[Quantitative evaluation of biological activity of toxic agents (unicellular model)].
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Environmental Pollutants↗
The preventive effect of vitamin D3 on radiation-induced hair toxicity in a rat model.
Our aim is to investigate the protective effect of vitamin D3 especially from radiation-induced hair toxicity. A model of skin radiation injury was developed and a single fraction of 20 Gy Gamma irradiation was applied to the right dorsal skin of fourteen rats. All animals were randomly divided into 2 groups: Group I: irradiation alone (n = 7) and Group II: irradiation and 0.2 microg vitamin D3 given IM (n = 7). Fifty days after post-irradiation rats were sacrificed. The outcomes were evaluated on the basis of histopathological findings and immunohistochemical staining for Vitamin D receptor (VDR) in skin and hair follicles. The number of hair follicles in the radiation field for the group of animals irradiated without pretreatment was significantly lower than outside of the irradiated area (p = 0.016) as it is expected. Contrarily the number of hair follicles did not show significant difference in the pretreated group between the irradiated field and outside of the fields (p = 0,14). Skin of the vitamin D3 pretreated group demonstrated stronger immunoreactivity for VDR compared to irradiation alone group. These results indicate that administration of vitamin D3 may protect hair follicles from radiation toxicity. Further clinical trials should be conducted to prove the preventive effect of vitamin D3 as well as dosing and timing of the agent on radiation-induced alopecia.
Alopecia↗
Biotic ligand model of the acute toxicity of metals. 2. Application to acute copper toxicity in freshwater fish and Daphnia.
The biotic ligand model (BLM) was developed to explain and predict the effects of water chemistry on the acute toxicity of metals to aquatic organisms. The biotic ligand is defined as a specific receptor within an organism where metal complexation leads to acute toxicity. The BLM is designed to predict metal interactions at the biotic ligand within the context of aqueous metal speciation and competitive binding of protective cations such as calcium. Toxicity is defined as accumulation of metal at the biotic ligand at or above a critical threshold concentration. This modeling framework provides mechanistic explanations for the observed effects of aqueous ligands, such as natural organic matter, and water hardness on metal toxicity. In this paper, the development of a copper version of the BLM is described. The calibrated model is then used to calculate LC50 (the lethal concentration for 50% of test organisms) and is evaluated by comparison with published toxicity data sets for freshwater fish (fathead minnow, Pimephales promelas) and Daphnia.
Animals↗
Characterization of a developmental toxicity dose-response model.
The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.
Abnormalities, Drug-Induced↗
Biotic ligand model development predicting Zn toxicity to the alga Pseudokirchneriella subcapitata: possibilities and limitations.
Biotic ligand models have been developed for various metals (e.g. Cu, Ag, Zn) and different aquatic species. These models incorporate the effect of physico-chemical water characteristics (major cations, pH, dissolved organic carbon) on the bioavailability and toxicity of the metal. In this study, the individual effects of calcium, magnesium, potassium, sodium and pH on zinc toxicity to the green alga Pseudokirchneriella subcapitata (formerly and better known as Selenastrum capricornutum and Raphidocelis subcapitata) were investigated. Stability constants for binding to algal cells (K(BL)) were derived for those cations affecting zinc toxicity, using the mathematical approach proposed by De Schamphelaere and Janssen [Environ. Sci. Technol. 63, (2002) 48-54]. Potassium proved to be the only cation tested that did not alter zinc toxicity to algae significantly. Log (K(BL)) values for Ca, Mg and Na, derived at pH 7.5, were 3.2, 3.9 and 2.8, respectively. Toxicity tests performed at different pH values (5.5-8.0) indicated that competition between H(+) and Zn(2+) reduces zinc toxicity. However, the observed relationship between (H(+)) and the 72h-EbC(50) [expressed as microM (Zn(2+))] is not linear and suggests that pH affects the physiology of the biotic ligand. Although, in general, our findings seem to suggest that zinc toxicity to algae can be modelled as a function of key water characteristics, the results also demonstrate that the part of the conventional BLM-hypothesis-i.e. that the binding characteristics of the biotic ligand are independent of the test medium characteristics-is not valid for algae. The observed pH-dependent change of stability constants should therefore be further investigated and incorporated in future BL-modelling efforts with algae.
Chlorophyta↗
Crystalline and water soluble Cr(4+) and Cr(5+) model compounds for chromium toxicity studies.
We discuss two complexes of Cr(4+) for their possible utility as models for Cr toxicity studies. They are Cr(dien)(O2)2(.)H2O (dien = diethylenetriamine) and Cr(NH3)3(O2)2, which have been recently characterized by x-ray diffraction and magnetic techniques. We present their optical and infrared absorption spectra as quick aids in their identification procedure. We also summarize the general properties of some well-characterized Cr(5+) compounds. All of these compounds are water soluble with the Cr(5+) samples being fairly stable in basic solutions. They can all be prepared as pure crystals with a shelf life of over 2 years when stored in a refrigerator.
Chromium Compounds↗
An insect model for assessing mercury toxicity: effect of mercury on antioxidant enzyme activities of the housefly (Musca domestica) and the cabbage looper moth (Trichoplusia ni).
The effect of mercury as Hg2Cl2 and HgCl2 on the antioxidant enzyme levels and its toxicity was investigated in an insect model comprised of adult females of the common housefly, Musca domestica, and fourth-instar larvae of the cabbage looper moth, Trichoplusia ni. HgCl2 was found to be more toxic than Hg2Cl2 to both M. domestica and T. ni. The LC50s for M. domestica were 1.17% and 0.38% w/v concentration for Hg2Cl2 and HgCl2, respectively. For the more tolerant T. ni, the LC50S were 5.15% for Hg2Cl2 and 0.96% w/w concentration for HgCl2. The minimally acute LC5 dose of both oxidation states of Hg was approximately 0.005% for both insects (w/v for M. domestica and w/w for T. ni). At the LC5, both forms of Hg significantly induced the activity of superoxide dismutase in both insect species. Catalase was induced by both Hg2Cl2 and HgCl2 in M. domestica but was only induced by HgCl2 in T. ni. Glutathione-S-transferase, its peroxidase activity, and glutathione reductase activities were also significantly altered in most cases by Hg in both insects although the pattern of alternation was different between the two insects. It is evident that mercury induces oxidative stress in insects as it does in vertebrates. Our findings suggest that insects may serve as a valuable, non-mammalian model species to assess Hg-induced oxidative stress as a component of environmental toxicity.
Animals↗
QSTR with extended topochemical atom indices. Part 5: Modeling of the acute toxicity of phenylsulfonyl carboxylates to Vibrio fischeri using genetic function approximation.
In continuation of our recent efforts to model the acute toxicity of 56 phenylsulfonyl carboxylates to Vibrio fischeri using principal component factor analysis, the present paper deals with modeling of the same data set with extended topochemical atom (ETA) indices using genetic function approximation (GFA) as the statistical tool. The statistical quality of the best model using ETA descriptors is as follows: n=56, Q2=0.771, Ra2=0.861, R=0.935, F=69.0 (df5,50), s=0.172, AVRES=0.128. This equation was better in statistical quality than that obtained previously using principal component factor analysis as the data-preprocessing step. An attempt was also made to model the data set with different nonETA parameters (topological indices including Wiener, Hosoya Z, molecular connectivity, kappa shape, Balaban J and E-State parameters apart from physicochemical parameters like AlogP98, MolRef and H_bond_acceptor) and the best model showed the following quality: n=56, Q2=0.805, Ra2=0.820, R=0.913, F=53.5 (df4,51), s=0.196, AVRES=0.136. An attempt to use both ETA and nonETA parameters lead to an equation which is marginally better than the best ETA model: n=56, Q2=0.779, Ra2=0.865, R=0.937, F=71.7 (df5,50), s=0.169, AVRES=0.127. Use of the ETA indices suggested negative contributions of steric bulk, functionality of C10, volume of substituents on C10 and functionalities of chloro and nitro substituents at X1 position and positive contributions of functionalities of C4 and C1 and presence of substituents with electronegative atoms, especially at R2 and R3 positions. Furthermore, absence of substituents at R2 and R3 positions decreases toxicity. This study corroborates the results obtained from principal component factor analysis and suggests that ETA parameters are sufficiently rich in chemical information to encode the structural features contributing significantly to the acute toxicity of phenylsulfonyl carboxylates to V. fischeri.
Aliivibrio fischeri↗
Interspecies quantitative structure-activity relationship model for aldehydes: aquatic toxicity.
The present study proposes a generic interspecies quantitative structure-activity relationship (QSAR) model that can be used to predict the acute toxicity of aldehydes to most species of aquatic organisms. The model is based on the flow-through fathead minnow (Pimephales promelas) 50% lethal concentration (LC50) data combined with other selected fish acute toxicity data and on the static ciliate (Tetrahymena pyriformis) 50% inhibitory growth concentration (IGC50) data. The toxicity of Schiff-base acting aldehydes was defined using hydrophobicity, as the calculated log 1-octanol/water partition coefficient (log Kow), and reactivity, as the donor delocalizability for the aldehyde O-site (D(O-atom)). The fish model [log 1/LC50 = -2.503(+/-1.950) + 0.480(+/-0.052) log Kow + 18.983(+/-6.573) D(O-atom), n = 62, r2 = 0.619, s2 = 0.241, F = 48.0, Q2 = 0.587] compares favorably with the ciliate model [log 1/IGC50 = -0.985(+/-1.309) + 0.530(+/-0.044) log Kow + 11.369(+/-4.350) D(O-atom), n = 81, r2 = 0.651, s2 = 0.147, F = 72.9, Q2 = 0.626]. The fish and ciliate surfaces appear to be parallel, because they deviate significantly only by their intercepts. These observations lead to the development of a global QSAR for aldehyde aquatic toxicity [log E(-1) = bE(Organism) + 0.505(+/-0.033) log Kow + 14.315(+/-3.731) D(O-atom), n = 143, r2 = 0.698, s2 = 0.187, S2(Fish) = 0.244, S2(Ciliate) = 0.149, F = 98, Q2 = 0.681]. The general character of the model was validated using acute toxicity data for other aquatic species. The aldehydes global interspecies QSAR model could be used to predict the acute aquatic toxicity of untested aldehydes and to extrapolate the toxicity of aldehydes to other aquatic species.
Aldehydes↗
Induction of MnSOD gene expression in a hepatic model of TNF-alpha toxicity does not result in increased protein.
The model of toxic liver injury was used to examine the role of manganese superoxide dismutase (MnSOD) expression in cellular resistance to tumor necrosis factor (TNF)-alpha toxicity. The effects of the hepatotoxin D-galactosamine (GalN) and lipopolysaccharide (LPS) on hepatic and splenic TNF-alpha and MnSOD expression were studied. Treatment with GalN and LPS alone or in combination led to equivalent increases in hepatic and splenic TNF-alpha gene expression. Hepatic MnSOD mRNA levels were not affected by GalN or GalN with LPS but were increased 13-fold by LPS alone. Splenic MnSOD mRNA levels were increased twofold by GalN and 12-fold by either LPS alone or GalN plus LPS. The determination of MnSOD protein content, however, revealed no changes in hepatic or splenic steady-state levels of the protein with any of the treatments, despite the marked increases in MnSOD gene expression. Hepatic MnSOD enzyme activity was also unchanged by LPS or GalN plus LPS administration. Biosynthesis of MnSOD protein in rat hepatocytes isolated from an in vivo LPS-treated rat was unchanged compared with control. MnSOD mRNA levels were increased when GalN treatment was combined with uridine rescue, but again no change in protein was seen. The lack of any increase in MnSOD protein after GalN or LPS administration indicates that MnSOD upregulation is not involved in cellular resistance against TNF-alpha cytotoxicity in the liver in vivo.
Animals↗
Application of multi-component Damage Assessment Model (MDAM) for the toxicity of metabolized PAH in Hyalella azteca.
Biotransformation and time-dependent toxicity of pyrene and fluorene, in the presence and absence of the biotransformation inhibitor 6-propylpiperonyl butyl diethylene glycol ether known as piperonyl butoxide (PBO), were investigated in Hyalella azteca. Toxicokinetics and biotransformation were determined in both short- and longterm experiments. For pyrene, the uptake rate coefficient (ku = 99 +/- 9 L kg(-1) h(-1)), elimination rate constant for parent compound (kep = 0.050 +/- 0.008 h(-1)), biotransformation rate constant (km = 0.016 +/- 0.003 h(-1)), and elimination rate constant for metabolites (kem = 0.021 +/- 0.007 h(-1)) were determined from a short-term study. For fluorene, ku (130 +/- 30 L kg(-1) h(-1)) and kep (1.7 +/- 0.2 h(-1)) were estimated based on km (0.015 +/- 0.002 h(-1)) and kem (0.011 +/- 0.002 h(-1)) determined from a long-term study. At steady state, the percent metabolites for pyrene and fluorene were 43% and 58%, respectively, determined from km/(km +/- kem). Time-dependent toxicity was determined as both lethal water concentration and lethal body residue in the presence and absence of PBO. Co-exposure to PBO decreased the median lethal residue (LBR50) for parent pyrene and shortened the median lethal time (LT50). Pyrene toxicity was explained by the body residues of parent pyrene and PBO, where the metabolites' contribution was negligible. Forfluorene, co-exposure to PBO increased the LBR50 for parent fluorene and shortened the LT50. Thus, fluorene metabolites contributed significantly to the toxicity. Using a multicomponent damage assessment model, the toxicodynamic parameters, damage accrual rate coefficient, and damage recovery rate constant for parent pyrene and parent fluorene were very similar and estimated to be from 0.009 to 0.020 micromol(-1) g h(-1) and from 0.003 to 0.013 h(-1), respectively, and the incipient LBR50 at the infinite time (LBR50(t = infinity)) was from 0.24 to 0.46 micromol g(-1), respectively. These values are similar to the reported LBR50(t = infinity) for other nonpolar narcotics such as pentachlorobenzene (PCBz, 0.38 +/- 0.13 micromol g(-1)) and dichlorophenylchloroethylene (DDE, 0.41 +/- 0.19 micromol g(-1)). For fluorene metabolites, these values were 0.10 +/- 0.03 micromol(-1) g h(-1), 0.034 +/- 0.021 h(-1), and 0.33 +/- 0.23 micromol g(-1), respectively. However, for pyrene metabolites, since toxicity of pyrene metabolites was negligible, the parameters could not be estimated.
Amphipoda↗
Refinement and field validation of a biotic ligand model predicting acute copper toxicity to Daphnia magna.
A previously developed biotic ligand model (BLM) was validated for its capacity to predict acute 48-h EC(50) values of copper to Daphnia magna in 25 reconstituted media with different pH values and concentrations of artificial dissolved organic carbon, Ca, Mg and Na. Before the BLM validation, fitting of measured (with a copper ion-selective electrode) and calculated (with the BLM) Cu(2+)-activity was performed by adjusting the WHAM model V (i.e. the metal-organic speciation part of the BLM) copper-proton exchange constant to pK(MHA)=1.9. Using this value, the 48-h EC(50) values observed agreed very well with BLM-predicted EC(50) values for tests performed at pH<8, but not at all for tests performed at pH>8. Additional experiments demonstrated that this was due to toxicity of the CuCO(3) complex, which is the most abundant inorganic copper species at pH>8. This was incorporated into the initial BLM by allowing the binding of CuCO(3) (next to Cu(2+) and CuOH(+)) to the biotic ligand of D. magna. The affinity of CuOH(+) and CuCO(3) for the biotic ligand was approximately five- and 10-fold lower than that of Cu(2+), respectively. With the refined BLM, 48-h EC(50) values could be accurately predicted within a factor of two not only in all 25 reconstituted media, but also in 19 natural waters. This validated and refined BLM could support efforts to improve the ecological relevance of risk assessment procedures applied at present.
Animals↗
Monitoring of pH inhibition on microbial activity in a continuous flow reactor by pseudo toxic concentration (C(PT)) concept and time delay model.
The pseudo toxic concentration (C(PT)) concept was introduced as a quantification method to describe pH as an inhibitor concentration. In this research, the applicability of the C(PT) concept model for the detection of pH inhibitions was expanded for a continuous flow activated sludge reactor. A pilot equipped with an inhibition detection system was installed. Inhibitory wastewater was injected for 1 h and the relative activity was calculated by the maximum respiration rate. At the same time, the coefficients for the C(PT) concept model were estimated. At the dynamic conditions, the estimated relative activity by the C(PT) concept model showed time lag compared to the measured one. However, the time lag problem was successfully resolved by introducing a transfer function into the C(PT) concept model. The C(PT) concept model combined with a transfer function (C(PT) + TF model) successfully tracked the variation of the relative activity under dynamic conditions. The C(PT) + TF model could detect 50% inhibition faster than the respirometry based method by approximately 10 min. Moreover, it had additional advantages such as being inexpensive, easy to install and simple to operate. In conclusion, the C(PT) + TF model was an effective and convenient detection method of pH inhibition.
Bioreactors↗
Modeling cyanide release from nitriles: prediction of cytochrome P450 mediated acute nitrile toxicity.
A mechanism-based model for prediction of acute nitrile toxicity was developed using octanol-water partition coefficients (log P) and estimated rates of alpha-hydrogen atom abstraction as variables. Relative rates of hydrogen atom abstraction were derived from differences in heats of formation for ground-state and radical geometries and radical ionization potentials. Calculated energies of activation for all potential sites of oxidation for a given nitrile were used to estimate partitioning of metabolites among multiple oxidative pathways. logP and the resulting corrected rate constants for alpha-carbon oxidation were effective variables in an acute toxicity model of structurally diverse nitriles. The pharmacokinetics of substrate disposition is discussed in the context of multiple metabolic pathways. Structure-toxicity relationships are also discussed.
Cyanides↗
Modification of ryanodine toxicity by dantrolene and halothane in a model of malignant hyperthermia.
Ryanodine toxicity in animals has been suggested to constitute a model of malignant hyperthermia. Dantrolene is known to block the development of malignant hyperthermia triggered by halothane in susceptible swine. The authors studied the influences of dantrolene and halothane on the effects of ryanodine in vitro in isolated rat diaphragm muscle segments, and in vivo in mice, to explore the validity of this model. In the diaphragm experiments, dantrolene was found to block or delay the development of contractures produced by ryanodine and to delay the potentiation of ryanodine-induced contractures caused by halothane. In mice, ryanodine at various dosages was injected and animals surviving after one hour were examined. Such survivors appeared grossly to be normal, and may constitute a model for the malignant hyperthermia patient. They were found to be susceptible to halothane and to succinylcholine, being killed by treatment with these two agents at dosages that were not lethal to control mice. Pretreatment of mice for 48 hours with orally administered dantrolene, followed by injection of ryanodine and then halothane anesthesia, decreased the lethality of ryanodine but did not reduce the number of deaths caused by the subsequent exposure to halothane. That the effects of ryanodine in vitro and in vivo are diminished and potentiated by dantrolene and halothane, respectively, would suggest that the ryanodine toxicity model of malignant hyperthermia may have validity and is worthy of further study. A prediction from this model is that the terminal cisternae of skeletal muscle sarcoplasmic reticulum may be altered in MH.
Alkaloids↗