Animal model: Oxygen toxicity in nonhuman primates.
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Animals↗
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The role of catecholamines in cocaine toxicity: a model for cocaine "sudden death".
Sudden death associated with cocaine abuse is preceded by a state of agitated delirium. We postulated that release of catecholamines associated with this stress enhanced toxicity from cocaine. Thus we investigated the effect of catecholamine infusion [(epinephrine (7.25 ugml-1), norepinephrine (4.4 ugml-1) and dopamine (8.0 ugml-1), infused at 6 ml h-1] on the toxicity from concomitant infusion of cocaine (1 mg-kg-1 min-1). Two groups of rats were studied in order to isolate distinct toxicity endpoints: convulsions and respiratory arrest in conscious, and, circulatory arrest in anesthetized and ventilated rats. Catecholamines were administered at either full or 1/2 strength to establish a dose response effect on cocaine toxicity. Catecholamine infusion in a dose dependent fashion provoked earlier convulsions and respiratory arrest in conscious rats and circulatory arrest in anesthetized and ventilated rats. Despite lower cocaine cumulative dose administration, rats receiving catecholamines had similar plasma cocaine concentrations at the onset of convulsions and respiratory arrest compared to those with cocaine infusion alone. The data suggest that catecholamines enhance the convulsive, respiratory and circulatory toxicity of cocaine by a pharmacokinetic interaction.
Animals↗
Modeling zinc toxicity for terrestrial invertebrates.
Acute and chronic ecotoxicity tests with zinc were performed with the earthworm Eisenia fetida, the potworm Enchytraeus albidus, and the springtail Folsomia candida. To assess the influence of the soil type on zinc toxicity for these soil invertebrates, these tests were carried out in a standard artificial soil, a sandy and a loamy field soil. Based on the results of this experimental work and data taken from literature, models were developed relating the ecotoxicity of zinc to the most important parameters controlling bioavailability: pH and cation exchange capacity. Models were developed for E. fetida and F. candida using the regression technique partial least squares projection to latent structures (PLS). Acute as well as chronic toxicity data of both organisms could be normalized on the basis of the pH and the cation exchange capacity of the test soils. For other terrestrial invertebrates, not enough data were available to develop reliable models.
Animals↗
Mathematical modeling of toxicity problems in aquaria.
The identification of an actual or potential toxicity problem in an aquatic system immediately poses several questions of practical importance. Is the toxic agent still being added to the system? Where is the toxin coming from? Are the current filtration systems removing it? How soon will it be reduced to an acceptable level? How can it be removed faster? These questions in turn suggest an equally important question. What samples should be examined? Analysis of animal tissues from bioassays is the most common investigative technique in use, but alternatives do exist. Testing of water has not been utilized to its fullest potential. The need for an orderly approach to sampling and interpretation has been a major factor in this under utilization. Mathematical modeling through the use of toxicokinetics can be used to maximize the efficiency of analysis of a toxic accident by water sampling. Strategies of sampling and interpretation of results will be discussed using the tools of toxicokinetic modeling.
Kinetics↗
A rabbit model of toxic shock syndrome: clinicopathological features.
The complete pathogenesis of toxic shock syndrome (TSS) has yet to be elucidated. Unmasking the complex interactions among bacterial products, host factors, and possibly tampon components requires a suitable in vivo model. For this purpose, subcutaneous chambers implanted in rabbits were inoculated with Staphylococcus aureus isolated from patients with TSS. Infected rabbits developed illness characterised by multisystem involvement that included periportal inflammation of the liver, erythrophagocytosis in the spleen and lymph nodes as well as extreme vascular dilatation and epithelial lesions similar to those described in patients with TSS. Concentrations of serum creatinine (P less than 0.03) and triglycerides (P less than 0.04) were significantly raised in rabbits infected with TSS strains compared with rabbits infected with non-TSS strains of S. aureus. Both TSS and non-TSS strains of S. aureus produced fever and diarrhoea, but TSS strains were significantly (P less than 0.05) more lethal and more likely to produce respiratory distress and lowered blood pressure. This model may help to prove or disprove proposed mechanisms for the development of TSS.
Animals↗
[Experimental model of toxic hepatitis (author's transl].
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Animals↗
Mechanistic insight into acetylcholinesterase inhibition and acute toxicity of organophosphorus compounds: a molecular modeling study.
Acute toxicity of organophosphorus (OP) compounds results mainly from irreversible acetylcholinesterase (AChE) inhibition; however OP toxicity frequently hinges on prior biotransformations that produce toxic metabolites. To account for both precursor metabolic effects and primary AChE inhibition, we included absorption, distribution, metabolism, excretion (ADME) effects, ligand binding, and reactive AChE phosphorylation and aging in a detailed but computationally expedient phenomenological toxicity model. Ligand negative accessible surface area (NASA) was used as a generic ADME descriptor, while relevant metabolic, phosphorylation, and aging reactions were assessed via quantum chemical enthalpy calculations, and the binding affinity of the Michaelis complex was quantified via Comparative Molecular Field Analysis (CoMFA). The resulting model correlates very well (R2 = 0.90) with experimental acute toxicity measurements and provides useful mechanistic insight into the underlying toxicity. Model predictivity was validated by leave-one-out cross-validation (Q2 = 0.82). The Michaelis binding affinity descriptor has the largest weight in our model, but subsequent covalent inhibition and prior ADME effects also exhibit significant effects.
Absorption↗
Toxicity of model aliphatic amines and their chlorinated forms.
Aliphatic amines can be found in many wastewater effluents from industry, agriculture, pharmacy, and food processing. Amines can induce toxicological responses that are relevant in biochemical treatment processes, as well as in natural waters. This research compared the toxicity and inhibition caused by three aliphatic amines (n-propylamine, ethylmethylamine, and trimethylamine) and their chlorinated derivatives. The chemistry of chlorine interactions with these compounds was characterized by using membrane introduction mass spectrometry (MIMS). Acute toxicity assays were conducted by using a Microtox system with Phosphobacterium phosphoreum (also known as Vibrio fischeri) for the aliphatic amine compounds and their corresponding chlorinated derivatives, as identified by MIMS. Inhibition tests were conducted by using the oxygen utilization rate test with an enhanced nitrifier culture. The median effective concentration (EC50) values for chloropropylamine, chloroethylmethylamine, and chlorodimethylamine obtained by Microtox with a contact time of 15 min were 12.68, 19.72, and 15.92 microM, respectively. The EC50 values of these aliphatic chloramines from the Microtox test decreased by roughly one order of magnitude as a result of chlorination. Inhibition of nitrifiers also was observed in these amines. Trimethylamine and n-propylamine caused greater inhibition to nitrifiers than did ethylmethylamine under similar concentrations. Nitrifier inhibition from these amines increased after chlorination. The results of these tests indicated that aliphatic amines and their chlorinated derivatives could induce environmentally relevant toxicity responses in treatment settings and in receiving waters.
Amines↗
Development of streptococcal pyrogenic exotoxin C vaccine toxoids that are protective in the rabbit model of toxic shock syndrome.
Streptococcal pyrogenic exotoxin C (SPE C) is a superantigen produced by many strains of Streptococcus pyogenes that (along with streptococcal pyrogenic exotoxin A) is highly associated with streptococcal toxic shock syndrome (STSS) and other invasive streptococcal diseases. Based on the three-dimensional structure of SPE C, solvent-exposed residues predicted to be important for binding to the TCR or the MHC class II molecule, or important for dimerization, were generated. Based on decreased mitogenic activity of various single-site mutants, the double-site mutant Y15A/N38D and the triple-site mutant Y15A/H35A/N38D were constructed and analyzed for superantigenicity, toxicity (lethality), immunogenicity, and the ability to protect against wild-type SPE C-induced STSS. The Y15A/N38D and Y15A/H35A/N38D mutants were nonmitogenic for rabbit splenocytes and human PBMCs and nonlethal in two rabbit models of STSS, yet both mutants were highly immunogenic. Animals vaccinated with the Y15A/N38D or Y15A/H35A/N38D toxoids were protected from challenge with wild-type SPE C. Collectively, these data indicate that the Y15A/N38D and Y15A/H35A/N38D mutants may be useful as toxoid vaccine candidates.
Animals↗
Potentiation of the toxicity of model hepatotoxicants by acetaminophen.
A 24-hr oral pretreatment of rats with 1.6 g/kg acetaminophen potentiated hepatotoxicity of allyl alcohol, bromobenzene, carbon tetrachloride, 1,1-dichloroethylene, and thioacetamide, as assessed by elevation of serum alanine aminotransferase activity and histopathological examination. Doses, of these hepatotoxicants, which did not cause hepatocellular necrosis, became necrogenic after acetaminophen pretreatment with all toxicants except thioacetamide. Acetaminophen pretreatment did not decrease the threshold dose of toxicity for thioacetamide but did accentuate hepatotoxic doses. Acetaminophen pretreatment potentiated lethality of allyl alcohol and 1,1-dichloroethylene. Upon necropsy, these rats had congested livers and appeared to suffer from hypovolemic shock. We conclude that while acetaminophen was not necrogenic at the doses used in this study, it produced alterations that make hepatocytes much more susceptible to hepatotoxic insult.
1-Propanol↗
A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury.
BACKGROUND: Several studies have demonstrated that bone marrow contains a subpopulation of stem cells capable of participating in the hepatic regenerative process, even if some reports indicate quite a low level of liver repopulation by human stem cells in the normal and transiently injured liver. AIMS: In order to overcome the low engraftment levels seen in previous models, we tried the direct intraperitoneal administration of human cord blood stem cells, using a model of hepatic damage induced by allyl alcohol in NOD/SCID mice. METHODS: We designed a protocol based on stem cell infusion following liver damage in the absence of irradiation. Flow cytometry, histology, immunohistochemistry and RT-PCR for human hepatic markers were performed to monitor human cell engraftment. RESULTS: Human stem cells were able to transdifferentiate into hepatocytes, to improve liver regeneration after damage and to reduce the mortality rate both in both protocols, even if with qualitative and quantitative differences in the transdifferentiation process. CONCLUSIONS: We demonstrated for the first time that the intraperitoneal administration of stem cells can guarantee a rapid liver engraftment. Moreover, the new protocol based on stem cell infusion following liver damage in the absence of irradiation may represent a step forward for the clinical application of stem cell transplantation.
Animals↗
[A comparative evaluation of the effect of different types of sapropel on dynamic liver function in intact rats and in the modelling of toxic hepatitis].
A course of silicic sapropel applications compared to calcareous sapropel induced a reversible fall of total lipid concentration in blood serum of intact rats. Sapropels of different kinds and of the same kind but obtained from different depths of the same deposit varied by their ability to correct hepatic function in rats with toxic hepatitis. The highest benefit was registered in application of carbonate sapropels taken from the depth of 1.5-2.5 m.
Animals↗
Behaviour of oligodendrocytes and Schwann cells in an experimental model of toxic demyelination of the central nervous system.
Oligodendrocytes and Schwann cells are engaged in myelin production, maintenance and repairing respectively in the central nervous system (CNS) and the peripheral nervous system (PNS). Whereas oligodendrocytes act only within the CNS, Schwann cells are able to invade the CNS in order to make new myelin sheaths around demyelinated axons. Both cells have some limitations in their activities, i.e. oligodendrocytes are post-mitotic cells and Schwann cells only get into the CNS in the absence of astrocytes. Ethidium bromide (EB) is a gliotoxic chemical that when injected locally within the CNS, induce demyelination. In the EB model of demyelination, glial cells are destroyed early after intoxication and Schwann cells are free to approach the naked central axons. In normal Wistar rats, regeneration of lost myelin sheaths can be achieved as early as thirteen days after intoxication; in Wistar rats immunosuppressed with cyclophosphamide the process is delayed and in rats administered cyclosporine it may be accelerated. Aiming the enlightening of those complex processes, all events concerning the myelinating cells in an experimental model are herein presented and discussed.
Animals↗
[Cytoprotective effect of antihypoxic and antioxidant preparations on cultured human cells in a model of toxic response].
An oxidative stress is considered to be one of the major mechanisms of cytotoxicity. The purpose of present work was to study effects of some drugs with antihypoxic/antioxidant activity in cultured human lung embryonic fibroblasts under conditions of cytotoxic response, provoked by cationic or anionic antiseptics. The following preparations were under study: Mafusol (Na-fumarate), superoxide dismutase from human erythrocytes (SOD), cytochrome c, alpha-tocopherol and Thioctacid T (lipoate) which were applied at concentrations comparable with those, employed in clinical application. The combinations of the used drugs were also under study. The cytotoxic response was induced by an application of antiseptics into the cell incubation medium in 2-5 fold dilutions up to minimum toxic doses for 2-24 h. The drugs under study were introduced simultaneously with antiseptics. The maximum cytoprotective effect was revealed in the case of combination fumarate-alpha-tocopherol; the combination fumarate plus SOD being the second in effectiveness. When the drugs were introduced separately, the most effective proved to be fumarate, followed by vitamin E and cytochrome c. SOD and lipoate did not reveal any cytoprotective activity in our experimental conditions. The designed model of cytotoxicity in vitro can be considered as a prospective test-system for the screening of cytoprotective drugs and their combinations.
Antioxidants↗
Landscape of current toxicity databases and database standards.
Having readily available historical information for modeling toxicity has become important throughout the various stages of research and development. The high cost of late-phase attrition and recent international regulatory legislations have made even more acute the need to be able to mine the fragmented data and information available across diverse databases. In addition, the general trend to accelerate regulatory processes globally makes the effective use of existing data an imperative. To achieve efficient screening, develop profiles and gain the ability to cross reference, databases must be interoperated to allow data exchange and integration. Several database standards and controlled vocabulary initiatives have been used in the development of toxicity data models to transform the current landscape. This review describes the major databases of toxicological information now available, and provides a simple example of standardization that demonstrates the benefits of a toxicity database containing such qualified data.
Animals↗
Crystal structure of a colicin N fragment suggests a model for toxicity.
BACKGROUND: Pore-forming colicins are water-soluble bacteriocins capable of binding to and translocating through the Escherichia coli cell envelope. They then undergo a transition to a transmembrane ion channel in the cytoplasmic membrane leading to bacterial death. Colicin N is the smallest pore-forming colicin known to date (40 kDa instead of the more usual 60 kDa) and the crystal structure of its membrane receptor, the porin OmpF, is already known. Structural knowledge of colicin N is therefore important for a molecular understanding of colicin toxicity and is relevant to toxic mechanisms in general. RESULTS: The crystal structure of colicin N reveals a novel receptor-binding domain containing a six-stranded antiparallel beta sheet wrapped around the 63 A long N-terminal alpha helix of the pore-forming domain. The pore-forming domain adopts a ten alpha-helix bundle that has been observed previously in the pore-forming domains of colicin A, la and E1. The translocation domain, however, does not appear to adopt any regular structure. Models for receptor binding and translocation through the outer membrane are proposed based on the structure and biochemical data. CONCLUSIONS: The colicin N-ompF system is now the structurally best-defined translocation pathway. Knowledge of the colicin N structure, coupled with the structure of its receptor, OmpF, and previously published biochemical data, limits the numerous possibilities of translocation and leads to a model in which the translocation domain inserts itself through the porin pore, the receptor-binding domain stays outside and the pore-forming domain translocates along the outer wall of the trimeric porin channel.
Binding Sites↗
Human primary renal cells as a model for toxicity assessment of chemo-therapeutic drugs.
Chemo-therapeutic drugs act on cancerous and normal cells non-selectively and often cause organ impairments during treatment. Improving safety or reducing toxicity becomes an important challenge for developing better anticancer drugs. In the present study, effects of selected anticancer drugs (camptothecin, doxorubicin, colchicine, paclitaxel, cisplatin, and carboplatin) on cell viability and proliferation was investigated. The anti-proliferative activity of each drug on cancer cells (human hepatoma HepG2) and human primary renal proximal tubule cells (hRPTECs and LLC-PK1) was determined with the [(3)H]thymidine incorporation assay. Results indicated all six drugs blocked cell proliferation in cancer and normal cells. When the anti-proliferation potency was ranked in hRPTECs based on EC50 values, camptothecin is the most potent, followed by doxorubicin, paclitaxel, colchicine, cisplatin and carboplatin. Cytotoxicity of drugs to hRPTECs was assessed with the ATP bioluminescence assay. Doxorubicin and cisplatin were known to induce nephrotoxicity in vivo and they were indeed cytotoxic to hRPTECs in our study with EC50 values at 11.2 and 39.6 microM. All other drugs are not cytotoxic in the concentrations tested. These drugs typically displayed separation of EC50s between potency (anti-proliferation) and cytotoxicity. The dose separation provides a concentration range for each drug to act on cell proliferation without induction of significant cytotoxicity. Our results suggest that hRPTEC system can serve as an in vitro model for assessing potential nephrotoxicity of chemo-therapeutic drugs.
Antineoplastic Agents↗
Aminoimidazole carboxamide ribonucleoside toxicity: a model for study of pyrimidine starvation.
Aminoimidazole carboxamide ribonucleoside (AIC-R), a purine precursor, has biphasic effects on the growth of Chinese hamster fibroblasts. At 200 microM AIC-R cell growth is almost completely arrested, while at 50 and 700 microM AIC-R cell growth is comparable to that observed in the absence of nucleoside. The growth inhibition produced by AIC-R is the consequence of inhibition of the orotate phosphoribosyltransferase-orotidylic decarboxylase (OPRT-ODC) reactions, as evidenced by a 87% reduction in the intracellular concentrations of UTP and CTP, accumulation of orotate in the medium, and restoration of normal growth by inclusion of 100 microM uridine in the medium. Inhibition of pyrimidine nucleotide synthesis at 200 microM AIC-R is associated with an 82% reduction in the intracellular concentration of PP-ribose-P and a 150% increase in the concentration of purine nucleotides. Restoration of cell growth to a normal rate at 700 microM AIC-R--a condition under which PP-ribose-P remains depressed and purine nucleotide concentrations are also depressed (40% of control)--and absence of toxicity at 50 microM AIC-R--a condition under which purine nucleotide concentrations are increased by 150% and PP-ribose-P concentration is normal--suggest that the inhibition of OPRT-ODC observed at 200 microM AIC-R is caused by the combination of the reduction in PP-ribose-P and increase in purine nucleotides. These studies provide a better understanding of the control of the OPRT-ODC reactions in the cell and provide additional insight into the basis of pyrimidine starvation induced by purine nucleosides.
Aminoimidazole Carboxamide↗