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PubMed1999

Structure-toxicity relationships for benzenes evaluated with Tetrahymena pyriformis.

Toxicity data for 200 substituted benzenes tested in the two-day Tetrahymena pyriformis population growth impairment assay representing the neutral narcosis, polar narcosis, respiratory uncoupling, and weak and strong electrophilic mechanisms of toxic action were evaluated. A quantitative structure-toxicity model correlating toxic potency [log(IGC(50)(-)(1))] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log K(ow)) and electrophilic reactivity quantified by the molecular orbital parameter, maximum superdelocalizability (S(max)), was developed. This model [log(IGC(50)(-)(1)) = 0.50(log K(ow)) + 9.85(S(max)) - 3.47; n = 197, r(2) = 0.816, s = 0.34, F = 429, Pr > F = 0.0001] allows for the prediction of acute potency without the a priori identification of the mechanism of action. The examination of residuals reveals that neutral narcotics with high volatility (e.g., methyl- and chloro-substituted benzenes) and highly reactive fluoro- and nitro-containing derivatives are fitted poorly. A comparison of observed (obs) and predicted (pred) toxicities on the additional set of derivatives [log(obs IGC(50)(-)(1)) = 1.05[log(pred IGC(50)(-)(1))] + 0.02; n = 20, r(2) = 0.979, s = 0.13, F = 825, Pr > F = 0.0001] validated the model as a good predictor of toxicity regardless of the mechanism of toxic action.

Animals↗
PubMed2002

Structure-toxicity relationships for aliphatic chemicals evaluated with Tetrahymena pyriformis.

Quantitative structure-activity relationships were developed for the toxicity data of 500 aliphatic chemicals tested in the two-day Tetrahymena pyriformis population growth impairment assay. These chemicals represented a number of structural classes spanning a variety of mechanisms of toxic action including narcoses and electrophilic mechanisms. A series of quantitative structure-toxicity models correlating toxic potency [log(IGC(50)(-1))] with a limited number of mechanistically interpretable descriptors were developed for toxicological domains within the data set. The descriptors included the 1-octanol/water partition coefficient (log K(ow)) (for hydrophobicity) and the energy of the lowest unoccupied molecular orbital (E(lumo)) to quantify electrophilic reactivity. Neutral (nonpolar) narcosis was well modeled by the equation [log(IGC(50)(-1)) = 0.723(0.140) (log K(ow)) - 1.79(0.031); n = 215, r(2) (adj.) = 0.926, s = 0.274, r(2) (pred.) = 0.925]. Chemical classes fitting this domain included saturated alcohols, ketones, nitriles, esters, and sulfur-containing compounds. When the neutral narcotic chemicals were combined with diester narcotics, carboxylic sodium salts, Schiff-based forming aldehydes, electrophilic compounds capable of acting by a S(N)2 mechanism, and proelectrophiles, the model [log(IGC(50)(-1)) = 0.45(0.014) (log K(ow)) - 0.342 (0.035) (E(lumo)) - 1.11(0.05); n = 353, r(2) (adj.) = 0.859, s = 0.353, r(2) (pred.) = 0.857] provided a good fit to the data. The model [log(IGC(50)(-1)) = 0.273(0.018) (log K(ow)) - 0.116(0.056) (E(lumo)) - 0.558(0.054); n = 35, r(2) (adj.) = 0.873, s = 0.141, r(2) (pred.) = 0.838] provided an excellent fit of the data for compounds containing a carboxyl [RC(=O)O] group. The toxicity of aliphatic amines [RCN] was modeled by the equation [log(IGC(50)(-1)) = 0.676(0.048) (log K(ow)) - 1.23(0.08) n = 30, r(2) (adj.) = 0.873, s = 0. 336, r(2) (pred.) = 0.848]. The potency of saturated aliphatic isothiocyanates was a constant (0.0202 mM). Aliphatic chemicals that did not model well by equations involving log K(ow) and E(lumo) included amino alcohols and alpha-haloactivated compounds.

Animals↗
PubMed2002

Modeling the toxicity of polar and nonpolar narcotic compounds to luminescent bacterium Shk1.

Luminescent bacterium Shk1 was created for the purpose of testing and screening the toxicity of activated sludge wastewater treatment plant influent to avoid toxic shock to the wastewater treatment plant microorganisms. The toxicity of a number of organic compounds was tested using an assay employing Shk1. Because these compounds exhibit toxicity by mechanisms of both polar and nonpolar narcosis, their toxicity cannot be properly modeled together using a quantitative structure-activity relationship model based on the logarithm of the octanol-water partition coefficient (log K(ow)). A solvation parameter model was developed to describe and predict the nonspecific (i.e., polar and nonpolar narcosis) toxicity of organic compounds to Shk1, which does not depend on the discrimination between polar and nonpolar narcotic compounds. The statistically significant model descriptors were the McGowan's characteristic volume (V(x)) and the hydrogen-bond basicity (sigmabetaH). The model was similar to the solvation parameter model developed for Vibrio fischeri, but it did not include an excess molar refraction (R) term.

Hydrogen Bonding↗
PubMed1987

A rabbit model of toxic shock syndrome that uses a constant, subcutaneous infusion of toxic shock syndrome toxin 1.

We have developed a rabbit model of toxic shock syndrome that uses a subcutaneous infusion pump to administer toxic shock syndrome toxin 1 (TSST-1). A dose of 150 micrograms, infused at a constant rate over a period of 7 days, resulted in a characteristic illness highlighted by fever, conjunctival hyperemia, cachexia, and lethargy. The illness was uniformly fatal, with a mean interval until death of 3.2 +/- 0.4 days. Serial determinations of serum chemistries confirmed the multisystem nature of this illness. Rabbits developed profound hypocalcemia, with levels falling from 15.5 +/- 0.2 to 7.6 +/- 0.4 mg/dl under the influence of TSST-1. Blood urea nitrogen and creatinine rose dramatically, in the setting of oliguria or anuria. Serum glutamicpyruvic transaminase was the most reliable indicator of hepatic dysfunction, with the mean rising from 48 U/liter before administration of TSST-1 to 546 U/liter among rabbits surviving 2 days of the infusion. Creatine phosphokinase also rose dramatically in 10 of 16 rabbits. Rabbits demonstrated relative neutrophilia and lymphopenia as well as an increase in the partial thromboplastin time. Histopathologic examination demonstrated disease of multiple organs, particularly the liver, spleen, and lymph nodes, all of which demonstrated inflammation, thrombosis, hemorrhage, and erythrophagocytosis. The concurrent administration of prednisolone with TSST-1 prevented death in four of four rabbits and greatly lessened the morbidity. Rabbits were not protected from morbidity or mortality by the concurrent administration of polymyxin B. We believe that a constant, subcutaneous infusion of TSST-1 in rabbits provides a reproducible model for studying the pathogenesis of TSS.

Adrenal Cortex Hormones↗
PubMed2006

Development of a multi-component Damage Assessment Model (MDAM) for time-dependent mixture toxicity with toxicokinetic interactions.

A new mixture toxicity model was developed to predict the time-dependent toxicity of a mixture with toxicokinetic interactions directed specifically toward addressing biotransformation. The Damage Assessment Model (DAM), a toxicokinetic-toxicodynamic model that describes and predicts the time-dependent toxicity of a single compound, was extended to a multicomponent model for mixture toxicity. The model assumes that cumulative damage from the parent compound, metabolites, and/or a biotransformation inhibitor are additive, and the sum of the cumulative damage determines mixture toxicity. Since incorporation of the damage addition hypothesis into the DAM was equivalent to an independent action model for mixture toxicity, it was applied to describe the combined effect of mixture components with potentially dissimilar modes of action. From the multicomponent DAM, a time-dependent toxic unit model was derived and applied to determine the toxic units of mixture components. This model suggests a series of experimental designs required to assess the role of biotransformation in the toxicity of metabolized organic compounds and a data analysis method to separately estimate toxicodynamic parameters forthe parent compound and metabolites.

Animals↗
PubMed1989

Quantification and toxicity of group A streptococcal pyrogenic exotoxins in an animal model of toxic shock syndrome-like illness.

Toxic shock-like syndrome isolates of group A streptococci were evaluated for production of pyrogenic exotoxins (also called SPEs, scarlet fever toxins, and erythrogenic toxins). The isolates were consecutively obtained during 1987 and 1988. Of these isolates, 23 of 26 made SPE type A, 10 of 26 made SPE B, and 8 of 26 made SPE C. SPE A was produced in significantly greater amounts than SPEs B and C (3.2 micrograms/ml of culture fluid compared with 0.7 and 0.6 microgram/ml, respectively). SPE A, administered in miniosmotic pumps implanted subcutaneously in rabbits, was significantly more toxic than SPE C; seven of eight rabbits succumbed after challenge with 150 or 300 micrograms of SPE A, compared with one of six after challenge with SPE C.

Animals↗
PubMed1993

Toxicity of recombinant toxic shock syndrome toxin 1 and mutant toxins produced by Staphylococcus aureus in a rabbit infection model of toxic shock syndrome.

Menstrually associated toxic shock syndrome (TSS) is attributed primarily to the effects of staphylococcal exotoxin toxic shock syndrome toxin 1 (TSST-1). A region of the 194-amino-acid toxin spanning residues 115 through 144 constitutes a biologically active site. Several point mutations in the TSST-1 gene in that region result in gene products with reduced mitogenic activity for murine T cells. In this study we evaluated the toxicity of recombinant TSST-1 and several mutants of TSST-1 made by transformed Staphylococcus aureus during in vivo growth in a rabbit infection model of TSS. The toxicities of the transformed strains of S. aureus for rabbits correlated with the mitogenic activities of the recombinant toxins. An isolate originally obtained from a patient with a confirmed case of TSS (S. aureus 587) implanted in a subcutaneous chamber served as a positive control. TSST-1 produced in vivo led to lethal shock within 48 h, and a TSST-1-neutralizing antibody (monoclonal antibody 8-5-7) administered to rabbits challenged with S. aureus 587 prevented fatal illness. Rabbits infected with transformed S. aureus RN4220 expressing wild-type toxin (p17) or mutant toxins retaining mitogenic activity for T cells succumbed within a similar time frame. Blood chemistries of samples obtained from infected animals before death indicated abnormalities in renal and hepatic functions similar to those induced by parenteral injection of purified staphylococcal TSST-1. Mutant toxin 135 (histidine modified to alanine at residue 135) possessed only 5 to 10% of the mitogenic activity of wild-type toxin. Rabbits challenged with transformed S. aureus RN4220 expressing mutant toxin 135 exhibited only mild transient illness. Mutant toxin 135 retained reactivity with monoclonal antibody 8-5-7 and by several criteria was conformationally intact. Toxin from a double mutant, 141.144, with alanine substitutions at residues 141 (histidine) and 144 (tyrosine), also was devoid of mitogenic activity. In this case, antibody recognition was lost. Mutant toxins 115 and 141 were found to possess approximately half-maximal mitogenic activity. Rabbits challenged with S. aureus RN4220 expressing either 115 or 141 toxin succumbed to lethal shock. We conclude that the ability of TSST-1 to activate murine T cells in vitro and its expression of toxicity leading to lethal shock in rabbits are related phenomena.

Animals↗
PubMedDate not supplied

A two-dimensional model for simulating the transport and fate of toxic chemicals in a stratified reservoir.

A two-dimensional reservoir toxics model is essential to establishing effective water resources management and protection. In a reservoir, the fate of a toxic chemical is closely connected with flow regimes and circulation patterns. To better understand the kinetic processes and persistence and predict the dissipation of toxic contaminants in the reservoir during a spill or storm runoff event, a toxics submodel was developed and incorporated into an existing laterally integrated hydrodynamics and transport model. The toxics submodel describes the physical, chemical, and biological processes and predicts unsteady vertical and longitudinal distributions of a toxic chemical. The two-dimensional toxicant simulation model was applied to Shasta Reservoir in California to simulate the physico-chemical processes and fate of a volatile toxic compound, methyl isothiocyanate (MITC), during a chemical spill into the Sacramento River in 1991. The predicted MITC concentrations were compared with those observed. The effect of reservoir flow regimes on the transport and fate of the toxic substance was investigated. The results suggested that the persistence of MITC is significantly influenced by different flow regimes. Methyl isothiocyanate is more persistent in the reservoir under an interflow condition due to reduced volatilization from deep layers than under an overflow condition. In the overflow situation, the plume moved more slowly toward the dam and experienced greater dissipation. This analysis can assist in toxic spill control and reservoir management, including field sampling and closure of water intakes.

Forecasting↗
PubMed1998

Oxidative toxicity in models of neurodegeneration: responses to melatonin.

In this brief review the antioxidative actions of melatonin are summarized and they are discussed relative to several models of oxidative neurotoxicity. Melatonin is a ubiquitously acting antioxidant. It has been shown to scavenge the hydroxyl radical, peroxyl radical, singlet oxygen and the peroxynitrite anion; secondarily, it also scavenges the superoxide anion radical. In addition, melatonin reportedly stimulates a number of antioxidative enzymes including glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. On the other hand, melatonin inhibits the pro-oxidative enzyme nitric oxide synthase. Besides these actions which help to resist oxidative damage, melatonin prevents membrane rigidity, reduces polymorphonuclear cell infiltration into damaged tissue, limits the adhesion of leucocytes to endothelial cells, thereby increasing blood flow and reducing edema. Some or all of these actions may have been operative in the experimental models of oxidative neurotoxicity that were improved by melatonin treatment. In brief, melatonin has been found to protect the CNS from beta-amyloid toxicity, experimental models of Parkinsonism, excitotoxicity, nitric oxide toxicity, aminolevulinic acid, lipopolysaccharide, hyperbaric hyperoxia, L-cysteine, cyanide and ischemia/reperfusion injury.

Journal Article↗
PubMed1994

Mathematical model of toxicity monitoring sensors incorporating microbial whole cells.

A model is presented that describes aspects of the transient and steady-state behaviour of toxicity monitoring biosensors that incorporate living microbial cells immobilized in a thin layer between an amperometric electrode and a porous (non-tortuous) membrane. In the example considered here, respiratory or photosynthetic electron-transport activity is monitored by using artificial redox mediators to divert electrons from the electron-transport systems to the working electrode poised at a suitable reducing potential. Such biosensors are being developed for a range of environmental monitoring applications. The mathematical model is used to demonstrate how the response of practical devices can be manipulated and to indicate potential pitfalls in the interpretation of toxicity assessment data derived by such biosensors.

Biosensing Techniques↗
PubMed1998

Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity.

Model cell lines developed from MCF7 breast carcinoma cells were used to examine the roles of glutathione S-transferase P1-1 (GSTP1-1) and multidrug resistance protein (MRP) in the protection of cells from 4-nitroquinoline 1-oxide (4NQO) toxicities. Increased expression of GSTP1-1 alone in MCF7 cells results in limited protection from the formation of 4NQO-derived covalent adducts of nucleic acids but affords no protection from 4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formation and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO-SG) conjugate formation and a MRP-dependent increase in QO-SG efflux. These data indicate that MRP is an important export transporter for the glutathione conjugate of the carcinogen, 4NQO. Moreover, this MRP-dependent efflux activity is necessary to achieve the full protection from 4NQO toxicity-protection that is potentiated by GSTP1-1-mediated QO-SG formation.

4-Nitroquinoline-1-oxide↗
PubMedDate not supplied

Tumor models: assessing toxicity in efficacy studies.

Efficacy studies in animal tumor models provide an early opportunity to collect preliminary information on toxicity. When screening and evaluating cytotoxic chemotherapeutic agents, efficacy studies usually include at least 1 dosage level that causes severe toxicity and death. Pathologic evaluation in early efficacy studies may reveal major target organs, dosage/schedule relationships, pharmacokinetic/toxicity relationships, effects of formulation and route of administration, maximum tolerated dose, cause of death, and reversibility of changes in normal tissues. Intraperitoneal formulations are frequently used to establish proof of concept for promising compounds (hits) from in vitro screens; however, these crude formulations may also induce intraperitoneal inflammation and confound the interpretation of both efficacy and toxicity. Efficacy studies conducted in the later stages of drug discovery may be used to refine the dose and schedule proposed for phase I clinical trials. Efficacy studies in animal tumor models provide useful toxicologic data for screening potential drug candidates, optimizing the therapeutic index, and designing both preclinical and clinical development programs.

Animals↗
PubMed2006

Changes of the hepatic proteome in murine models for toxically induced fibrogenesis and sclerosing cholangitis.

We investigated the changes in the hepatic proteome in murine models for toxic-induced fibrogenesis and sclerosing cholangitis. A comprehensive comparison of protein changes observed is made and the mechanistical basis of the expression changes is discussed. Hepatic fibrosis was induced by repetitive intraperitoneal CCl4 treatment of BALB/c mice or developed spontaneously in BALB/c-ATP-binding cassette, subfamily B, member 4 (Abcb4) knock out mice. Fibrosis was verified by a morphometric score and assessment of hydroxyproline content of liver tissue, respectively. The innovative difference in-gel electrophoresis (DIGE) technique was used to analyse protein expression levels of the mouse proteome. Results were confirmed by Western blotting and real-time RT-PCR. In CCl4-induced fibrosis 20 out of 40 and in BALB/c-Abcb4(-/-) mice 8 out of 28 differentially expressed proteins were identified utilizing DIGE. Only two proteins, selenium-binding protein (Sbp2) and carbonic anhydrase 3, have been unidirectionally expressed (i.e. down-regulated) in both models. Relevant differences in the pathogenesis of toxically induced liver fibrosis and sclerosing cholangitis exist. The only novel protein with regard to liver fibrosis depicting a unidirectional expression pattern in both animal models was Sbp2. An explicit protein function could not be clarified yet.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Optimizing drug regimens in cancer chemotherapy by an efficacy-toxicity mathematical model.

In cancer chemotherapy, it is important to design treatment strategies that ensure a desired rate of tumor cell kill without unacceptable toxicity. To optimize treatment, we used a mathematical model describing the pharmacokinetics of anticancer drugs, antitumor efficacy, and drug toxicity. This model was associated with constraints on the allowed plasma concentrations, drug exposure, and leukopenia. Given a schedule of drug administrations, the mathematical model optimized the drug doses that can minimize the tumor burden while limiting toxicity at the level of the white blood cells. The main result is that the optimal drug administration is an initial high-dose chemotherapy up to saturation of constraints associated with normal cell toxicity and a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were used in a feasibility study. Simulations with the optimized protocol showed better performances than usual clinical protocols. Model-based optimal drug doses provide for greater cytoreduction, while limiting the risk of unacceptable toxicity.

Antineoplastic Agents↗
PubMed1991

Validation of a toxicity testing model by evaluating oxygen supply and energy state in the isolated perfused rat kidney. Single-pass preparation without albumin.

Validation of a toxicity testing model concerning energy metabolism was attempted by evaluating the oxygen supply and energy state in an isolated perfused rat kidney of single-pass preparation without albumin. Perfusion was performed at a temperature of 31 degrees C, flow rate of 11.0 mL/g/min, and pressure of 81-104 mmHg. The perfusate was saturated with 95% O2/5% CO2. After preperfusion for 30 min, the redox states of cytochrome aa3 and c and pyridine nucleotides (PN) in the perfused kidney were measured to be stable for 90 min by a scanning reflectance spectrophotometry and surface fluorometry, respectively. During the same period, the contents of ATP and inorganic phosphate (Pi) in the perfused kidney were also measured to be stable by 31P-NMR spectroscopy. The oxygen supply to the cell was more than the amount required for the basal metabolism of the cell. For assessment of the effects of chemical agents on the renal cell metabolism, this preparation of the perfused rat kidney was considered to have several advantages, despite some of its inherent limitations in the function of the kidney.

Adenosine Triphosphate↗
PubMed2006

From organisms to populations: modeling aquatic toxicity data across two levels of biological organization.

A critical step in estimating the ecological effects of a toxicant is extrapolating organism-level response data across higher levels of biological organization. In the present study, the organism-to-population link is made for the mysid, Americamysis bahia, exposed to a range of concentrations of six toxicants. Organism-level responses observed were categorized as no effect, delayed reproduction, reduced overall reproduction, or both reduced overall reproduction and survival. Population multiplication rates of each toxicant concentration were obtained from matrix models developed from organism-level endpoints and placed into the four categories of organism-level responses. Rates within each category were compared with growth rates modeled for control populations. Population multiplication rates were significantly less than control growth rates only for concentrations at which overall reproduction and both reproduction and survival were significantly less than the control values on the organism level. Decomposition analysis of the significant population-level effects identified reduced reproduction as the primary contributor to a reduced population multiplication rate at all sublethal concentrations and most lethal concentrations. Mortality was the primary contributor to reduced population growth rate only when survival was less than 25% of control survival. These results suggest the importance of altered reproduction in population-level risk assessment and emphasizes the need for complete life-cycle test data to make an explicit link between the organism and population levels.

Animals↗
PubMedDate not supplied

A quantitative structure-toxicity relationships model for the dermal sensitization guinea pig maximization assay.

We have developed quantitative structure-toxicity relationship (QSTR) models for assessing dermal sensitization using guinea pig maximization test (GPMT) results. The models are derived from 315 carefully evaluated chemicals. There are two models, one for aromatics (excluding one-benzene-ring compounds), and the other for aliphatics and one-benzene-ring compounds. For sensitizers, the models can resolve whether they are weak/moderate or severe sensitizers. The statistical methodology, based on linear discriminant analysis, incorporates an optimum prediction space (OPS) algorithm. This algorithm ensures that the QSTR model will be used only to make predictions on query structures which fall within its domain. Calculation of the similarities between a query structure and the database compounds from which the applicable model was developed are used to validate each skin sensitization assessment. The cross-validated specificity of the equations ranges between 81 and 91%, and the sensitivity between 85 and 95%. For an independent test set, specificity is 79%, and sensitivity 82%.

Administration, Topical↗