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PubMedDate not supplied

Potentiation of inhaled staphylococcal enterotoxin B-induced toxicity by lipopolysaccharide in mice.

Nonhuman primates are the established model for evaluating toxic responses to staphylococcal enterotoxins (SEs), as they react similarly to humans. Rodents are generally considered unresponsive to SEs. Binding affinities and T-cell reactivity suggest that SE binds more efficiently to primate major histocompatability complex class II receptors than to mouse receptors. We investigated the potentiation of staphylococcal enterotoxin B (SEB) inhalation toxicity by lipopolysaccharide (LPS) in BALB/c mice. Lethality occurred only when SEB was potentiated by LPS. Neither SEB nor LPS produced lethal effects alone. Temporal responses of interleukin 1 alpha, tumor necrosis factor alpha, interleukin 2, and interferon-gamma evoked by inhaled SEB were enhanced by LPS. By 24 hr after intoxication, serum cytokines decreased to baseline levels, and consistent pulmonary perivascular leukocytic infiltrates were evident histologically. Histologic lesions induced by inhalation exposure to SEB by mice, with or without potentiation by LPS, were similar to those in the rhesus monkey. Predominant pulmonary lesions included severe, diffuse interstitial and alveolar pulmonary edema, leukocytic infiltrates, mild perivascular edema, and alveolar fibrin deposition. Although the mechanism of aerosolized SEB-induced toxicity has not been completely resolved, similarities in histologic lesions, cytokine responses, and acute dose-response suggest the LPS-potentiated mouse model may be a credible alternative to the nonhuman primate model.

Animals↗
PubMed2001

A mathematical model of the kinetics of beta-amyloid fibril growth from the denatured state.

Spontaneous conversion of beta-amyloid peptide (Abeta) from soluble monomer to insoluble fibril may underlie the neurodegeneration associated with Alzheimer's disease. A complete description of Abeta self-association kinetics requires identification of the oligomeric species present and the pathway of association, as well as quantitation of rate constants and reaction order. Abeta was rendered monomeric and denatured by dissolution in 8 M urea, pH 10. "Refolding" and fibrillization were initiated by rapid dilution into phosphate-buffered saline, pH 7.4. The kinetics of growth were followed at three different concentrations, using size exclusion chromatography, dynamic light scattering, and static light scattering. A multi-step pathway for fibril formation and growth was postulated. This pathway included 1) rapid commitment to either stable monomer/dimer or unstable intermediate, 2) cooperative association of intermediate into a multimeric "nucleus," 3) elongation of the "nucleus" into filaments via addition of intermediate, 4) lateral aggregation of filaments into fibrils, and 5) fibril elongation via end-to-end association. Differential and algebraic equations describing this kinetic pathway were derived, and model parameters were determined by fitting the data. The utility of the model for identifying toxic Abeta oligomeric specie(s) is demonstrated. The model should prove useful for designing compounds that inhibit Abeta aggregation and/or toxicity.

Amyloid beta-Peptides↗
PubMed1994

Acute subdural hematoma: is the blood itself toxic?

Recently developed rodent models of acute subdural hematoma have shown an associated large area of infarction underlying the clot. Excitotoxic processes have been postulated to play an important role in the extensive cell death seen with these models. However, whether increased pressure, vasoactive effects, or toxicity of the blood itself is responsible for initiating or sustaining these processes remains unclear. To study the effect of blood itself, an opaque layer of autologous clot was placed on the widely exposed parietal cortex of 15 Long-Evans rats and left in place for 72 h. In control animals the cortical surface was exposed but no blood was placed and contact with blood products was carefully limited. These animals were compared to a group in whom blood was injected into the closed subdural space. Histologic analysis showed that the majority of the cortex in both control and experimental animals in the open cranial model group appeared normal. Scattered small, discrete hemorrhagic lesions on the cortical surface of both control and experimental animals were seen, which had the appearance of focal mechanical trauma or vessel avulsion. There was no significant difference in average volume of lesions between experimental and control animals (9.1 versus 9.7 mm3, p = 0.85). No areas of infarction or selective neuronal loss were seen. In comparison, animals in which blood was injected into the subdural space had significantly larger lesions underlying clot, averaging 133.6 mm3 in volume (p < 0.0003). Blood in prolonged contact with the cortical surface in the absence of increased pressure, ischemia, or other insult is insufficient to cause underlying infarction like that seen when a similar volume of blood is injected into the closed subdural space.

Animals↗
PubMed2005

Predicting sediment metal toxicity using a sediment biotic ligand model: methodology and initial application.

An extension of the simultaneously extracted metals/acid-volatile sulfide (SEM/AVS) procedure is presented that predicts the acute and chronic sediment metals effects concentrations. A biotic ligand model (BLM) and a pore water-sediment partitioning model are used to predict the sediment concentration that is in equilibrium with the biotic ligand effects concentration. This initial application considers only partitioning to sediment particulate organic carbon. This procedure bypasses the need to compute the details of the pore-water chemistry. Remarkably, the median lethal concentration on a sediment organic carbon (OC)-normalized basis, SEM*(x,OC), is essentially unchanged over a wide range of concentrations of pore-water hardness, salinity, dissolved organic carbon, and any other complexing or competing ligands. Only the pore-water pH is important. Both acute and chronic exposures in fresh- and saltwater sediments are compared to predictions for cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn) based on the Daphnia magna BLM. The SEM*(x,OC) concentrations are similar for all the metals except cadmium. For pH = 8, the approximate values (micromol/gOC) are Cd-SEM*(xOC) approximately equal to 100, Cu-SEM*(x,OC) approximately equal to 900, Ni-SEMoc approximately equal to 1,100, Zn-SEM*(x,OC) approximately equal to 1,400, and Pb-SEM*(x,OC) approximately equal to 2,700. This similarity is the explanation for an empirically observed dose-response relationship between SEM and acute and chronic effects concentrations that had been observed previously. This initial application clearly demonstrates that BLMs can be used to predict toxic sediment concentrations without modeling the pore-water chemistry.

Animals↗
PubMed1991

Concomitant evaluation of efficiency, acute and delayed toxicities of combined treatment of radiation and CDDP on an in vivo model.

The efficiency, acute and delayed toxicities of different radio-chemotherapeutic combinations were assessed on an in vivo model (Krebs II ascitic carcinoma grafted to female Swiss mice). Mice were given whole abdomen irradiation (WAI) 2.5 to 10 Gy as a single dose (WAI). CDDP was given intraperitoneally at 0.5 to 4 mg/kg dose level, 12 hr before or after WAI. There was a relationship between dose of CDDP and increase of life span (ILS) of mice. However, WAI did not increase the life span. When a single dose of 2 mg/kg CDDP was given prior to a 2.5 Gy WAI, the ILS reached 47%. By contrast, it was only 37% when treatment sequence was reversed. When the WAI dose level was increased to 5 Gy, the ILS was not increased. The jejunal crypt cell number, determined 3 days after the last treatment, was not modified, regardless of the treatment sequence. There was no delayed renal toxicity. The study on the Krebs II ascites model confirms the tumor cell therapeutic potentiation without exacerbation of normal tissue damage.

Animals↗
PubMed2006

Xenopus laevis is a potential alternative model animal species to study reproductive toxicity of phytoestrogens.

This study investigated effects of phytoestrogen quercetin on the gonadal development in Xenopus laevis. X. laevis at Nieuwkoop and Faber stage 46/47 were exposed to 50, 100 and 200 microg/L quercetin till 1 month postmetamorphosis. Gonads from frogs at 1 and 3 months postmetamorphosis were examined in gross morphology and histology. The highest dose of quercetin as well as estradiol (E2) significantly increased the percentages of phenotypic females. Exposure to quercetin at all doses induced abnormal testes with certain ovarian characteristics to some degree in gross morphology, including ovotestes. The abnormality rate exceeded 10% in each quercetin treatment. Histologic examination revealed that some abnormal testes exhibited intersexuality with testicular structure and ovarian structure or oocytes interspersed in testicular structure at 1 month postmetamorphosis. At 3 months postmetamorphosis, testicular abnormalities were more obvious, such as necrosis or apoptosis of spermatogonia, occurrence of developed or undeveloped oocytes, delay of the development of seminiferous tubes without or less late stage spermatocytes. The results have shown that quercetin cannot only feminize but also impair testicular development of X. laevis, i.e. X. laevis is sensitive to phytoestrogen. It is suggested that X. laevis might be an alternative model species to study reproductive toxicity of phytoestrogens.

Animals↗
PubMed2005

Dose-incidence modeling: consequences of linking quantal measures of response to depletion of critical tissue targets.

In developing mechanistic PK-PD models, incidence of toxic responses in a population has to be described in relation to measures of biologically effective dose (BED). We have developed a simple dose-incidence model that links incidence with BED for compounds that cause toxicity by depleting critical cellular target molecules. The BED in this model was the proportion of target molecule adducted by the dose of toxic compound. Our modeling approach first estimated the proportion depleted for each dose and then calculated the tolerance distribution for toxicity in relation to either administered dose or log of administered dose. We first examined cases where the mean of the tolerance distribution for toxicity occurred when a significant proportion of target had been adducted (i.e., more than half). When a normal distribution was assumed to exist for the relationship of incidence and BED, the tolerance distribution based on administered dose for these cases becomes asymmetrical and logarithmic transformations of the administered dose axis lead to a more symmetrical distribution. These linked PK-PD models for tissue reactivity, consistent with conclusions from other work for receptor binding models (Lutz et al., 2005), indicate that log normal distributions with administered dose may arise from normal distributions for BED and nonlinear kinetics between BED and administered dose. These conclusions are important for developing biologically based dose response (BBDR) models that link incidences of toxicity or other biological responses to measures of BED.

Animals↗
PubMed2005

Exposure-pathway models explain causality in whole sediment toxicity tests.

Measurements of lethal effect concentrations (LC50) and bioaccumulation following water-only and whole-sediment exposures of the amphipod, Melita plumulosa, and the bivalve, Tellina deltoidalis, to copper, were combined with bioenergetic-based kinetic models of exposure pathways to explain causality in whole-sediment toxicity tests. For both organisms, lethal body concentrations (LBCs) were greater for water-only exposures than for sediment exposures and indicated that the rate of copper accumulation and/or the mode of toxicity of copper assimilated were different for dissolved and particulate phases. The net assimilation of copper, expressed as a lethal exposure concentration (LEC) that was independent of the postexposure copper efflux, was shown to better explain the observed toxicity. The LEC of copper was the same for both water-only and whole-sediment toxicity tests. It is predicted that, for each species, a large range of effect concentrations may be measured for sediments having the same total copper concentration. These are conditional effect concentrations, as their value will be determined by total copper concentrations, partitioning (Kd) relationships (sediment properties), organism physiology (uptake rates from waters, assimilation efficiencies from solids), and organism feeding behavior (feeding selectivity). The importance of these factors to the development of sediment quality guidelines for metals based on species sensitivity distributions is discussed.

Amphipoda↗
PubMed2002

Chemotherapy and bone marrow reserve: lessons learned from autologous stem cell transplantation.

Cytotoxic chemotherapy is often complicated by hematopoietic toxicity. The degree of aplasia and the rapidity of count recovery following chemotherapy are indicative of bone marrow reserve. Patients who generally have a normal bone marrow function will recover from chemotherapy-induced cytopenia relatively rapidly. In contrast, patients that have poor bone marrow reserve will have significantly prolonged period of aplasia. Predicting the hematopoietic toxicity of radioimmunotherapy is an important dosimetry consideration. Unfortunately, there are no good models for predicting toxicity from chemotherapy that could be applied to radioimmunotherapy. However, models used to predict the ability to harvest autologous stem cells for use after high dose chemotherapy may be useful in predicting bone marrow reserve and potential toxicity from radioimmunotherapy. These models indicate that the successful mobilization of stem cells into the peripheral blood is inversely proportional to exposure to stem cell toxic drugs. Establishing criteria that will help predict the amount of myelotoxicity sustained from radioimmunotherapy could lead to improved dosimetry and ultimately to better therapy for patients.

Antineoplastic Agents↗
PubMed2004

Evaluation of acute hematologic and long-term pulmonary toxicities of radioimmunotherapy of Cryptococcus neoformans infection in murine models.

We evaluated acute hematological and long-term pulmonary toxicity of radioimmunotherapy in murine models of Cryptococcus neoformans infection. Activities up to 250 microCi were well tolerated by healthy A/JCr mice for (213)Bi-18B7 and (188)Re-18B7 monoclonal antibodies. In infected mice, doses up to 150 microCi produced only transient toxicity. The lungs of treated mice had no evidence of radiation fibrosis.

Animals↗
PubMedDate not supplied

Neuroprotective effects of estrogens: potential mechanisms of action.

Epidemiological studies associate post-menopausal estrogen use with a reduction in risk of Alzheimer's disease, a reduction in risk of Parkinson's disease, and death from stroke. The neuroprotective efficacy of estrogens have been well described and may contribute to these clinical effects. Estrogen-mediated neuroprotection has been described in several neuronal culture model systems with toxicities including serum-deprivation, beta-amyloid-induced toxicity, excitotoxicity, and oxidative stress. In animal models, estrogens have been shown to attenuate neuronal death in rodent models of cerebral ischemia, traumatic injury, and Parkinson's disease. Although estrogens are known to exert several direct effects on neurons, the cellular mechanisms behind the neuroprotective efficacy of the steroid are only beginning to be elucidated. In this review, we summarize the data supporting a neuroprotective role for estrogens in both culture and animal models and discuss neuronal effects of estrogens that may contribute to the neuroprotective effects. These effects include activation of the nuclear estrogen receptor, altered expression of bcl-2 and related proteins, activation of the mitogen activated kinase pathway, activation of cAMP signal transduction pathways, modulation of intracellular calcium homeostasis, and direct antioxidant activity.

Animals↗
PubMed1999

Parameter uncertainty and variability in evaluative fate and exposure models.

The human toxicity potential, a weighting scheme used to evaluate toxic emissions for life cycle assessment and toxics release inventories, is based on potential dose calculations and toxicity factors. This paper evaluates the variance in potential dose calculations that can be attributed to the uncertainty in chemical-specific input parameters as well as the variability in exposure factors and landscape parameters. A knowledge of the uncertainty allows us to assess the robustness of a decision based on the toxicity potential; a knowledge of the sources of uncertainty allows us to focus our resources if we want to reduce the uncertainty. The potential dose of 236 chemicals was assessed. The chemicals were grouped by dominant exposure route, and a Monte Carlo analysis was conducted for one representative chemical in each group. The variance is typically one to two orders of magnitude. For comparison, the point estimates in potential dose for 236 chemicals span ten orders of magnitude. Most of the variance in the potential dose is due to chemical-specific input parameters, especially half-lives, although exposure factors such as fish intake and the source of drinking water can be important for chemicals whose dominant exposure is through indirect routes. Landscape characteristics are generally of minor importance.

Animals↗
PubMed2004

Vascular medial hyperplasia following chronic, intermittent exposure to 4,4'-methylenedianiline.

4,4'-Methylenedianiline (DAPM) is an aromatic amine used in the synthesis of polyurethanes and epoxy resins. Acute exposure to DAPM produces hepatobiliary toxicity in humans as well as animal models. However, the toxic effects of intermittent DAPM exposure have not been explored. We treated male and female rats with 25 mg DAPM/kg or vehicle once per week for 17-22 wk. Though concentric fibrosis around bile ducts of the liver was noted, vascular medial hyperplasia was also prominent. Morphometric analysis of histologic sections revealed that in male rats, vessel wall area increased relative to lumen area in hepatic arteries by 22 wk. However, in female rats, wall areas of both hepatic and pulmonary arteries increased relative to lumen area by 17 wk. In both male and female rats, increased wall thickness was localized to the medial layer; no intimal changes were noted. In vitro treatment of vascular smooth muscle cells (VSMC) with 25-100 microM DAPM resulted in increased DNA synthesis and VSMC proliferation. To test whether the observed alterations in cell cycle control involved VSMC-mediated metabolism of DAPM to electrophilic intermediates, cells were treated with DAPM or DAPM plus 50 microM N-acetylcysteine (NAC). Coincubation with NAC afforded dramatic protection against DAPM-induced VSMC proliferation. Though DAPM had no appreciable effect on levels of reduced glutathione, oxidized glutathione, or oxidant production, DAPM increased glutathione-S-transferase activity in VSMC. These data indicate that DAPM can initiate VSMC proliferation, possibly via VSMC-mediated metabolism of DAPM to reactive intermediates.

Acetylcysteine↗
PubMed2003

Anti-inflammatory action of sulfoaryl 3,3-disubstituted triazenes in rat experimental edema models.

The acute toxicity and anti-inflammatory activity of eleven potassium salts of sulfobenzene and sulfonaphthalene 3,3-disubstituted triazenes have been examined in rats with carrageenin- and bentonite-induced edema using a 50 mg/kg p.o. dose. All compounds were found to exhibit anti-inflammatory activity significantly exceeding that of acetylsalicylic acid and ibuprofen, and were less toxic than these reference drugs. The most pronounced anti-inflammatory activity was shown by the potassium salt of 4-(piperazin-1-ylazo)benzenesulfonic acid.

Animals↗
PubMed2000

Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats.

PURPOSE: Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal. METHOD: The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM. RESULTS: Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models. CONCLUSIONS: This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.

Animals↗
PubMed1993

Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity.

Defects in neurotransmitter glutamate transport may be an important component of chronic neurotoxicity in diseases such as amyotrophic lateral sclerosis. There are no reliable models of slow glutamate neurotoxicity. Most previous in vitro systems have studied the rapid neurotoxic effects of direct-acting glutamate agonists. Therefore, we developed a model of slow toxicity in cultured organotypic spinal cord slices. The model was based on selective inhibition of glutamate transport, which continuously raised the concentration of glutamate in the culture medium. This resulted in the slow degeneration of motor neurons over several weeks. Motor neuron toxicity was selectively prevented by non-N-methyl-D-aspartate glutamate receptor antagonists and glutamate synthesis or release inhibitors but not by N-methyl-D-aspartate receptor antagonists. Thus, selective inhibition of glutamate transport produces a model of clinically relevant slow neurotoxicity and appears to be mediated by the action of non-N-methyl-D-aspartate receptors. This data supports the hypothesis that the slow loss of motor neurons in amyotrophic lateral sclerosis could be due, in part, to defective glutamate transport.

Amyotrophic Lateral Sclerosis↗
PubMedDate not supplied

Combining chemodescriptors and biodescriptors in quantitative structure-activity relationship modeling.

In view of the wide distribution of halocarbons in our world, their toxicity is a public health concern. Previous work has shown that various measures of toxicity can be predicted with standard molecular descriptors. In our work, biodescriptors of the effect of halocarbons on the liver were obtained by exposing hepatocytes to 14 halocarbons and a control and by producing two-dimensional electrophoresis gels to assess the expressed proteome. The resulting spot abundances provide additional biological information that might be used in toxicity prediction. QSAR models were fitted via ridge regression to predict eight dependent toxicity measures: d37, arr, EC50MTT, EC50LDH, EC20SH, LECLP, LECROS, and LECCAT. Three predictor sets were used for each-the chemodescriptors alone, the biodescriptors alone, and the combined set of both chemo- and biodescriptors. The results differed somewhat from one dependent to another, but overall it was shown that better results could be obtained by using both chemo- and biodescriptors in the model than by using either chemo- or biodescriptors alone. The library of compounds used was small and quite homogeneous, so our immediate conclusions are correspondingly limited in scope, but we believe the underlying methodologies have broad applicability at the interface of chemical and biological descriptors.

Animals↗