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PubMed2005

Testing threshold and hormesis in a random effects dose-response model applied to developmental toxicity data.

Here we describe a random effects threshold dose-response model for clustered binary-response data from developmental toxicity studies. For our model we assume that a hormetic effect occurs in addition to a threshold effect. Therefore, the dose-response curve is based on two components: relationships below the threshold (hormetic u-shaped model) and those above the threshold (logistic model). In the absence of hormesis and threshold effects, the estimation procedure is straightforward. We introduce score tests that are derived from a random effects hormetic-threshold dose-response model. The model and tests are applied to clustered binary data from developmental toxicity studies of animals to test for hormesis and threshold effects. We also compare the score test and likelihood ratio test to test for hormesis and threshold effects in a simulated study.

Animals↗
PubMed1989

Development of a tracheal implant xenograft model to expose human bronchial epithelial cells to toxic gases.

A tracheal implant model was developed which enabled exposure of differentiated normal human bronchial epithelial cells (NHBE) to a single exposure of a model toxic gas (formaldehyde). NHBE cells were grown in vitro in explant culture under defined serum-free conditions from previously frozen bronchial segments, harvested, and used to repopulate de-epithelialized rabbit tracheas. Rabbit tracheal segments repopulated with NHBE cells were implanted into the subcutis of congenitally athymic nude mice. Following graft vascularization, the xenografted NHBE cells differentiated and formed a mucociliary epithelial surface which lined approximately 50% of the surface of the implant lumen. Eight weeks post-implantation both ends of the implanted grafts were cannulated, and formaldehyde (HCHO) vapor (0, 6, or 15 ppm) in humidified air was passed through the tracheal lumens. Representative epithelial surfaces were examined by light and scanning electronmicroscopy, and autoradiography prior to, immediately after, and 48 hr following a 1-hr exposure to the test vapors. Light microscopic examination of implant sections immediately following exposure to 6 and 15 ppm HCHO detected cessation of ciliary activity, which recovered by 48 hr post-exposure. Scanning electron microscopic examination of the epithelial surface demonstrated mild morphologic changes, restricted to those implants exposed to 15 ppm. Findings immediately following HCHO exposure included swelling and exfoliation of individual cells, deciliation, and mucus release. Changes present after 48 hr included presence of flattened cells with few short microvilli and focal increase in the number of S-phase nuclei in the basal epithelium. These results demonstrate the utility of tracheal implants for single short-term exposure of differentiated human bronchial epithelial cells to gaseous agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Nutritional considerations in designing animal models of metal toxicity in man.

In recent years, exposure of man to increasing amounts of metals has occurred rather generally from industrial contamination and variably from intake of dietary mineral supplements. Adverse effects of individual metals can be markedly altered by dietary levels of other essential and nonessential inorganic elements, essential organic nutrients and other nonessential dietary components. Experimental diets for establishing baseline responses to excess elements should be formulated to meet the animal's requirements only. These reference diets can then be modified to mimic man's average dietary intake as well as meal patterns. Improved animal models should provide better data for assessing hazards of excess metal intake by man.

Aging↗
PubMed2002

A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity.

Antioxidant drugs have been reported to protect pancreatic islets from the adverse effects of chronic exposure to supraphysiological glucose concentrations. However, glucose has not been shown to increase intracellular oxidant load in islets, nor have the effects of increasing or inhibiting glutathione peroxidase (GPx) activity on islet resistance to sugar-induced oxidant stress been studied. We observed that high glucose concentrations increased intracellular peroxide levels in human islets and the pancreatic beta cell line, HIT-T15. Inhibition of gamma-glutamylcysteine synthetase (gammaGCS) by buthionine sulfoximine augmented the increase in islet peroxide and decrease in insulin mRNA levels, content, and secretion in islets and HIT-T15 cells induced by ribose. Adenoviral overexpression of GPx increased GPx activity and protected islets against adverse effects of ribose. These results demonstrate that glucose and ribose increase islet peroxide accumulation and that the adverse consequences of ribose-induced oxidative stress on insulin mRNA, content, and secretion can be augmented by a glutathione synthesis inhibitor and prevented by increasing islet GPx activity. These observations support the hypothesis that oxidative stress is one mechanism for glucose toxicity in pancreatic islets.

Acetylcysteine↗
PubMed1999

Toxic equivalency factors of polychlorinated dibenzo-p-dioxins in an ovulation model: validation of the toxic equivalency concept for one aspect of endocrine disruption.

Polychlorinated dibenzo-p-dioxins (PCDDs) are structural analogues, which produce a similar spectrum of biological and toxicological responses in animals, albeit with differential potencies. Very consistent structure-activity relationships have been found for acute toxicity and some biochemical effects among these compounds. For the current experiments, the gonadotropin-primed immature female rat model was used to study the effect of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7, 8-pentachlorodibenzo-p-dioxin (PeCDD), and 1,2,3,4,7, 8-hexachlorodibenzo-p-dioxin (HxCDD) on ovulation. Single doses of different PCDDs and their mixture were given orally to 23-day-old rats. Gonadotropin from pregnant mare's serum (PMSG) was injected (5 IU) 24 h later to induce follicular maturation. Rats were decapitated at various times after PMSG, blood was collected, and ovarian weight was measured. Serum concentrations of 17beta-estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PrL) were determined by radioimmunoassay. Ovulation was measured at 72 h after injection of PMSG by counting ova flushed from oviducts. PCDDs dose dependently decreased the number of ova per ovary and reduced ovarian weight gain induced by PMSG. The slopes of the dose-response curves generated by individual PCDDs and/or their mixture were similar. PMSG-induced increase in serum E2 was enhanced on the day of expected ovulation by PCDDs; in contrast, serum P4 and FSH were decreased at that same time point. PCDDs also altered the temporal pattern of serum E2, FSH, and LH but not that of PrL. Histologically the effect of all three PCDDs consisted of ova trapped in preovulatory follicles and a lack of or reduced number of corpora lutea. The results indicate that the PCDDs, tested in the present model, have the same mode of action on ovulation and the reproductive hormones, e.g., LH, FSH, P4 and E2. Furthermore, the dose responses of the individual congeners are parallel to each other and also to that of their equipotent mixture, which represent a validation of the TEQ concept for one aspect of endocrine disruption, that is for inhibition of ovulation.

Animals↗
PubMed2006

Development of a biotic ligand model (BLM) predicting nickel toxicity to barley (Hordeum vulgare).

A biotic ligand model (BLM) was developed to predict nickel toxicity, affecting root growth of barley (Hordeum vulgare), in nutrient solutions. The extent to which Ca(2+), Mg(2+), Na(+), K(+) ions and pH each influenced nickel toxicity was determined. Higher activities of Mg(2+) linearly increased the 4d EC50 Ni (2+) , while Ca(2+), Na(+), K(+) and H(+) activities did not significantly influence Ni(2+) toxicity. Stability constants for the binding of Ni(2+) and Mg(2+) to the biotic ligand were obtained: logK(NiBL)=5.27 and logK(MgBL)=3.47. Further, it was calculated that on average 57% of the biotic ligand sites needed to be occupied by nickel to induce 50% root growth inhibition. Auto-validation of the BLM indicated that predicted EC50s differed from the observed EC50s by a factor of less than 2, indicating that the BLM concept may also be used to predict metal toxicity to terrestrial plants.

Hordeum↗
PubMed2003

Phase I studies of weekly administration of cytotoxic agents: implications of a mathematical model.

Certain toxic effects of cytotoxic anticancer agents typically evolve over weeks. When such agents are administered weekly, these effects are cumulative. With such schedules, good medical practice mandates dose modifications with mild or moderate toxicity in order to avoid progression to serious or life-threatening toxicity. These modifications lead to differences between scheduled and delivered doses. Phase I studies are designed to identify the maximum tolerated dose for a given schedule. Yet neither standard phase I study designs nor the theoretical literature acknowledge the existence or incorporate the impact of dose modifications upon phase I study outcomes. Our purpose was to better understand the impact of dose reductions/omissions upon outcomes of phase I studies of weekly administration of cytotoxic agents. We created a mathematical model in which toxicity was represented as a power function of dose in order to represent extremes of behavior observed with actual cytotoxic agents in the clinic. We used the model to simulate dosing and toxicity experiences across a wide range of doses. From these simulations we identified "best doses" according to a variety of traditional and novel criteria. We find the concept of maximum tolerated dose inadequate for the determination of best doses. We also suggest a strategy for a new phase I study design which can be used to estimate the "best dose" corresponding to a specified delivery rate. In summary, identification of best doses requires attention, not only to dose limiting toxic events, but also to delivered dose rates and schedule adherence.

Antineoplastic Agents↗
PubMed2000

Toxoids of streptococcal pyrogenic exotoxin A are protective in rabbit models of streptococcal toxic shock syndrome.

Streptococcal pyrogenic exotoxins (SPEs) are superantigens that have been implicated in causing streptococcal toxic shock syndrome (STSS). Most notably, SPE serotype A is made by nearly all M-protein serotype 1 and 3 streptococci, the M types most associated with the illness (these strains contain one or more other SPEs, and those proteins are likely also to contribute to disease). We have prepared double-, triple-, and hexa-amino-acid mutants of SPE A by PCR and other mutagenesis procedures. The sites chosen for mutation were solvent-exposed residues thought to be important for T-cell receptor (TCR) or major histocompatibility complex (MHC) class II interaction. These mutants were nonsuperantigenic for human peripheral blood mononuclear cells and rabbit and mouse splenocytes and were nonlethal in two rabbit models of STSS. In addition, these mutants stimulated protective antibody responses. Interestingly, mutants that altered toxin binding to MHC class II were more immunogenic than mutants altering TCR binding. Collectively, these studies indicate that multiple-site mutants of SPE A are toxoids that may have use in protecting against the toxin's effects in STSS.

Animals↗
PubMed1993

EO9: a novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models.

EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, EO9 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, EO9 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared to leukaemia cell lines both in the Corbett two-tumour assay and in the disease-oriented human tumour cell line panel of the U.S. National Cancer Institute. In the latter system activity was particularly apparent in colon, melanoma and central nervous system lines, together with some renal and non-small cell lung lines. Preferential cytotoxicity towards hypoxic versus aerobic EMT6 mouse mammary tumour cells was observed. In vivo, EO9 was inactive against the P388 murine leukaemia, while exerting significant antiproliferative effects against several murine and human solid tumours, including the generally resistant MAC mouse colon tumours and gastric, ovarian and breast xenografts. These results confirmed in vitro observations of preferential solid tumour activity. In animal toxicology studies, EO9 induced vascular congestion in the gastrointestinal tract, but no significant bone marrow toxicity. The LD10 value of EO9 after a single intravenous injection into mice was 9 mg/kg (27 mg/m2). A dose of one-tenth of the mouse equivalent LD10 (2.7 mg/m2), the recommended starting dose for clinical phase I studies, was found to be safe in rats. Considering its distinct mechanism of bioactivation as compared to mitomycin C, its preferential solid tumour activity, its excellent activity against hypoxic cells, and lack of significant bone marrow toxicity in animals studies, EO9 has been selected for clinical evaluation within the framework of the EORTC.

Adenocarcinoma↗
PubMed2002

Modeling multi-drug chemotherapy: tailoring treatment to individuals.

BACKGROUND: Predicting and tailoring optimal cancer treatments presents a major challenge. METHODS: A computational model (kinetically tailored treatment, or KITT model) is developed to predict drug combinations, doses, and schedules likely to be effective in reducing tumor size and prolonging patient life. Treatment strategies may be tailored to individuals based on tumor cell kinetics. The model incorporates intra-tumor heterogeneity and evolution of drug resistance, apoptotic rates, and cell division rates. Tumor growth may follow an exponential or a Gompertzian trajectory. Drug pharmacodynamic and pharmacokinetic models are used. Toxicity is modeled in several ways. RESULTS: A key prediction of KITT is that including cytostatic drugs like tamoxifen and herceptin during treatment with cytotoxic drugs substantially increases the probability of cure and prolongs patient life. Results also suggest that altering drug scheduling may be more effective but not more toxic than dose escalation. CAF chemotherapy (cyclophosphamide, adriamycin, and 5-fluorouracil) is predicted to be more effective than CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). KITT also suggests that tumors with a high proliferative index (PI) may respond better to drug combinations incorporating two cell-cycle phase-specific drugs than do tumors with a low PI. Tumors with a low PI, in contrast, are predicted to respond better to regimens involving two cell-cycle phase-non-specific drugs than do tumors with a high PI. These predictions are borne out by clinical trial results published in the literature, which are discussed. Simulated predictions of the model match well with results from a clinical trial by Silvestrini et al. (2000. Int. J. Cancer 87, 405). The results of simulating the growth of 26896 tumors are used to construct a decision tree for prognosis to identify the key tumor and treatment variables. CONCLUSION: Additional tests of the model are needed in which physicians collect information on apoptotic and proliferative indices, cell-cycle times, and drug resistance from biopsies of each individual's tumor. Computational models may become important tools to help optimize and tailor cancer treatments.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions.

Recent studies suggest that increased activity of cyclin-dependent kinase 5 (Cdk5) may contribute to neuronal death and cytoskeletal abnormalities in Alzheimer's disease. We report here such deregulation of Cdk5 activity associated with the hyperphosphorylation of tau and neurofilament (NF) proteins in mice expressing a mutant superoxide dismutase (SOD1(G37R)) linked to amyotrophic lateral sclerosis (ALS). A Cdk5 involvement in motor neuron degeneration is supported by our analysis of three SOD1(G37R) mouse lines exhibiting perikaryal inclusions of NF proteins. Our results suggest that perikaryal accumulations of NF proteins in motor neurons may alleviate ALS pathogenesis by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates.

Amyotrophic Lateral Sclerosis↗
PubMed1992

Modeling of toxicological effects of fire effluents: prediction of toxicity and evaluation of animal model.

Methodology for the prediction of the toxic effects of fire effluents has made considerable progress [1,2]. As emphasized by Hartzell [2] a limiting factor has often been the availability and quality of analytical input data. The Finney model [3] was used to predict the lethal potency and would appear to have utility as a tool in reducing the number of experimental animals used in material testing. However, pilot bioassay data are indispensable to validate the prediction and to categorize fire effluents into narcosis inducing, irritant or of causing unusual or unexpected toxicity. The comparison of predicted and actually observed carboxy-hemoglobin levels is considered to be a sensitive but indirect tool to assess whether major effects on respiration occurred. All laboratory combustion toxicity methods suffer from several types of limitations. However, they might be expected to be relatable to at least some stages of actual fires. Due to a lack of a clearly defined 'generation process'--if compared with conventional inhalation toxicity studies--the classification into broad categories of relative toxic potency seemed to be more appropriate than an absolute classification scheme.

Animals↗
PubMed1974

The Mongolian gerbil as a model for lead toxicity. I. Studies of acute poisoning.

Mongolian gerbils fed diets containing lead acetate maintained body weight comparable to gerbils fed the same diet without added lead. Intranuclear lead inclusion bodies in epithelial cells of the proximal convoluted tubules of the kidney were first observed at 4 weeks, and increased in number to about 50 per high power field at 12 weeks. At this time, a corticomedullary area of empty-appearing tubules was prominent. Transmission electron microscopy confirmed the increase in number and size of nuclear lead inclusion over the 12-week period. Cytoplasmic changes observed in proximal tubule cells containing lead inclusions were considered indicative of acute lethal injury. Distinct cytoplasmic fibrillar structures, first apparent at 8 weeks, were present in some proximal tubular lining cells and strongly resembled newly formed intranuclear lead inclusions. After 12 weeks, the total amount of lead present in the gerbil kidney was four to six times greater than that in rat kidney as determined by atomic absorption spectrophotometry. A hypothesis has been formulated that relates the more efficient nephron of the gerbil kidney to the rapid and extensive development of intranuclear inclusion bodies and the greater accumulation of total lead.

Animals↗
PubMed1990

Domoic acid-induced neurovisceral toxic syndrome: characterization of an animal model and putative antidotes.

A rodent model of neurovisceral toxic syndrome induced by the neuroexcitant amino acid, domoic acid, is described, along with the activity of a putative antidote, the nonselective excitotoxin antagonist, kynurenic acid. Both an extract of contaminated mussels and pure domoic acid induced a characteristic syndrome including: sluggishness, scratching stereotypy, convulsions and death. Autopsy revealed gastric and duodenal lesions and peritoneal ascites. Kynurenic acid significantly obtunded these behavioral and physiological effects, particularly when given 60-75 min after the toxic insult. Probenecid, a blocker of organic acid transport, and tryptophan, a precursor of endogenous brain kynurenic acid, increased the time frame in which kynurenic acid exerted its protective effects. Kynurenic acid alone, in nontoxin-challenged animals significantly blocked cold-stress gastric lesions, significantly reduced basal gastric acid secretion and was protective to a lesser degree against ethanol-induced gastric mucosal injury. The murine model of domoate toxicity represents an inexpensive, reliable and sensitive biological assay for screening commercial shellfish for excitotoxin contamination. We are currently exploring kynurenic acid and other compounds for possible therapeutic use in both current and any future victims of neuroexcitant amino acid toxicosis.

Animals↗
PubMed1975

[A novel model of experimental toxic hepatitis/acute degenerative hepatitis induced by frog virus 3 (FV3) in the mouse (author's transl)].

The i.p. or i.v. injection of frog virus 3 (FV3) in mice produces a hepatitis which leads to the death of the animals within 24 h. This hepatitis is of a purely toxic nature since the virus does not develop at 37 degrees C. The toxic effect of the virus, which can be differentiated from the infectious effect, involves one or more structural proteins. The first pathological changes occur during the first few hours after the injection in the vicinity of the nuclei of the liver parenchyma cells in the form of changes in the chromatin and nucleoplasm. The inhibition of the synthesis of cellular macromolecules and of the function of nuclear enzymes points to the fact that it is the nucleus that is first and foremost attacked. Necrosis and biochemical disturbances in the vicinity of the cytoplasm appear later on. Premedication of the mice with a water-soluble silymarin salt leads to a distinct rise in the survival rate of the animals. The protective function of silymarin is dependent on the dose and on the duration of the premedication. The LD50 of FV3 in those mice which had previously been given silymarin, is approximately three times that of the animals which received no premedication.

Animals↗
PubMed2006

GFP assay as a sensitive eukaryotic screening model to detect toxic and genotoxic activity of azaarenes.

Azaarenes are nitrogen-containing polyaromatic heterocyclic compounds (NPAHs). The majority of the azaarenes found in the environment originate from anthropogenic sources. Concentrations of NPAHs found in the environment are reported to be one to two orders of magnitude lower than polycyclic aromatic hydrocarbons (PAHs) concentrations, yet their biological effects can be of similar magnitude. Very few studies on the genotoxicity of azaarenes are available in the literature. In the present study, a preliminary profile of both the toxic and genotoxic potential of 5 PAHs and their 20 aza-analogues were investigated. To assess the toxic and genotoxic activity, a green fluorescent protein (GFP) assay based on the yeast Saccharomyces cerevisiae was selected. To compare the sensitivity of this eukaryotic short-term assay with bacterial screening tests, the Toxi-Chromotest for toxicity and SOS-Chromotest for genotoxicity assessment were also performed. This comparison indicates that in most cases, the yeast GFP assay is apparently of comparable specificity to the bacterial toxicity or genotoxicity tests with respect to the correlation of positive/negative responses, but much more sensitive with respect to the effective concentration values. In the cases of phenazine, phenanthridine, 1,10-phenanthroline, or 4,7-phenanthroline, one to two orders of magnitude lower IC20 and minimum genotoxic concentration values in the yeast GFP assay were observed. In this study, the authors present evidence that genotoxicity assessment using the yeast GFP assay can provide a simple system to monitor the activity of these environmental pollutants that could possess mutagenic potential at low concentrations.

Biological Assay↗
PubMed1995

An in vitro model for arsine toxicity using isolated red blood cells.

A novel test system using isolated red blood cells (RBCs) and arsine (AsH3) in aqueous solution was developed to allow quantitation of AsH3 exposure and to study the toxicity of AsH3 in vitro. In this system AsH3 gas was generated and dissolved in aqueous solution, the concentration was measured, and the standardized solution was mixed with rat or dog red blood cells (RBCs). AsH3 was found to be stable in solution at neutral pH for several hours, but was lost quickly from solution as the acidity was increased to pH 2. Approximately 74% of the initial 0.56 mM AsH3, measured as total arsenic, was found to be taken up by, or strongly associated with, dog RBCs within 5 min of incubation and 82% of the initial 0.49 mM AsH3 was found in rat RBCs after 10 min incubation. Following hypotonic lysis of rat RBCs, 55% of the cell-associated arsenic was found in the membrane fraction with the balance found in the cytosolic fraction. The in vitro technique was used to examine factors influencing AsH3 toxicity using hemolysis as the end point. Hemolysis levels in dog and rat RBC incubations were found to increase with time after exhibiting a lag phase of about 30 min. At the AsH3 concentrations used, maximum levels of hemolysis were observed by 2 hr; maximum hemolysis at room temperature for dog RBCs was 20% and for rat RBCs was 22%. Increasing the temperature from room temperature to 37 degrees C resulted in increased hemolysis in dog RBCs (36%) and rat RBCs (90%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗