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G Zbinden

Publications and source records attributed to G Zbinden.

At least 37 records · Page 2Linked to original sources
PubMed1988

Nephrotoxicity screening in rats: a validation study.

A validation of our non-invasive screening test for the detection of renal damage (Zbinden et al. 1988) is presented. The test is based on repetitive, quantitative urine analysis in groups of six female Sprague-Dawley rats treated on 5 consecutive days with low doses of test substances. Higher doses were administered in the following weeks until nephrotoxic effects or signs of general toxicity were observed. Thirteen reference substances (hexachloro-1:3-butadiene [HCBD], cisplatin, carboplatin, suramin, chloroform, neomycin, rifampicin, phenacetin, phenylbutazone, methicilline, sodium oxalate, ethylene glycol and furosemide) were used. The percentage of rats reaching the test criteria, i.e., pathologic values defined on the basis of measured control values, was determined. In the controls, the overall percentage of rats reaching or exceeding the test criteria was 4.48%, a value that is close to the expected 5%. Evidence of nephrotoxicity was found with all reference compounds. Elevated excretion of cells and occurrence of cylinders were the most sensitive indicators of renal damage. Hematuria was the most frequent finding. Of the other urine constituents measured the enzyme malate dehydrogenase (MDH) was frequently increased. Water consumption, urine volume, pH and specific gravity were occasionally, and protein, glucose, electrolytes, amino acids and gamma-glutamyl-transpeptidase (GGT) were only rarely changed. It is concluded that the screening which is based on quantitative and repeated urine analysis is a useful procedure to detect nephrotoxic chemicals acting by a variety of mechanisms. The histopathological examination of the kidneys contributed useful information of the nature of the toxic effects, but as a screening tool it is less sensitive than quantitative urine analysis.

Animals↗
PubMed1988

Evaluation of thyroid gland activity by hormone assays and flow cytometry in rats.

Spontaneous variations in the activity of thyroids and changes induced by methimazole, phenobarbital and 2,4--diaminoanisole sulfate were assessed in rats by repeated measurements of serum T3, T4 and TSH concentrations and cell cycle analysis in isolated nuclei of the thyroids. Methimazole caused a decrease in T3 and T4, and elevation in TSH, reduction of cells in G1 and increase in the percentage of cells in S and G2 phases. With phenobarbital T4 concentrations were decreased, but a mitogenic effect was only seen after 8 weeks. With 2,4-diaminoanisole sulfate the most prominent change observed was a decrease in T3 concentrations.

Animals↗
PubMed1988

Reduction and replacement of laboratory animals in toxicological testing and research. Interim report 1984-1987.

The reasons reduction and replacement of laboratory animals are advancing rapidly in basic biomedical research, and why in industrial toxicology progress is much slower, are analyzed. Reference is made to a previous report from our laboratory, and the general concept of the program is outlined. Encouraging developments concerning acceptance of new concepts in acute toxicity testing by various regulatory agencies are reviewed (OECD, IKS, EEC, and Bureau of Pharmaceutical Affairs, Ministry of Health and Welfare, Japan). On the basis of new concepts proposed by the British Toxicology Society, a program which attempts to evaluate acute toxicity of chemicals as far as possible without causing mortality was started. Continuous in-cage monitoring of motility of animals, regular control of general health, body weight, food and water consumption, and body temperature are used as variables. The possibilities of reducing animal use in toxicology by application of toxicological screening procedures are explained. Screening tests under development include an operant conditioning technique to detect adverse drug interactions with ethanol and a procedure for the detection of nephrotoxic properties. The successful completion of a collaborative program designed to upgrade toxicity testing with contraceptive steroids and to abolish the 7-year beagle and 10-year monkey studies is reported. The application of in vitro cytotoxicity tests for assessment of irritant and corrosive properties of chemicals is discussed and some encouraging progress on regulatory acceptance of such tests (OECD) is reported. A new test developed at the institute is described. An in vitro model for the investigation of chemically induced changes of collagen synthesis in human fibroblasts is presented. Other cell culture methods under development include a culture system of chick brain, retina, and menings cells for the study of neurotoxic chemicals and neurobehavioral teratogens, primary hepatocyte cultures for the study of drug effects on DNA and protein synthesis and ploidy, using flow cytometry, and various in vitro models for the assessment of genotoxic and tumor-promoting activities and malignant cell transformation. The problem of analgesic treatment of animals with chronic pain was investigated. Several analgesics were evaluated, and treatment modalities providing demonstrable analgesia for prolonged periods of time in mice and rats were worked out.

Animal Welfare↗
PubMed1987

Effects of mitoxantrone and doxorubicin on energy metabolism of the rat heart.

In animal models anthracyclines and anthracenediones show similar antineoplastic activity but somewhat different cardiotoxicity. The effects of doxorubicin and the free base of mitoxantrone (NSC-279836) on the energy metabolism of the rat heart were compared. Both compounds not only reduced oxygen consumption in heart mitochondria ex vivo, but also uncoupled oxidative phosphorylation, inhibited creatine phosphate kinase, and damaged the semipermeability of the inner mitochondrial membrane (measured as creatine influx). The effects on the myocyte membrane activities, calcium transport, and Na/K, Mg, and Ca ATPases were slightly different for the two compounds. Cardiotoxicity of the two compounds may have its origin in their interference with heart cell energy metabolism.

Animals↗
PubMed1986

Detection of cardiotoxic hazards.

For the detection and quantitative assessment of cardiovascular toxicity, the morphological and biochemical studies used in routine toxicity tests must be supplemented with functional and metabolic measurements. Examples are given which show that the cardiotoxic effects of allylamine and emetine can be detected early by blood pressure and ECG monitoring. The same techniques are helpful in assessing potential drug interactions. For the hypoglycemic agent MTG measurement of mitochondrial function proved to be the most adequate method to demonstrate cardiotoxic hazard.

Allylamine↗
PubMed1986

Invited contribution: acute toxicity testing, public responsibility and scientific challenges.

Knowledge of the acute toxic effects of chemicals is important for the protection of exposed humans. Since sufficient information in humans is often lacking, experiments on laboratory animals must be performed. The LD50 test, which requires large numbers of animals, has become the preferred procedure. It is now widely criticized on scientific and ethical grounds. This paper reviews the possibilities of using fewer animals to obtain relevant information on the acute hazards of chemical substances, but it also identifies the reasons why the traditional testing approaches cannot be changed immediately. An important problem is the practice of basing legal decisions on classification of chemicals in official lists of hazardous substances and for labeling purposes on LD50 values. Proposals are presented on how pain and suffering of the animals included in acute toxicity tests can be reduced. The use of in vitro systems for the evaluation of the hazardous properties of chemicals is discussed.

Lethal Dose 50↗
PubMed1986

A rapid cell membrane permeability test using fluorescent dyes and flow cytometry.

A reliable and rapid test to detect cytotoxic chemicals which affect cell membranes is described. Fluorescein diacetate freely penetrates intact cells where it is hydrolyzed to its fluorochrome, fluorescein, which is retained in the cell due to its polarity. On the other hand, ethidium bromide is known to be excluded from the intact cell, staining only nucleic acids of membrane-damaged cells. The combination of both fluorochromes results in counter-staining: intact cells fluoresce green (cytoplasm) and membrane-damaged cells fluoresce red (nucleus and RNA). Rat thymocytes freshly isolated without enzyme treatment were incubated simultaneously with test substance and dye solution fluorescein diacetate and ethidium bromide. A two-parameter analysis was performed on a flow cytometer with an on-line computer. Concentration-dependent effects of various detergents and solvents were quantified by measuring the amount of dye retention, i.e., the decrease or increase in fluorescein--fluorescence (peak shift), and the decrease in dye exclusion (increase in ethidium bromide-staining) relative to the untreated control. The assay can be used for rapid monitoring of chemical insults to cell membranes which precede the decrease of the viability measured by pure dye exclusion techniques.

Animals↗
PubMed1986

Quantitative and qualitative changes of serum proteolytic activity in rats with liver damage induced by galactosamine.

Serum proteolytic activity was determined in galactosamine-treated rats and in controls. Injection of the hepatotoxin at a dose of 400 mg/kg resulted in a 3.4-fold elevation in the serum proteolytic activity, while AST (aspartate aminotransferase), ALT (alanine aminotransferase) and bilirubin were increased by factors of 3.9, 8.8 and 4.5, respectively. Studies with proteinase inhibitors revealed that the serum proteolytic activity was partially metal-dependent as well as puromycin and antipain sensitive. Differences in susceptibility to a combination of N-ethylmaleimide and antipain indicated presence of different proteolytic systems in the sera of liver damaged and control rats. Separation of serum proteinases by gel filtration showed that the galactosamine-intoxicated rat serum contained activity which did not appear in the control serum. This activity was partially metal dependent, antipain and N-ethylmaleimide sensitive, and was more susceptible to dithiothreitol than the control activity. These findings demonstrate that hepatocellular damage induced by galactosamine caused not only an increase in serum proteinases, but was also associated with the appearance of enzymes not normally released by the liver of untreated animals.

Animals↗
PubMed1986

Collagen synthesis in growing human skin fibroblasts.

Collagen and noncollagen protein synthesis in cultured human skin fibroblasts was studied in relation to different growth phases. In order to quantify collagen synthesis, we determined the release of incorporated radioactivity using purified bacterial collagenase. Collagen as well as noncollagen protein synthesis markedly decreased during fibroblast growth. On the other hand, we found a 3-fold increase in relative collagen synthesis (i.e. collagen synthesis compared to total protein synthesis) comparing cells in the log growth phase with cells in the stationary growth phase.

Adult↗
PubMed1986

Comparison of exogenous growth stimuli for chemically transformed cells: growth factors, serum and cocultures.

Rat tumor cells isolated from 2 fibrosarcomas which differed in their degree of differentiation were exposed to growth-stimulating influences in soft agar. The effects of growth factors (epidermal growth factor, fibrosarcoma growth factor and insulin), of fetal calf serum and of cocultured normal mesenchymal cells of rats and nude mice were compared. Each of the 3 growth factors exerted a specific response and dose dependence. Increasing concentrations of serum stimulated the number of cells which formed clones in soft agar. Experiments using combinations of growth factors and fetal calf serum demonstrated that a complex optimal mixture of growth stimuli was responsible for the efficient growth-promoting activity of the serum. In cocultures with normal cells, cloning efficiency of tumor cells was enhanced and growth of tumor cells was accelerated. This stimulus was due to the constant release of an agar-diffusible growth-stimulating factor by the normal, nondividing cells. Cocultured mouse cells showed an even higher growth-stimulating activity than rat fibroblasts. Cells obtained from the poorly differentiated fibrosarcoma responded, in relative terms, better to all growth-stimulating influences, than those derived from the well-differentiated tumor.

Animals↗
PubMed1986

Neurobehavioral screening in rats: validation study.

The usefulness of a neurobehavioral check-list for the detection and characterization of neurotoxic effects of chemical compounds was evaluated in rats. The animals were given single doses of the test compounds, and higher or lower doses of the substances were administered in subsequent weeks, depending on the outcome of the experiments. The testing procedure proved to be useful for detecting the neurobehavioral hazards of psychotherapeutics and other drugs with known neurobehavioral side-effects. However, the investigational technique was less satisfactory for evaluating alcohols and various neurotoxic agents. With these compounds, even repeated dosing did not improve the predictability of the testing scheme. Swimming performance was also investigated and was found to be impaired only in rats treated with neuroleptic drugs. Based on this validation study, the advantages and pitfalls of the neurobehavioral check-list approach are discussed.

Alcohols↗
PubMed1985

Characterization of proteolytic systems in human and rat urine.

Activities of proteolytic enzymes were detected in rat and human urine by using [125 l] iodo-insulin B chain as a substrate. The pH optimum of human urine activity was in the acidic range (pH 2.0) whereas the rat urine had two pH optima, one at the acidic range similar to human urine and another at pH 7.5. The activities were linear with time and amount of enzyme. Study with various proteinase inhibitors revealed that the acidic pH activities of human and rat urine were apparently of carboxyl endopeptidases since they were totally inhibited by pepstatin 10-8M. The neutral pH proteolysis of rat urine was inhibited by chelating agents and therefore it was considered as a metalloendopeptidase activity. These findings show the difference between the content of urinary proteolytic enzymes in humans and in rats by using a sensitive and simple radioactive assay.

Animals↗