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Biomedical subjects

J Schlatter

Publications and source records attributed to J Schlatter.

At least 37 records · Page 2Linked to original sources
PubMed1999

Occurrence of emodin, chrysophanol and physcion in vegetables, herbs and liquors. Genotoxicity and anti-genotoxicity of the anthraquinones and of the whole plants.

1,8-Dihydroxyanthraquinones, present in laxatives, fungi imperfecti, Chinese herbs and possibly vegetables, are in debate as human carcinogens. We screened a variety of vegetables (cabbage lettuce, beans, peas), some herbs and herbal-flavoured liquors for their content of the 'free' anthraquinones emodin, chrysophanol and physcion. For qualitative and quantitative analysis, reversed-phase HPLC (RP-LC), gas chromatography-mass spectrometry (GC-MS) and RP-LC-MS were used. The vegetables showed a large batch-to-batch variability, from 0.04 to 3.6, 5.9 and 36 mg total anthraquinone per kg fresh weight in peas, cabbage lettuce, and beans, respectively. Physcion predominated in all vegetables. In the herbs grape vine leaves, couch grass root and plantain herb, anthraquinones were above the limit of detection. Contents ranged below 1 mg/kg (dry weight). All three anthraquinones were also found in seven of 11 herbal-flavoured liquors, in a range of 0.05 mg/kg to 7.6 mg/kg. The genotoxicity of the analysed anthraquinones was investigated in the comet assay, the micronucleus test and the mutation assay in mouse lymphoma L5178Y tk+/- cells. Emodin was genotoxic, whereas chrysophanol and physcion showed no effects. Complete vegetable extract on its own did not show any effect in the micronucleus test. A lettuce extract completely abolished the induction of micronuclei by the genotoxic anthraquinone danthron. Taking into consideration the measured concentrations of anthraquinones, estimated daily intakes, the genotoxic potency, as well as protective effects of the food matrix, the analysed constituents do not represent a high priority genotoxic risk in a balanced human diet.

Animals↗
PubMed1999

Selected phenolic compounds in cultivated plants: ecologic functions, health implications, and modulation by pesticides.

Phenolic compounds are widely distributed in the plant kingdom. Plant tissues may contain up to several grams per kilogram. External stimuli such as microbial infections, ultraviolet radiation, and chemical stressors induce their synthesis. The phenolic compounds resveratrol, flavonoids, and furanocoumarins have many ecologic functions and affect human health. Ecologic functions include defense against microbial pathogens and herbivorous animals. Phenolic compounds may have both beneficial and toxic effects on human health. Effects on low-density lipoproteins and aggregation of platelets are beneficial because they reduce the risk of coronary heart disease. Mutagenic, cancerogenic, and phototoxic effects are risk factors of human health. The synthesis of phenolic compounds in plants can be modulated by the application of herbicides and, to a lesser extent, insecticides and fungicides. The effects on ecosystem functioning and human health are complex and cannot be predicted with great certainty. The consequences of the combined natural and pesticide-induced modulating effects for ecologic functions and human health should be further evaluated.

Animals↗
PubMed1999

Population pharmacokinetics of methotrexate in the guinea pig.

The population pharmacokinetics of an antitumoral and antiinflammatory agent, methotrexate (MTX), a folic acid antagonist, was studied in guinea pigs. Animals received an acute intraperitoneal injection of 0.25, 1 or 5 mg/kg MTX. Blood sampling was carried out for 12 hrs. after MTX administration and plasma drug concentrations were measured by fluorescence polarization immunoassay. The pharmacokinetic (PK) parameters were computed using the bayesian population model. MTX reached the level of detection at 3 hrs. for the animals injected with the lowest dose (0.25 mg/kg), at 3.5 hrs. for those animals which had the intermediate dose (1 mg/kg) and more than 6 hrs. for animals having received the highest dose (5 mg/kg). Each kinetic parameter (half life, total clearance - CLt, volume of distribution at steady state - VDSS, mean residence time - MRT - and area under curve - AUC) didn't show any significant difference between doses. MTX kinetic was linear for the first two doses (0.25 and 1 mg/kg MTX) and non-linear thereafter. MTX presented a one compartment distribution.

Animals↗
PubMed1998

Determination of cisapride and norcisapride in human plasma using high-performance liquid chromatography with ultraviolet detection.

A simple, rapid and reproducible high-performance liquid chromatographic assay for cisapride and norcisapride in human plasma is described. Samples of plasma (150 microl) were extracted using a C18 solid-phase cartridge. Regenerated tubes were eluted with 1.0 ml of methanol, dried, redissolved in 150 microl of methanol and injected. Chromatography was performed at room temperature by pumping acetonitrile-methanol-0.015 M phosphate buffer pH 2.2-2.3 (680:194:126, v/v/v) at 0.8 ml/min through a C18 reversed-phase column. Cisapride, norcisapride and internal standard were detected by absorbance at 276 nm and were eluted at 4.3, 5.3 and 8.1 min, respectively. Calibration plots in plasma were linear (r>0.998) from 10 to 150 ng/ml. Intraday precisions for cisapride and norcisapride were 3.3% and 5.4%, respectively. Interday precisions for cisapride and norcisapride were 9.6% and 9.0%, respectively. Drugs used which might be coadministered were tested for interference.

Chromatography, High Pressure Liquid↗
PubMed1997

Dose response for the stimulation of cell division by caffeic acid in forestomach and kidney of the male F344 rat.

Caffeic acid (CA, 3,4-dihydroxycinnamic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by immunohistochemical analysis of incorporated 5-bromo-2'-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.40 and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1. 8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriate.

Animal Feed↗
PubMed1997

Dexamethasone and flumethasone residues in milk of intramuscularly dosed cows.

A field study was performed to assess the level of drug residues in milk after therapeutic application of highly potent synthetic glucocorticoids. Dexamethasone was tested either as a crystalline suspension or as a combination of sodium phosphate and phenylpropionate esters. Intramuscular injection of these preparations in lactating dairy cows (60 micrograms dexamethasone/kg body wt) yielded drug residues in milk of up to 8.4 ng/mL 12 h after treatment. These dexamethasone residues fell to below 1.0 ng/mL within 3 days after treatment. Intramuscular injection of an aqueous flumethasone preparation (13.5 micrograms/kg body wt) produced drug residues in milk in the range of 0.7-1.2 ng/mL 12 h after treatment, whereas flumethasone was below the detection limit of 0.23 ng/mL 2 days after administration. These results indicate that toxicologically significant residues may arise transiently in the milk during the first 2-3 days after intramuscular injection of synthetic glucocorticoids. Urine from the same animals contained 5- to 50-fold higher glucocorticoid concentrations than the corresponding milk samples. Thus, urine analysis appears to be an effective method to monitor the use of synthetic glucocorticoids in food producing animals.

Animals↗
PubMed1995

The occurrence of ochratoxin A in coffee.

Ochratoxin A (OA) is a nephrotoxic and nephrocarcinogenic mycotoxin which is predominantly produced by the two ubiquitous fungal genera, Aspergillus and Penicillium. OA is found in foodstuffs, predominantly in cereals but also in coffee beans. Inconsistent results have been published regarding the influence of roasting on the OA content in roasted beans and the transfer into the coffee brew. In the present study an HPLC method was used for the detection of OA in green and roasted coffee beans as well as in the coffee brew. For qualitative confirmation and quantification of low OA levels in roasted coffee beans and coffee brew an additional clean-up step by immunoaffinity column was applied before HPLC analysis. In green coffee beans OA was detected in 13 out of 25 commercial samples analysed (detection limit, 0.5 micrograms OA/kg). Roasting (250 degrees C, 150 sec) of naturally contaminated green beans or beans inoculated with A. ochraceus resulted only in a small reduction in the OA level. OA was also found to be eluted into the brew. Of 40 coffee brews prepared from commercially available samples OA was detected in 18 brews by HPLC and/or additional immunoaffinity column clean-up in the range of 0.4 to 7.8 micrograms OA/kg equivalent ground coffee. Our preliminary results suggest, therefore, that regular coffee consumption may contribute to exposure of humans to OA.

Chromatography, High Pressure Liquid↗
PubMed1993

Cell-cycle and ploidy analysis in bone marrow and liver cells of rats after long-term consumption of irradiated wheat.

Rats were fed for 4 or 90 days either with 70% freshly irradiated wheat (0.25, 0.75 or 2.25 kGy) and 30% complementary feed or with a control diet. None of the parameters examined (food consumption, body weight, haematological analysis, histopathological inspection of thymus, lung, liver, spleen and kidney, DNA analysis of bone marrow cells and nuclei from liver cells by flow cytometry) showed any statistically significant association with the feeding regimen. Minor changes in ploidy of liver cells and cell cycling of bone marrow cells were detectable (wheat-irradiation dose-dependent increase in G2/M-phase bone marrow cells up to 0.6%, decrease of 8C nuclei up to 1.1% in liver cells). From the pattern of alterations observed in our study, radiolytic by-products of wheat irradiation with a spindle poison-like activity can be excluded. Polyploid cells do not accumulate within the 90-day feeding period. The minor effects on cell cycle and ploidy observed are qualitatively comparable with the effects seen after food restriction in animal studies. It is suggested that an altered composition of fatty acids (the components of wheat most sensitive to irradiation) is responsible for these marginal effects. Our findings may explain the earlier findings of Bhaskaram and Sadasivan (American Journal of Clinical Nutrition 1975, 28, 130-135) who reported an increase in the number of polyploid cells in the lymphocytes of malnourished children fed irradiated wheat. The most likely mechanisms for such an effect are adaptive, constitutively regulated processes, similar to those which respond to food restriction. It is concluded that the consumption of irradiated wheat does not, therefore, pose any health risk to humans.

Analysis of Variance↗
PubMed1993

The relative importance of mutagens and carcinogens in the diet.

Known mutagens and carcinogens in the diet were compiled and the risk of cancer was estimated on the basis of average exposure levels in Switzerland and carcinogenic potencies from rodent bioassays. The analysis showed that, except for alcohol, the sum of all known dietary carcinogens could only explain a few percent of the cancer deaths attributed by epidemiologists to dietary factors. The discrepancy was explained by a "carcinogenicity" of excess macronutrients. This hypothesis was based on an evaluation of dietary restriction experiments in rats and mice, where a dramatic reducing effect on spontaneous tumour formation was seen. From these experiments, a "carcinogenic potency" was deduced for food in excess (TD50 approximately 16 g/kg per day). Overnutrition in Switzerland was converted into excess food intake and the cancer risk estimated on the basis of the TD50 value. The resulting risk of 60,000 cases per one million lives would allow to explain by overnutrition almost all "diet-related" cancer deaths in humans.

Animals↗
PubMed1992

The potential genotoxicity of sorbates: effects on cell cycle in vitro in V79 cells and somatic mutations in Drosophila.

Sodium sorbate, potassium sorbate and an oxidation product of sodium sorbate, 4,5-epoxy-2-hexenoic acid, were tested for their genotoxic potential in cultured V79 Chinese hamster cells and in somatic cells of Drosophila melanogaster (wing spot test, SMART). In Drosophila only the epoxide showed a weak genotoxic effect. In V79 cells, freshly prepared sodium sorbate solutions at the highest concentrations only (2.5 mg/ml, 24 hr exposure) arrested mitosis at the G2/M cell cycle phase and potassium sorbate (2.5 mg/ml) had no effect. This arrest was reversible after a 24-hr recovery interval. Sodium sorbate solutions stored for up to 208 days were cytotoxic at 2.5 mg/ml, induced cell cycle arrest in the G2/M phase and increased cellular protein content, indicating an action similar to spindle poisoning and a chemical stress reaction (adaptation processes, modification of transcription). Potassium sorbate solutions stored for 28 days were also cytotoxic. With 4,5-epoxy-2-hexenoic acid at concentrations up to 0.01 mg/ml no effects were seen. At higher concentrations (at least 0.1 mg/ml) cell killing was observed, which probably resulted from unphysiologically lowered pH in the culture medium. Overall, the results are interpreted as an indication of a weak genotoxic potential of stored sodium sorbate solutions. Thus, sorbic acid and its potassium salt at the concentrations used for food preservation can still be considered as safe for human consumption.

Animals↗
PubMed1992

Genotoxicity and cell transformation studies with sorbates in Syrian hamster embryo fibroblasts.

Sorbic acid, sodium sorbate and potassium sorbate were tested for their genotoxic potential in the Syrian hamster embryo (SHE) fibroblast micronucleus assay and the SHE cell transformation test in vitro. Sorbic acid and potassium sorbate showed no activity in either test system. When freshly prepared sodium sorbate solutions were used, no genotoxic or cell-transforming activity was detected. However, sodium sorbate as stored solution, which previously had been heated and sonicated to facilitate solubilization, yielded a positive response in both test systems. It is concluded that oxidation products of sodium sorbate that possess genotoxic and cell-transforming properties are formed under conditions of heating, sonication and storage.

Animals↗
PubMed1992

Chemical carcinogens and overnutrition in diet-related cancer.

The intake of known dietary carcinogens was compiled and the cancer risk was estimated on the basis of carcinogenic potencies in animals as derived from the Carcinogenic Potency Database by Gold and co-workers. The total cancer risk was compared with the number of cancer cases attributed by epidemiologists to dietary factors (one-third of all cancer cases, i.e. approximately 80,000 per one million lives). Except for alcohol, the known dietary carcinogens could not account for more than a few hundred cancer cases. This was seen both with the DNA-reactive carcinogens (heterocyclic aromatic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, estragole, aflatoxin B1, ethyl carbamate, to name the most important factors) as well as with those carcinogens which have not been shown to react with DNA (e.g. caffeic acid and the carcinogenic metals arsenic and cadmium). Residues and contaminants turned out to be negligible. Among the various possibilities to explain the discrepancy we investigated the role of overnutrition. Dietary restriction in animals is well known for its strong reducing effect on spontaneous tumor formation. These data can be used to derive a carcinogenic potency for excess macronutrients: the tumor incidence seen with the restricted animals is taken as a control value and the increased tumor incidence in the animals fed ad libitum is attributed to the additional feed intake. For excess standard diet in rats, a carcinogenic potency TD50 of 16 g/kg/day was deduced from a recent study. Overnutrition in Switzerland, estimated to be 5.5 kcal/kg/day, was converted to excess food (1.9 g/kg/day) and the cancer incidence was calculated. The result, 60,000 cancer cases per one million lives, is provocatively close to the number of cases not explained by the known dietary chemical carcinogens. Mechanistic studies will be required to test our hypothesis and investigate the role of different types of macronutrients in overnutrition.

Carcinogens↗
PubMed1991

The real role of risk assessment in cancer risk management.

Regulatory actions taken to reduce the risk of harmful effects of exposure to chemicals often are not commensurate with the toxicological risk assessment. A number of factors relating to psychology, sociology, economics and politics rather than science and medicine affect the final decision. Werner Lutz and colleagues illustrate the situation using the leukemia-inducing chemical benzene as an example.

Benzene↗
PubMed1991

Dietary intake and risk assessment of phototoxic furocoumarins in humans.

The question of whether the furocoumarin content of vegetables is sufficient to induce phototoxic skin reactions after ultraviolet irradiation was examined in two experiments with four human volunteers. In a first experiment, 300 g of celery roots (total phototoxic furocoumarin content 28.2 micrograms/g) was ingested. No skin reactions were observed after UVA exposure (1.5-9 J/cm2), and the blood levels of the furocoumarins--psoralen, 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen (5-MOP)--were below the analytical detection limit of 2 ng/ml. To investigate the phototoxic effects of a mixture of the two most important furocoumarins in vegetables, after gastro-intestinal uptake, 8-MOP and 5-MOP (15 mg each) were ingested separately in a 50% alcoholic solution. A strong and persistent erythema was induced in three out of the four subjects (UVA dose: 3-25 J/cm2). The blood levels immediately before UVA irradiation varied between 14 and 114 ng/ml (8-MOP), and 17 and 70 ng/ml (5-MOP). In the subject who did not show phototoxicity, the blood levels remained at trace levels (3 ng/ml). Two subjects were also tested with a mixture of 10 mg 8-MOP plus 10 mg 5-MOP; in one subject the mixture induced pigmentation only, while in the other a mild-to-medium erythema was induced. The blood levels of the furocoumarins in the two subjects were similar (12-15 ng/ml for 8-MOP and 5-MOP). It is concluded that in humans the phototoxic threshold dose of furocoumarin mixtures is of the order of 10 mg 8-MOP plus 10 mg 5-MOP, which is equivalent to about 15 mg 8-MOP per person (blood levels of 8-MOP and 5-MOP at 30 min after ingestion of about 10-15 ng/ml each). This phototoxic threshold dose was not reached by the consumption of celery roots and other conventional vegetables under normal dietary habits (experimental intake of 2-8 mg per subject of the potentially phototoxic furocoumarin mixture). However, the safety factor between the possible actual intake of furocoumarins and the phototoxic threshold dose is about 2-10, which is relatively small.

5-Methoxypsoralen↗