[Prevention of coronary heart disease with statins. Which patients profit?]. / KHK-Prävention mit Statinen. Welche Patienten profitieren?

Statins are generally considered as safe drugs with a very favorable cost-efficacy-ratio. Calculation of health expenses limits the prescription of statins in primary prevention to persons on high risk (i.e. 20% risk of a coronary infarction within the next 10 years). Prescription of statins in secondary prevention of atherosclerosis is mandatory. Advanced age, impairment of renal function or polypharmacotherapy increase the incidence of severe side-effects, especially myopathy and rhabdomyolysis. These patients should be given statins with lesser risk of these side-effects. Combination of statins with fibrates has attracted public concern, but may be indicated in persons with otherwise not treatable hyperlipidemia. These patients need intensive monitoring, just as patients on other drugs that are metabolized via the enzyme CYP3A4. Patients on statins should get dietary counseling, as an appropriate diet increases the effect of statins.

Uptake of oxygen from the intestine-- experiments with rabbits.

BACKGROUND: Venous portal blood contributes essentially to the oxygen supply of the liver. The effect of oxygen enriched water, applied into the stomach, on oxygenation of portal blood was investigated in rabbits. MATERIAL AND METHODS: 15 anaesthetized rabbits were given 30 ml water, containing 45, 80 or 150 mg O2/l, by a gastric tube. Oxygen pressure was monitored continuously by a measuring probe in the stomach, the abdominal cavity and in the gastric as well as in the portal vein. RESULTS: Intragastrically applied water delivered oxygen slowly, according to the increase in its temperature. The released oxygen was found to penetrate into the abdominal cavity, and a dose-response relationship between oxygen pressure in the stomach and the abdominal cavity was established. 45 mg O2/l water resulted in a negligible increase of oxygen concentration in the abdomen, while 80 or 150 mg O2/l lead to an increase of oxygen by 10 rsp. 20 mmHg in the abdomen, and by up to 14 mmHg in the portal vein. Oxygen penetration occurred according to the known physical and physiological parameters of gas diffusion. Diffusion of oxygen was enhanced, if concurrently with oxygen the water was enriched with CO2. CONCLUSIONS: Our results show that intragastrically applied oxygenated water with more than 45 mg O2/l delivers O2 into the abdominal cavity and the portal vein. This effect may be of clinical relevance in states of impaired liver perfusion such as fatty liver or hepatitis.

Distribution and excretion of TEGDMA in guinea pigs and mice.

The monomer triethyleneglycoldimethacrylate (TEGDMA) is used as a diluent in many resin-based dental materials. It was previously shown in vitro that TEGDMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of 14C-TEGDMA applied via gastric, intradermal, and intravenous administration at dose levels well above those encountered in dental care were examined in vivo in guinea pigs and mice as a test of the hypothesis that TEGDMA reaches cytotoxic levels in mammalian tissues. 14C-TEGDMA was taken up rapidly from the stomach and small intestine after gastric administration in both species and was widely distributed in the body following administration by each route. Most 14C was excreted within one day as 14CO2. The peak equivalent TEGDMA levels in all mouse and guinea pig tissues examined were at least 1000-fold less than known toxic levels. The study therefore did not support the hypothesis.

Anti-obesity drugs: use, mechanisms and clinical importance.

The high prevalence of obesity (>20% in industrialized countries) and its serious health risks, cause severe individual and public costs. Pharmacological interventions are available, such as dietary products and drugs acting on the absorption of nutrients, the production of hormones regulating the feeling of hunger and satiety, and the expenditure of energy. The individual benefit of these pharmacological interventions depends on the efficiency of these measures and the side-effects associated with them. The afflicted patient, and very often even the treating physician, are unable to evaluate the risk/benefit ratio of these drugs for the individual patient. This article describes the possibilities and limitations of pharmacological interventions to treat obesity and gives information on the indications for dietary, pharmacological and surgical interventions.

Biological clearance of TEGDMA in guinea pigs.

The excretion of the dental composite component triethylene glycol dimethacrylate (TEGDMA) in feces and urine in vivo and, using the pendular perfusion technique with segments of jejunum and colon, the biliary and enteric excretion in situ were investigated in anesthetized guinea pigs. In the in situ experiments guinea pigs (n = 4) received TEGDMA (0.02 mmol/kg body weight labelled with a tracer dose 14C-TEGDMA 0.7 kBq/g body weight) injected into the jugular vein. In the in vivo experiments guinea pigs (n = 4) received TEGDMA (+14C-TEGDMA; same dose as above) via a gastric tube. Urine and feces were collected for 24 h. In the in situ experiments organs were removed from the guinea pigs 60 min after the beginning of the experiment, and the 14C radioactivity measured. During the 60-min perfusion period the calculated amount of 14C radioactivity excreted into the total jejunum and colon was 0.9 +/- 0.2% and 1.9 +/- 0.1% of the dose administered, respectively (means +/- SEM). Of the 14C-TEGDMA dose, 3.7 +/- 0.2% was found in the bile. A significantly (P < 0.05) higher bile/blood concentration ratio was found 10 min after injection of TEGDMA as compared with the ratios at 20 to 60 min. The following 14C activities (percent of the dose) per total organ were found in guinea pigs (in situ experiment; means +/- SEM): 6.9 +/- 1.7 (muscle), 3.9 +/- 0.5 (kidney), 3.3 +/- 0.1 (skin), 1.4 +/- 0.1 (blood), and 1.2 +/- 0.1 (liver). The 14C activity in all other organs was < 0.4%. The total 14C recovery in all organs tested was 17.5 +/- 1.8%. Over 24 h the amounts of 14C activity excreted in the feces and urine were 0.5 +/- 0.1% and 14.7 +/- 1.8% of the dose administered, respectively (means +/- SEM). The following 14C activities (percent of the dose) per total organ or contents of organs were found (means +/- SEM): 1.4 +/- 0.3 (liver), 0.8 +/- 0.3 (muscle), 0.5 +/- 0.1 (skin), and 0.5 +/- 0.1 (contents of cecum). The 14C activity in all other organs was < 0.2%. The total 14C recovery in all organs tested was 3.9 +/- 0.9%. In a second series of in vivo experiments exhaled air from the animals was captured during the 24-h experimental period. Of the administered dose, 61.9 +/- 4.6% of the 14C (means +/- SEM; n = 4) was exhaled as 14C-carbon dioxide. The results indicate a rapid clearance of 14C-TEGDMA and/or 14C-TEGDMA metabolite(s) from the organism and exhalation is the major route of elimination.

[New therapy approaches in rheumatoid arthritis. Preventing early joint destruction]. / Neue Therapieansätze bei rheumatoider Arthritis. Frühzeitig die Gelenkdestruktion aufhalten.

New perceptions about the cellular and molecular interactions involved in the inflammatory process have created a basis for specific treatment of rheumatoid arthritis. The therapeutic arsenal has now been expanded to include more selective inhibitors of cyclooxygenase, antibodies and antagonists of the cytokines, and an inhibitor of pyrimidine synthesis. Large clinical trials have demonstrated the efficacy of early immunomodulatory treatment aimed at preventing joint destruction, as well as the superiority of the combination therapy over monotherapy with a long-acting antirheumatic agent. To date, uniform criteria for the evaluation of the results of treatment are, however, lacking.

Cytotoxicity of dental composite components and mercury compounds in pulmonary cells.

The cytotoxic potentials of the dental composite components triethyleneglycoldimethacrylate (TEGDMA) and 2-hydroxy-ethylmethacrylate (HEMA) as well as mercuric chloride (HgCl2) and methyl mercury chloride (MeHgCl) were investigated. Proliferating A549 and L2 cell monolayers were cultured in the absence or presence of composite components or mercurials. Twenty-four hours later the tetrazolium salt XTT (sodium 3'-[1-phenyl-aminocarbonyl)-3,4-tetrazolium]bis(4-methoxy-6-nitro)benzenesulphonic acid) was added. Formazan formation was quantified using a microtiter plate reader. EC50 values were obtained as half-maximum-effect concentrations from fitted curves. EC50 values were in A549 cells (mean values +/- standard deviation; n = 12; micromol/l); HEMA 8854+/-1882; TEGDMA 1821+/-529; HgCl2 41+/-7 and MeHgCl 27+/-3. EC50 values in L2 cells were: HEMA 191+/-28; TEGDMA 112+/-16; HgCl2 25+/-6 and MeHgCl 8+/-6. All tested substances induced a dose-dependent loss of viability in A549 and L2 cells after 24 h. The EC50 values of both mercurials were significantly (p < 0.05) lower compared to the values of both composite components. TEGDMA was about 5-fold (A549 cells) and about 2-fold (L2 cells) more toxic compared to HEMA. It is to be assumed that the risk of lung cell damage by dental composite components is even more unlikely.

Cytotoxicity of dental composite components and mercury compounds in lung cells.

OBJECTIVE: The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA), as well as mercuric chloride (HgCl2) and methylmercury chloride (MeHgCl) was investigated on the release of lactatedehydrogenase (LDH) from alveolar epithelial lung cell lines in vitro. METHODS: The confluent cell layers from the A549 (human, malignant) and the L2 cells (rat) were incubated with various concentrations of HEMA, TEGDMA, MeHgCl and HgCl2 at 37 degrees C in 2% (v/v) CO2 atmosphere for 8h. In further experiments the L2 cells were incubated with the same compounds for 6-48 h. LDH release was measured and the values were expressed as percentage of the LDH content. The values were plotted on a concentration log-scale and the substance concentration at the maximum slope was assessed as effective concentration (EC50). RESULTS: A significant (p<0.05) increase in the LDH release was found in the L2 cells after 8-h incubation with HEMA (4 mmol/l), TEGDMA (2 mmol/l), MeHgCl (0.01 mmol/l) and HgCl2 (0.015 mmol/l), and in A549 cells with HEMA (14 mmol/l), TEGDMA (15 mmol/l), MeHgCl (0.15 mmol/l) and HgCl2 (0.05 mmol/l), compared to controls. The EC50 values from compounds in the L2 cells are shown in the following table (mean; sem in parentheses; n=3-6; #n=1): [see text]. SIGNIFICANCE: The toxic effect of HgCl2 and MeHgCl from the L2 cells was about 100-700-fold higher than of the dental composite components. A significant (p<0.05) time dependent increase of toxicity was observed with TEGDMA, HEMA and MeHgCl.

Effect of zinc chloride on GSH synthesis rates in various lung cell lines.

Zinc toxicity has been linked to decreased reduced glutathione (GSH) and increased oxidized glutathione (GSSG) contents, which might be caused by a GSSG reductase inhibition by zinc. In this study we investigated zinc effects on GSH synthesis rates in various lung cell lines by thin-layer chromatography after (35)S-cysteine incorporation. Two alveolar epithelial cell lines (A549 and L2) and two human fibroblast-like lung cell lines (11Lu and 16Lu) were used in this study. Equipotent protein synthesis inhibition for the different cell lines was reached after 2 h (L2, 11Lu), 3 h (16Lu), and 4 h (A549) zinc exposure (15-200 microM) to cells. Here GSH depletion and GSSG increase in A549 cells were markedly lower than in the other cell lines tested. Incorporation of cysteine (Cys) into GSH was not different in the cell lines tested, while 11Lu cells only demonstrated a decrease of newly synthesized GSH after 1 h of (35)S-Cys exposure when cells were exposed to zinc. Only 11Lu cells showed a markedly decreased Cys availability as compared with the other cell lines. In all cell lines the availability of Cys was not affected by exposure to zinc. No compensating increase in GSH synthesis rates was found after zinc-mediated cellular GSH depletion.

Active transport inhibition in rat small intestine by amphiphilic amines: an in vitro study with various local anaesthetics.

In the present investigation with rings of everted rat small intestine, amphiphilic amines such as local anaesthetics (e.g. lidocaine, procaine, tolycaine) were employed to study their effects on intestinal absorption of methyl alpha-D-glucoside, L-leucine, D-fructose, and 2-deoxy-D-glucose. All the amphiphilic amines tested, except for benzocaine, significantly inhibited Na(+)-dependent active uptake of methyl alpha-D-glucoside and L-leucine while leaving uptake of D-fructose (facilitated diffusion) and 2-deoxy-D-glucose (passive diffusion) unaffected. Increasing concentrations of lidocaine in the incubation medium inhibited the uptake of methyl alpha-D-glucoside (IC(50) approximately 3.5 mmol/L) and L-leucine (IC(50) approximately 6 mmol/L) in a dose-dependent manner. Complete reversibility of the inhibitory effect could only be achieved at short-term incubations (

Lack of effects of hydrocortisone pretreatment on zinc-induced changes in protein assemble.

Inhalational zinc intoxication may lead to the development of acute respiratory distress syndrome (ARDS). Pharmacological treatment of ARDS is based on glucocorticoids, while the efficiency of glucocorticoid treatment is discussed controversially. Glucocorticoid pretreatment of lung cell lines is known to cause disparate effects with regard to zinc susceptibility. Both substances are known to each interact with protein metabolism. In the present study, zinc effects were examined on hydrocortisone (HC)-pretreated lung cell lines by detection of content and synthesis of different proteins after two-dimensional (2D) gel electrophoresis. (1) In HC- pretreated fibroblast-like 11Lu and alveolar epithelial L2 cells, no zinc-mediated changes after silver staining of 2D gels were seen. Few differences occurred in HC-pretreated alveolar epithelial A549 cells that might be explained by the appearance of heat shock proteins (hsp) after zinc exposure. (2) In autoradiographs after 35S-Met incorporation only in 11Lu cells, small differences occurred after HC treatment as compared to controls without HC. (3) All cell lines tested demonstrated the same zinc-mediated changes in autoradiographs with a nearly complete loss of synthesized proteins and an appearance of a few new spots. These changes were reversible in all cell lines after washing out of external zinc. The new spots were transiently expressed for a few hours after zinc exposure. (4) The overall effect of HC pretreatment was rather unimpressive. The virtual lack of major effects does not support the hypothesis that a gross interaction between glucocorticoids and zinc at the cellular protein synthesis level would be an important mechanism of influence in zinc-induced lung injury.

The effect of physical activity on absorption and metabolism of an orally applied drug (pentoxifylline).

STUDY OBJECTIVE: In this study the effect of physical activity on absorption and metabolism of a therapeutic drug was investigated by comparing plasma concentrations and metabolism of pentoxifylline during rest and after standardized physical activity. METHODS AND PATIENTS: After an oral dose of 600 mg pentoxifylline plasma concentrations of the drug and its metabolite 1 were monitored in nine healthy volunteers during five hours with the persons at rest and in a second experiment after ability-adapted standardized bicycle ergonometry. MAIN RESULTS: In six of nine test persons exercise led to significant higher plasma concentrations of the drug at 2 hours after application (+77%; p <0.01) compared to the concentrations in the same persons at rest. Reductive metabolism of pentoxifylline decreased in all test persons after physical activity giving 19% lower maximal concentrations of metabolite 1 (p = 0.06, not significant) and a 16% lower area under the concentration time curve (p <0.02). CONCLUSIONS: Our results indicate that physical activity can influence absorption and metabolism of a drug.

Effect of dental materials on gluconeogenesis in rat kidney tubules.

The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA) as well as mercuric chloride (HgCl(2)) and methylmercury chloride (MeHgCl) on gluconeogenesis was investigated in isolated rat kidney tubules. From starved rats kidney tubules were prepared and isolated by digestion with collagenase. Every 10 min up to 60 min 1-ml samples were drawn from the cell suspension for quantitating the glucose content. Glucose formation in controls was 3.3 +/- 0.2 nmol/mg. per min (mean +/- SEM, n=21). Relative rates of glucose formation were obtained by expressing individual rates as a percentage of the corresponding control. X-Y concentration curves (effective concentration, EC) of the substances were calculated by fitting a four-parametric sigmoid function to the relative rates of glucose formation at various test concentrations. At the end of the incubation period cell viability was assessed by trypan blue exclusion. Cell viability decreased within the 60 min interval from 90 to approx. 80% (controls), <25 (HEMA), <20 (TEGDMA), <10 (MeHgCl), and <10% (HgCl(2)). Values of 50% effective concentration (EC(50)) were calculated from fitted curves. EC(50) values were (mmol; mean +/- SEM; n=4): HEMA, 17.7 +/- 2.9; TEGDMA, 1.8 +/- 0.2; MeHgCl, 0.018 +/- 0.0005; and HgCl(2), 0. 0016 +/- 0.0005. The toxic effect of HgCl(2) was approximately 1000 or 10 000 higher than that of the dental composite components TEGDMA or HEMA, respectively.

Influence of glutathione on zinc-mediated cellular toxicity.

The effect of zinc on various pulmonary cell lines has been studied by measuring the depletion of total cellular glutathione after exposure to zinc(II) chloride at different concentrations. Total cellular glutathione (cGS) was measured at 31+/-3 nmol/mg, 3.8+/-0.6 nmol/mg, and 3.7+/-1.2 nmol/mg protein in A549, L2, and 11Lu cells, respectively. After treatment with buthionine sulfoximine (BSO), the cGS levels decreased by 20% in A549 cells and below 0.2 nmol/mg in L2 and 11Lu cells. Exposure of A549 cells to 25-200 microM ZnCl2 for 4 h alone decreased the cGS content to 60-80%. There was little additional effect in BSO-pretreated cells. In L2 and 11Lu cells, the decrease of cGS was 70-85% following exposure to 15-150 microM ZnCl2 for 2 h. If BSO was also used, the decrease in cGS was 85-95% in L2 cells and 75-85% in 11Lu cells. Exposure to 25-250 microM ZnCl2 for 2 h diminished protein synthesis as determined by radiolabeled methionine incorporation, with half-maximum inhibition (EC50) from 40-160 microM ZnCl2. To attain similar EC50 values in BSO-pretreated cells, only about half the zinc concentrations were required as compared to cells without pretreatment. The decrease of cGS was accompanied by an increased ratio of oxidized: reduced glutathione that was more pronounced in cells with low glutathione content.

Kinetic analysis of 59Fe movement across the intestinal wall in duodenal rat segments ex vivo.

Duodenal segments from iron-deficient and iron-adequate rats were luminally perfused ex vivo with solutions containing 1, 10, 50, 100, 200 and 500 micromol 59Fe/l. When duodenal tissue load and mucosal-to-serosal transport had reached a steady state, perfusion was continued without luminal 59Fe supply. Mobilization of 59Fe from the duodenal tissue into the serosally released absorbate followed first-order rate kinetics, which permitted calculation of the asymptotic maximum, the rate constant, and the initial mobilization rate for tissue-to-absorbate transfer. There was no evidence for adaptation of 59Fe tissue binding in iron-deficient segments. 59Fe tissue-to-absorbate transfer increased in proportion to the mobilizable fraction of recently absorbed iron in the tissue, which is indicative of simple diffusion or carrier-mediated transport below saturation. Regulation of the mucosal uptake step appears to determine the mobilizable 59Fe fraction and thus the adaptation of the overall iron absorption process to the demand. Iron retention in the duodenal tissue and iron transfer from here into the body appear not to be either regulated or rate limited.

Influence of zinc on protein metabolism in various lung cell lines.

Toxic cellular effects after exposure to elevated zinc concentrations affect protein metabolism. We separated proteins by 2D-PAGE after cellular zinc exposure in order to decide whether changes in protein metabolism of specific proteins by elevated zinc might be a main critical cellular effect. The investigation was performed with fibroblast-like (11Lu, 16Lu) and alveolar epithelial (L2, A549) lung cell lines. Silver staining and autoradiography after radiolabelled methionine incorporation of 2D gels of cellular proteins was executed in order to look for specific changes in protein content. Methionine incorporation decreased in a concentration- and time-dependent manner to values of 10% with 100 mumzinc chloride for 3hr in the non-malignant cell lines, while about 20% was reached with 200 mum after 4hr of incubation in the malignant A549 cells. In silver stained 2D gels of zinc-exposed cells only few differences as compared to controls were detectable. Autoradiograms of 2D gels after methionine incorporation showed few additional spots that could be heat shock proteins in alveolar epithelial cell lines after zinc exposure. Autoradiographically detectable methionine in 2D-gels obtained after exposure of cells to high zinc concentrations for time intervals greater than 1hr showed a time-dependent decrease in all cell lines. This decrease was accompanied by an increase of three characteristic spots at 28/9 (kDa/pI), 32/8 and 42/7.5 respectively, amounting to 15-30% of all incorporated radioactivity after 2-4hr of zinc exposure. When cells were allowed to recover from zinc poisoning, similar 2D gel spot patterns as compared to controls without zinc exposure were obtained in all cell lines tested.

Effects of omega-3 fatty acids on renal function and electrolyte excretion in aged persons.

Prostaglandin (PG) E2 formation, especially relevant for renal function in the state of renal vascular disease, is inhibited by omega-3 fatty acids. On the other hand, omega-3 fatty acids are under evaluation in chronic inflammatory kidney diseases, because of their ability to modulate immunologic cell response. We evaluated the effect of 1.7 g/d eicosapentaenoic acid (EPA), given with cod liver oil for four weeks to elderly persons with atherosclerosis. Enrichment of EPA coincided with inhibition of PG biosynthesis, transiently plasma creatinine increased, while creatinine clearance and excretion of solutes with the urine decreased in our experimental subjects. At the end of the four week study no effect of omega-3 fatty acids on renal function was found. Further studies are warranted to evaluate the potential benefit of omega-3 fatty acids on renal function in elderly persons.

Inhibition of protein synthesis by zinc: comparison between protein synthesis and RNA synthesis.

Inhalation of zinc fumes may lead to the acute respiratory distress syndrome. The mechanisms of pulmonary zinc toxicity are not yet understood. Therefore we investigated zinc-dependent depression of protein and RNA synthesis in rat and human lung cell lines. 1. After exposure to 120 or 150 micromol/l zinc, RNA synthesis as assessed by uridine incorporation decreased by 60-70% between 0 and 2 h exposition in rat alveolar type II cells (L2 cells) and human fibroblast-like cells (11Lu and 16Lu cells), and by 90% between 0 and 4 h in carcinoma-derived cells (A549 cells). 2. After 2 h exposure, L2, 11Lu, and 16Lu cells were half-maximally inhibited by 50 micromol/l zinc, whereas A549 cells were more resistant with half-maximal inhibition at 100 micromol/zinc. 3. Protein and RNA synthesis was inhibited in parallel in L2, 11Lu, and A549 cells as indicated by simultaneous determination of uridine and amino acid incorporation. In 16Lu cells, the decline in protein synthesis preceded RNA synthesis inhibition. Pretreatment with RNA synthesis inhibitors (amanitin or actinomycin D) had no effect on time curve and intensity of RNA synthesis inhibition. Taken together, our results indicate that the suppression of RNA and protein synthesis likely are independent phenomena, due to direct zinc effects on these biosynthetic pathways.

[Toxicologic risk assessment and prevention: rational and irrational approaches]. / Toxikologische Risikobewertung und -vermeidung: Rationalismen und Irrationalismen.

Worldwide, the management and evaluation of risks caused by chemical compounds are handled by the aid of threshold concentrations below of which one can be sure that no biological effect whatsoever can be observed. At the working place, we use the maximally tolerated concentration of the chemicals (MAK) and, in addition, the biologically tolerated concentrations (BTC) of the compounds either in blood or in other body fluids to which a male and/or female worker is exposed. These threshold concentrations should cover any toxic effect including on the one hand mere deviations of clinical chemical values without a disturbed function, i.e. symptoms of a disease as well as, on the other hand, carcinogenic, mutagenic and even allergic effects. Threshold concentrations, however, exist only for acute and chronic toxic effects and not for carcinogenic and/or mutagenic effects. In these cases, again, worldwide, the concept of minimizing the risks by the exposure is preferred since no toxicologist can be found to assure a "safe" concentration of a chemical compound that exert carcinogenic and/or mutagenic effects. With respect to these effects a proven carcinogenic and/or mutagenic effect in human beings must be discerned from a suspected effect on the basis of animal experiments or in vitro models. However, there exist also paradigms of a clearcut connection between a chemical substance or its metabolites causing carcinogenic and/or mutagenic effects in model experiments from which a clearcut suspect of similar reactions after the exposure of human beings can be drawn. In general, carcinogenic risks are overestimated in our societies. Following the data of experienced British epidemiologist most tumor diseases can be traced back to food consumption, beverages and tobacco and even sexual behavior must be ranked as cause for tumors before the rare exposure to dangerous chemicals at the working place. It is worthwhile to mention that natural toxins produced by bacteria and even infectious diseases or diseases caused by parasites are far more serious than the exposure to any man made chemical product including the Seveso poison, i.e. 2,3,7,8-TCDD, and related compounds. Vice-versa, the assumption that naturally occurring poisons could be neglected may lead to fatal experiences as for instances the outbreak of St-Anton's fire, i.e. the gangraeneous type of ergot alacaloide intoxication after having swallowed claviceps purpurea poisoned "Müsli" produced by rye collected in the fields and ground in a hand mill. In Middle-Europe, since 1880, when the threshold of 0.1% claviceps purpurea in rye was established, no poisonous epidemia of St. Anton's fire was observed.

Arsenic-copper interaction in the kidney of the rat: influence of arsenic metabolites.

The present study was an attempt to investigate whether the renal accumulation of Cu observed in the kidneys of rats and guinea-pigs exposed to arsenite (As-III) was an effect of arsenite alone or also shared by its metabolites--arsenate (As-V), dimethylarsinic acid and monomethylarsonic acid. The four arsenic compounds were administered subcutaneously and separately to rats for 12 days in increasing doses. Kidney, liver and blood were taken and analysed for As, Cu and other trace elements by atomic emission spectrometry. Results indicate that administration of As-V leads to renal Cu accumulation similar to that observed on administration of As-III and that the accumulation in both cases is dependent on the dose of arsenic, although higher doses of As-V were required to achieve renal Cu levels comparable to that of As-III. A constant molar As:Cu ratio independent of arsenic dose was obtained in the kidney. Dimethylarsinic acid did not affect renal Cu levels at all. Administration of monomethylarsonic acid led to a slight increase in renal Cu levels which did not increase further in spite of increased doses of monomethylarsonic acid. It is concluded from these studies that neither the metabolic transformation of inorganic arsenic to its methylated products nor its metabolites (dimethylarsinic acid and monomethylarsonic acid) caused the observed renal Cu accumulation, rather, the inorganic form of As, either in the trivalent or pentavalent form is responsible.