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W Forth

Publications and source records attributed to W Forth.

At least 37 records · Page 2Linked to original sources
PubMed1996

[Toxicologic risk assessment and prevention: rational and irrational approaches].

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.

Carcinogenicity Tests↗
PubMed1995

Reversal of oxophenylarsine-induced inhibition of glucose uptake in MDCK cells.

It has been shown that oxophenylarsine (PhAsO) inhibits glucose uptake in MDCK cells. In addition to the known impairment of cellular energy metabolism, this inhibition may contribute to the acute toxicity of trivalent organic arsenicals. We have investigated the effect of BAL, DMPS, DMSA, and other sulfur compounds on cellular incorporation of [U-14C]PhAsO and their efficacy to revert PhAsO-induced inhibition of glucose uptake. In the presence of [U-14C]PhAsO (2 microM), the radiolabel was steadily accumulated by the cells over 150 min without any signs of severe cell damage (e.g., altered morphology, increased LDH release). A notable decrease of cellular ATP was only observed at 150 min, whereas within 30 min uptake of D-[6-(14)C]glucose was reduced to 40% of controls. When BAL, DMPS, or DMSA was added after 30 min, the inhibition of glucose uptake was reversed, accompanied by a decrease in cell-associated radiolabel from [U-14C]-PhAsO. Water-soluble DMPS and DMSA required longer times than BAL for comparable effects. 2,3-Bis(acetylthio)propanesulfonamide, a thioester derivative, and dithiothreitol, a 1,4-dithiol, were effective only with the highest concentration tested (200 microM). 2-Mercaptoethanol neither reversed inhibition of glucose uptake nor influenced [U-14C]PhAsO incorporation. Our results show that inhibition of glucose uptake is a very early event in PhAsO cytotoxicity which occurs before any decrease of cellular energy metabolism and/or full cellular loading with arsenic comes into effect. The more rapid onset of action of lipophilic BAL compared to PhAsO action.

Adenosine Triphosphate↗
PubMed1995

Influence of glucose on the toxicity of oxophenylarsine in MDCK cells.

Trivalent arsenicals like oxophenylarsine (PhAsO) inhibit cellular pyruvate dehydrogenase, thus leading to a drop of acetylCoA formation and a slow-down of the citric acid cycle. Glucose may protect cells from arsenic toxicity, because increased glycolysis may prevent fatal shortage of ATP. On the other hand, PhAsO has been shown to inhibit glucose uptake in Madin-Darby canine kidney (MDCK) cells. We have investigated the effect of PhAsO on viability, ATP levels and glucose uptake of MDCK cells in the presence of normal (5 mmol/l) and low (0.01 mmol/l) glucose concentrations. At normal as well as at low glucose concentrations, cell viability as assessed by formazan formation was not affected by PhAsO concentrations up to 2 mumol/l within 3 h of observation. At higher PhAsO concentrations viability was diminished earlier and more pronounced in the presence of low glucose concentrations. 10 mumol/l PhAsO induced a drastic drop of ATP within 30 min which was followed by an almost complete loss of viable cells after 180 min in the presence of low glucose concentrations, while at normal glucose levels no influence on ATP contents or on cell viability was detected within 60 min of incubation. On the other hand, glucose uptake, determined as 14C accumulation by cells incubated for 10 min with D-[6-14C]-glucose, was inhibited by PhAsO at low as well as at normal glucose concentrations in a dose dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyl Coenzyme A↗
PubMed1995

Effect of DMPS and various adsorbents on the arsenic excretion in guinea-pigs after injection with As2O3.

The present experiments were performed to test the possibility of interrupting the enterohepatic circulation of arsenic (As). Therefore the efficacy of adsorbents to bind As and/or As-DMPS adducts in vitro and their effect on the excretion of As into the feces and urine in vivo were investigated after injection of As2O3 and DMPS in guinea-pigs. The adsorbents bentonite, activated charcoal or colestyramine, respectively, were tested. Only slight binding of 73As (< 5% of the 73As dose) was observed to all adsorbents in vitro. After addition of DMPS, a good binding was found for 73As to colestyramine (50%) or activated charcoal (60%), respectively. However, the 73As-DMPS adduct was removed from the activated charcoal during washing. In the first in vivo experiment, male guinea-pigs (n = 4/group) received As2O3 [0.02 mmol As(III)/kg s.c. labelled with a tracer dose of 73As(III) (0.14 kBq/g)], 30 min later DMPS (0.1 mmol/kg i.p.) and by gastric tube (10 ml/kg body wt) either saline, bentonite (1 g/kg), activated charcoal (1 g/kg) or colestyramine (0.2 g/kg), respectively. Urine and feces were collected for 24 h. No increase in 73As excretion into the feces was observed after administration of DMPS and all adsorbents, compared to control animals. In the second in vivo experiment male guinea-pigs (n = 4/group) received the same As2O3 (+ 73As)- and DMPS dose. In addition, with a gastric tube (10 ml/kg) saline, colestyramine (0.2 g/kg), DMPS (0.1 mmol/kg), or the combination of DMPS (0.1 mmol/kg) + colestyramine (0.2 g/kg) were administered according to the scheme given in the following table. The amount of feces excreted did not differ between groups. Excretion of 73As within the feces during the first 12 h after As injection is shown in the following table (mean +/- SEM). The same amount of 73As (34% of the 73As dose) was excreted into the urine from animals in groups 4 and 5 during this time. Obviously, the combined oral administration of DMPS + colestyramine markedly enhanced fecal excretion of As mobilized by DMPS i.p. It is suggested that interruption of enterohepatic circulation of As may be a valuable adjunct in the treatment of As poisoning.

Animals↗
PubMed1995

Influence of 2,3-dimercaptopropanol and other sulfur compounds on oxophenylarsine-mediated inhibition of glucose uptake in MDCK cells.

Trivalent monosubstituted organoarsenicals, e.g., oxophenylarsine (PhAsO), exert various detrimental effects on mammalian cells. In addition to their well known interference with pyruvate and ketoglutaric acid oxidation, the effect on other cellular functions such as uptake of glucose may contribute to their acute toxicity. Different effects of PhAsO on insulin-stimulated and insulin-independent uptake of hexoses in various tissues have been reported. It has been shown previously that PhAsO inhibits the stereospecific uptake of glucose in MDCK cells. In this work, the insulin dependence of glucose uptake in these cells and the effects of 2,3-dimercaptopropanol (BAL), dithiothreitol (DTT) and 2-mercaptoethanol (ME) on PhAsO-induced inhibition of glucose uptake were investigated. A 200 mumol l-1 concentration of insulin had no measurable effect on cellular 14C accumulation from D-[6(-14)C]glucose, indicating an insulin-independent hexose transport system. In the presence of 2 mumol l-(-1) of PhAsO, glucose uptake was lowered to less than 50% of controls within 30 min. Greater inhibition was observed with higher concentrations of PhAsO, but cell viability as assessed by formazan formation started to decrease at concentrations > or = to 5 mumol l-1, especially after longer exposure times. When BAL was added in a ten-fold molar excess 30 min after beginning incubation with PhAsO (2 mumol l-1, virtually complete recovery of inhibited glucose uptake occurred within 10 min after addition. ME at up to a 100-fold molar excess over arsenic had no influence on the inhibition of glucose uptake within 120 min after addition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Small-intestinal transfer mechanism of prunasin, the primary metabolite of the cyanogenic glycoside amygdalin.

1. The small-intestinal transfer of prunasin (D-mandelo-nitrile-beta-D-glucoside), the primary metabolite of amygdalin which is not absorbed in the small intestine as such, was studied in rat jejunum and ileum in vitro. 2. As shown by high pressure liquid chromatography, prunasin is transferred essentially intact across the intestinal wall, without cleavage of the glycosidic bond and thus no formation of benzaldehyde or cyanide during the mucosal passage. 3. Only the jejunal transfer of prunasin followed saturation kinetics (vmax = 1.6 mumol cm-1 min-1; KT = 460 mumol l-1) and exhibited a clearsodium-ion dependence. As indicated by the temperature dependence, only the jejunal mucosa-to-serosa transfer and the corresponding tissue uptake of prunasin required apparently high activation energies. Transfer in the terminal ileum showed diffusion characteristics. 4. Jejunal methyl alpha-D-glucoside transfer was inhibited by the presence of prunasin. Furthermore, the tissue uptake of methyl alpha-D-glucoside in rat jejunum was competitively inhibited by prunasin. 5. The results indicate that prunasin is absorbed unmetabolised in the jejunum of the rat via the transport system of glucose.

Amygdalin↗
PubMed1995

[Toxic compounds in our environment--challenge or cost of prosperity].

The goal of this contribution was the description of the possibilities as well as the limitations to which a toxicologist is confronted when evaluating potential toxic compounds to which human beings can be exposed during their lifetime. The number of substances is overwhelming. The available methods for the evaluation are not satisfactory for everybody. Nevertheless, the results are not as bad as sometimes is asserted: in the industrial societies, the expected life span of men increases. The evaluation of the effects is unsatisfactory especially for the carcinogenic and allergic potential of foreign compounds. This is the consequence of our limited knowledge about the biological processes underlaying these effects, or, in other words, research must be intensified in this field. Finally, the experiences of the public as well as of the media with risks and their evaluation are not satisfactorily developed. The intellectual development of the public is rather slow compared to that in business life and economics. This means that everybody oughts to acquire knowledge in order to be able to make appropriate decisions in a world increasingly complicated. Otherwise, our society ends up with a convenient home for the aged combined with a cemetery. And this, by the way, is less than a recreation center (Freizeitpark).

Animals↗
PubMed1994

Influence of glucocorticoids and activated charcoal on the lethality of rats after acute poisoning with T-2 toxin, diacetoxyscirpenol, or roridin A.

Lethal doses of the trichothecene mycotoxins T-2 toxin (1.5 mg/kg), diacetoxyscirpenol (DAS; 2.3 mg/kg) or roridin A (1.3 mg/kg) were intravenously administered to rats. When rats were treated with either activated charcoal (Superchar liquid, Norit A; 1 g/kg, po) or dexamethasone (8 mg/kg, iv) 30 min after poisoning with one of the trichothecenes, lethality was only marginally reduced. However, when the combination of activated charcoal (Superchar liquid or Norit A) and dexamethasone was administered, the survival rate of animals after 30 days was significantly enhanced by up to 50%. Comparison between 2 preparations of activated charcoal, Norit AR with a surface area of 1,000 m2/g and Superchar liquidR with a surface area of 3,000 m2/g, each in combination with dexamethasone, revealed no difference in their therapeutic efficacy. Prednisolone (60 mg/kg) was as effective as dexamethasone (8 mg/kg), each administered with activated charcoal, in preventing death in acute T-2 toxicosis.

Animals↗
PubMed1994

Oral and subcutaneous administration of cadmium chloride and the distribution of metallothionein and cadmium along the villus-crypt axis in rat jejunum.

The route of Cd uptake influences the distribution of Cd, other metals, and metallothionein (MT). Although intestinal MT levels related to the tissue mass did not show proximodistal gradients after sc administration of CdCl2, orally administered high doses of CdCl2 increased mucosal MT levels longitudinally from the duodenum to the ileum. The gradient abolished when the mucosal MT level was related to the intestinal length. To further elucidate this finding, three groups of rats were studied: a control group, a group receiving dietary CdCl2, and a group receiving sc injections of CdCl2. The small intestine was removed after a 14-d treatment. Midjejunal segments were mounted in a cryomicrotome and cut transversally into five layers along the villus-crypt axis. Mucosal enzymes were measured to control these sections. Cd was measured by AAS and MT by RIA. Alkaline phosphatase and lactase activities exhibited the typical villus-crypt gradient. Mucosal MT levels paralleled those of Cd. Although Cd and MT concentrations were high at the tip of the villi and low in the crypts after oral administration, sc treatment reversed that profile. A molar Cd-MT ratio of approx 10 or 1 was reached after po or sc treatment, respectively. This demonstrates that only oral Cd may lead to an accumulation of Cd in the mucosal tissue fairly exceeding the binding capacity of small intestinal MT. The results show that different routes of Cd intake lead to a different MT-induction pattern in the intestinal wall and that longitudinal Cd and MT concentration gradients in the small intestine observed after high oral doses are a result of their high levels at the villus tips.

Administration, Oral↗
PubMed1994

Effect of various antidotes on the biliary and intestinal excretion of arsenic in situ and into the feces in vivo in guinea-pigs after injection of As2O3.

The effect of various antidotes on the excretion of arsenic into the feces in vivo and on the biliary and enteric excretion in situ was investigated on segments of jejunum and colon in anesthetized guinea-pigs using the pendular perfusion technique, according to Henning and Forth (1982). In the in situ experiments guinea-pigs received As2O3 (0.02 mmol As(III)/kg) and 30 min later, British-Anti-Lewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) or 2,3-bis-(acetylthio)propanesulfonamide (BAPSA) (0.1 or 0.7 mmol/kg each) into the jugular vein. In the in vivo experiments guinea-pigs received As2O3 s.c. (same dose as above) and 30 min later the same antidotes (0.1 mmol/kg i.p.). The feces were collected for 24 h and the arsenic content measured. During the 60-min perfusion period the amount of arsenic excreted into the jejunum or colon was only 3% or 0.4% of the dose administered, respectively. Of the arsenic dose, 8% was found in the bile. None of the antidotes had an effect on the arsenic excretion into the jejunum or colon. No change in biliary excretion was found in animals treated with BAL, 0.1 or 0.7 mmol/kg, respectively. DMSA, BAPSA or DMPS, 0.1 mmol/kg, increased the biliary excretion of arsenic to 14, 33, or 43% of the dose administered and after 0.7 mmol/kg to 29, 37, or 42%, respectively. Furthermore, a significant increase (P > 0.05) was found for the bile/blood concentration ratio in the following order: control < BAL < DMSA < BAPSA approximately DMPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Intrinsic corporoantropyloric coordination of motility and gastric emptying.

This study examined changes in gastric motility after interruption of the intramural nervous circuitry from the proximal portion of the stomach to the antrum by a circumferential gastric myotomy. Seven extraluminal strain gauge force transducers and five platinum electrodes were implanted along the antropyloroduodenal region, and gastric emptying was studied by X-ray after a 280-g solid meat meal mixed with barium. The motility index increased aboral to the myotomy by 106 and 69% in the distal antrum and pylorus, respectively, in the first postprandial 30-60 min because of the loss of an inhibitory neural influence from the proximal part of the stomach. Destabilization of the basic electrical rhythm occurred in 50% of the dogs. This was apparent as tachyarrhythmia or bradyarrhythmia and an early postprandial 2-11% decrease in slow-wave frequency and a 100% increase in slow-wave amplitude. Coordination of corporoantropyloric contractions was disorganized. Frequent segmenting and antidromic contractions were associated with reduced periods of optimal emptying and disturbed intragastric chyme transport into the constricted antrum. A 10-30% gastric emptying delay of approximately 50 min was a consequence of myotomy despite an increased antroduodenal motor gradient after myotomy. The overall results suggest that intact intramural innervation and muscular continuity are essential for coordination of corporoantropyloric motility and normal gastric emptying.

Animals↗
PubMed1993

Isolated rat kidney tubules as a screening system for arsenic antidotes.

Gluconeogenesis is one of the metabolic pathways severely affected in acute arsenic poisoning. We have studied gluconeogenesis in isolated kidney tubules of male Sprague-Dawley rats to screen various sulfur compounds for antidotal properties against inorganic and organic arsenicals. Freshly prepared kidney cells from starved rats synthesized glucose from added pyruvate (10 mmol/liter) at a rate of 9.74 +/- 0.90 nmol/min/mg protein (mean +/- SD; n = 61). Gluconeogenesis was inhibited almost 90% in the presence of phenylarsonate (700 mumol/liter), arsenate (350 mumol/liter), arsenite (30 mumol/liter), or PhAsO (1 mumol/liter). mumol/liter). With effective antidotes the rate of gluconeogenesis was restored to almost control values within 10 min. Among 21 sulfur compounds tested, only BAL, DMPS, and DMSA were effective in PhAsO poisoning. With inorganic arsenic also DTE and DTT restored the rate of glucose formation. The observed in vitro efficacies were in good agreement with in vivo results obtained with male NMRI mice severely poisoned with arsenite (As2O3, 20 mg/kg approximately 0.2 mmol As/kg) or PhAsO (3.4 mg/kg approximately 0.02 mmol As/kg). We conclude that isolated kidney tubules are a useful in vitro screening system (a) to compare the metabolic toxicity of various arsenicals and (b) to evaluate potential antidotes.

Animals↗
PubMed1993

On the capacity of the rat intestine to excrete lithium ions at therapeutic and toxic plasma lithium concentrations.

Lithium (Li) excretion into the intestinal lumen was quantitated in rats in situ by use of a pendular perfusion technique. Male Sprague-Dawley rats were injected daily (7-10 days) i.p. with 1, 3, and 6 mmol LiCl per kg body weight (n = 9-12). Jejunal as well as ileal and colonic segments were perfused with isotonic saline containing 3H-PEG-4000. Perfusate samples were taken after 0, 5, 10, 20, and 60 min. At the highest dose toxic symptoms were observed. At 6 mmol Li per kg the plasma Li concentrations were higher than those linearly extrapolated from the lower-dose groups, which may be due to inappropriate renal excretion. The Li concentration in the perfusate increased linearly over time and was not significantly different between jejunal and colonic segments. The same ratio between the Li concentration in the plasma and in the luminal perfusate was observed in all groups. Intestinal Li excretion is not impaired by high plasma concentrations. The intestinal capacity to excrete Li is considerable: 45 cm of jejunum is able to excrete the intire plasma Li content in 30-40 min, when Li is not resupplemented from intracellular stores. The renal clearance of lithium (Li) decreases when toxic Li plasma concentrations are reached. Therefore, if it were possible to trap Li in the intestinal lumen, this excretion route might be of therapeutic interest in cases of Li intoxication with impaired renal Li-excretion.

Animals↗
PubMed1992

Effects of acetaminophen and antipyrine on non-inflammatory pain and EEG activity.

Antinociceptive effects of the 2 (each 1000 mg, orally) non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen (paracetamol) and antipyrine (phenazone) were investigated with a non-inflammatory experimental pain model in 32 healthy volunteers. Phasic pain was induced by intracutaneously applied brief electrical pulses (20 msec). Pain ratings, cerebral potentials and the EEG delta power were measured in response to the stimuli. Unspecific effects upon the vigilance system were evaluated by spontaneous EEG, auditory evoked potentials and reaction times. The investigation was performed as a placebo-controlled, double-blind crossover study. Blood samples were taken to monitor the plasma concentrations of the active agents. Ninety minutes after medication the 2 NSAIDs produced similar effects upon all pain-relevant target variables, although the mean plasma concentration of antipyrine (15 micrograms/ml) was approximately twice that of acetaminophen (7.5 microgram/ml). Both NSAIDs reduced pain ratings by 6%, late cerebral potentials by 19%, and stimulus-induced delta power of the EEG by 21%. The antipyrine effects emerged earlier, in agreement with its faster kinetics. Both NSAIDs could be differentiated by their effects upon spontaneous EEG activity. Whereas acetaminophen mainly enhanced the power in the theta range, antipyrine predominantly depressed the alpha frequencies. None of the drugs influenced auditory evoked potentials and reaction times. The central effects of acetaminophen and antipyrine are discussed with respect to antinociception and decrease in vigilance.

Acetaminophen↗
PubMed1992

Influence of organic and inorganic arsenicals on glucose uptake in Madin-Darby canine kidney (MDCK) cells.

The effect of organic (oxophenylarsine; PhAsO) and inorganic (arsenite) arsenicals on the availability of glucose to Madin-Darby canine kidney (MDCK) cells was investigated. The MDCK cells revealed stereospecific D-glucose uptake which was inhibited by both arsenicals in a time- and concentration-dependent manner. After 10 min (37 degrees C), the effects on D-glucose and 2-deoxy-D-glucose accumulation were analogous, suggesting an impaired hexose uptake. With arsenite, 0.5-1 mmol dm-3 were required for half-maximum inhibition (IC50), whereas PhAsO inhibited glucose uptake in the micromolar range (IC50 5-30 mumol dm-3). Under these conditions neither cell morphology nor cellular viability was affected. After 60 min, however, the inhibition of glucose utilization was paralleled by the formation of blebs, detachment of the monolayer and a loss of cellular viability as confirmed by dye exclusion, lactate dehydrogenase and potassium release. It is concluded that inhibition of glucose uptake may contribute to the acute toxicity, especially of organic arsenicals, by further aggravating the depletion of intracellular carbohydrates.

Animals↗
PubMed1992

Effect of various antidotes on biliary excretion of arsenic in isolated perfused livers of guinea pigs after acute experimental poisoning with As2O3.

The effect of the dithiols British Anti-Kewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) and a new metal binding agent 2,3-bis-(acetylthio)- propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs after acute experimental poisoning with As2O3 was investigated. Guinea pigs received As2O3, 10.0 mg/kg subcutaneously at 9 a.m. as a single injection. One hour after the injection the livers were perfused (2.5 ml x min.-1 x g-1 liver) with Krebs-Henseleit buffer and glucose for 80 min. After 40 min. of saline perfusion (control) 0.1 or 0.7 mmol/l BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effluent perfusate was measured. The biliary excretion of arsenic in control livers between 40 and 80 min. was 0.7% of the total arsenic liver content before perfusion (= arsenic liver content after perfusion + portion excreted in the bile+perfusate). After antidote addition (0.1 mmol/l) the excretion was 0.2% for livers perfused with BAL, 6.8% for DMSA, 10.6% for DMPS, and 11.1% for BAPSA, respectively. After 0.7 mmol/l antidote the excretion of arsenic was 0.1% in livers perfused with BAL, 9.6% for DMSA, 12.3% for DMPS, and 13.3% for BAPSA, respectively. Except BAL, all compounds and most effectively BAPSA increased biliary excretion of arsenic. This indicates that excretion of arsenic which normally is mainly renal is shifted towards faecal excretion by the dithiols.

Animals↗