Evidence that transmitter can be released from regions of the nerve cell other than presynaptic axon terminal: axonal release of acetylcholine without modulation.

Release of acetylcholine from isolated preganglionic axons of sympathetic nerve trunk (cervical preganglionic sympathetic branch) of the cat was studied. In response to depolarization (KCl, 48.4 mM) acetylcholine was released into the eserinized Krebs solution. This release was shown to be dependent on extracellular Ca2+. Electrical stimulation (1 Hz) enhanced the release of acetylcholine from the isolated axonal preparation. The release by stimulation proved to be tetrodotoxin-sensitive and Ca2+-dependent. Evidence has been obtained that the acetylcholine released from sympathetic nerve trunks originates from the axon and not from Schwann cells: 5 days after section of the nerve, there was no release in response to stimulation. The release of acetylcholine from the axon is unlike that from axon terminals in that the rate of release cannot be enhanced by the inhibition of Na, K-adenosine 5'-triphosphatase (ouabain 2 X 10(-5) M) and cannot be modulated by noradrenaline (10(-6) M) or by morphine. Furthermore, although isolated nerve trunks took up [3H]choline by a hemicholinium-sensitive process, no radioactivity could be released upon electrical stimulation. It is suggested that the release of acetylcholine is not confined to axon terminals, but that it can be non-synaptically released by depolarization from axons provided Ca2+ is present.

Embryotoxic effects of benzene and its methyl derivatives: toluene, xylene.

CFY rats were exposed to inhalation of 1000 mg/m3 (313ppm) benzene, 1500 mg/m3 (399 ppm) toluene, or 1000 mg/m3 (230 ppm) xylene for 24 h/day from day 9 to day 14 of pregnancy; to that of 1500 mg/m3 (399 ppm) toluene for 24 h/day from day 1 to day 8 of pregnancy, or 1000 mg/m3 (266 ppm) toluene for 8 h/day from day 1 to day 21 of pregnancy,. CFLP mice were exposed to inhalation of 500 mg/m3 (133 ppm) toluene for 24 h/day from day 6 to day 13 of pregnancy. Untreated animals and groups inhaling pure air served as controls. None of the solvents proved to be teratogenic, the incidence of malformations did not change as a result of exposure, though an increase in skeletal anomalies (extra ribs, fused sternebrae) was observed with all 3 solvents. Benzene and toluene also caused considerable retardation of fetal development. The growth retarding effect of toluene on fetal development in early pregnancy is of particular importance from the point of view of occupational hygiene.

Effects of vinyl chloride exposure alone and in combination with trypan blue--applied systematically during all thirds of pregnancy on the fetuses of CFY rats.

Vinyl chloride (VC) has been shown to be present in the fetal and maternal blood as well as in the amniotic fluid after the exposition of pregnant CFY rats to VC at an atmospheric concentration of 5500, 18 000 or 33 000 mg/m3 (approximately 2000, 7000 or 12 000 ppm) for 2.5 h on the 18th day of pregnancy, indicating the permeability of the placenta to the agent. Teratological investigation of the offspring of pregnant rats exposed continuously to VC at an atmospheric concentration of 4000 mg/m3 air (1500 ppm) during the first, second or last third of pregnancy has shown that VC has no teratological effect in the rat and has no embryotoxic effects either, when applied during the second or last third of pregnancy in the above concentration. Exposition to VC during the first third of pregnancy resulted in an increased fetal mortality and in the manifestation of embryotoxic effects. Fetal losses and induction of central nervous system malformation due to trypan blue administration were not potentiated by a combined exposure of pregnant rats to VC and the dye.

Study on the role of maternal sex steroid production and metabolism in the embryotoxicity of para-xylene.

CFY rats were exposed to inhalation of clean air or air containing para-xylene (3000 mg/m3) on the 10th, and 9th and 10th days of gestation. Uterine and ovarian venous blood flow, fetal weight, ovarian progesterone and 17 beta-oestradiol secretion, and the progesterone and 17 beta-oestradiol level of peripheral blood (uterine and femoral veins) were measured on the 11th day of gestation. Exposure to para-xylene decreased the weight of the fetuses and the progesterone and 17 beta-oestradiol levels of peripheral blood, but it did not influence the uterine and ovarian venous outflow and the ovarian progesterone and 17 beta-oestradiol secretion rate. It is concluded that para-xylene, by inducing the hepatic monooxygenase system, facilitates the biotransformation of progesterone and 17 beta-oestradiol, which is metabolized by this enzyme system. The decrease in the sex hormone level of peripheral blood is supposed to play a role in the embryotoxicity (retarding and lethal effects) of para-xylene.

Age dependent accumulation of cadmium in the human ovary.

Cadmium (Cd) was determined by atomic absorption spectrophotometry in small pieces (< 1 g) of healthy human ovaries excised for histologic examination. Cd levels in the ovary increased linearly between 30 and 65 years of age. Below 30 years, there was no age dependent increase and over 65 a tendency was observed for ovarian Cd levels to decrease. There was no difference in the Cd content of fresh luteal and nonluteal tissue taken from regularly cycling ovaries. In smokers, the amount of Cd in the ovaries was elevated compared to nonsmokers. In multiparous women (more than 3 children) a tendency of decreased Cd ovarian levels was observed. There was no difference between ovarian Cd content of physical and mental workers. It can be proposed that Cd may be a risk factor for conception and pregnancy in women in their forties.

Acute effects of cadmium on preovulatory serum FSH, LH, and prolactin levels and on ovulation and ovarian hormone secretion in estrous rats.

On the day of diestrus II CFY rats were given 5, 10, or 15 mg/kg cadmium chloride (CdCl2) or 1.0 mL/kg of 0.9% NaCl. On the next day a group of animals was anesthetized with pentobarbital and blood was collected from the aorta at 13:00, 15:00, 16:30, or 18:00 h. for FSH, LH, prolactin (PRL), progesterone (P), and estradiol-17 beta (E2) determination. On the day of the expected estrus, the second group of animals was anesthetized with pentobarbital and cannulas were inserted in one of the femoral arteries and veins, and in one of the utero-ovarian veins. Five-minute blood fractions were collected from the ovary for 40 min, and following the first blood samples, 10 IU hCG was injected iv. Ovarian venous outflow and blood pressure were continuously recorded. From the blood fractions, P and E2 were determined, and their secretion rates were calculated. In a third group of treated animals, the ovaries were excised for histological examination, and oviducts were flushed for counting oocytes. CdCl2 in the dose of 10 or 15 mg/kg increased the PRL serum levels at 13:00 h; it diminished FSH serum levels in the dose of 10 mg/kg and LH serum levels in the doses of 10 and 15 mg/kg at 15:00 h. The decrease in LH levels continued until 16:30 h in the dose of 10 mg/kg CdCl2. In estrous animals, CdCl2 did not influence the blood pressure and ovarian blood flow. In animals receiving 10 or 15 mg/kg CdCl2, a decrease in basal secretion of P occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral deficits due to prenatal exposure to cadmium chloride in CFY rat pups.

The postnatal behavioral effects of 0.20, 0.62 and 2.0 mg/kg cadmium chloride administered to pregnant CFY rats on gestational days 7 through 15 were evaluated. Offspring were tested starting on postnatal day 23 on a rotorod for motor coordination, in an open field device for motor activity and emotionality, in a water-filled tube for stress responses, in the acquisition and extinction of an instrumental shock-escape response and in a social interaction situation. All behavioral measures showed significant alterations at the medium and high dose of cadmium exposure. The results suggest that doses of cadmium chloride that produce no overt toxicity in the dam can have long-lasting behavioral alterations in the offspring.

Behavioral effects of prenatal methoxy-ethyl-mercury chloride exposure in rat pups.

A number of neurotoxic drugs, when administered prenatally, induce neurobehavioral impairments and cause delay of the development of central nervous functions, without morphological malformations. Experiments were undertaken to clarify the behavioral teratogenicity of the fungicide methoxy-ethyl-mercury chloride (MEMC). CFY rat dams were treated with different doses of MEMC during 7th-15th days of gestation (2.0, 0.62 and 0.02 mg/kg daily), perorally. Development of gait, motor coordination, behavior patterns in an open field test, swimming, and conditioned avoidance learning were tested at different ages of rat pups. MEMC did not cause any mortality of dams, but there was a mild ataxia at the 2.0 mg/kg treatment. While birthweight, number of offspring, ear-eye opening and gait were normal, unexpectedly high mortality occurred perinatally. After weaning, open field behavior was nearly normal, there was a mild decrease of rearing, grooming and ambulation and an initial preference for the periphery of the open field decreased. Ambulation increased significantly in 90-day-old pups. Motor coordination on a rotorod decreased in 23- and 36-day-old pups, but increased in 90-day-old pups at the 2.0 mg/kg dose. There was no difference among groups in amphetamine sensitivity tested in a swim stress test. During avoidance conditioning, pups treated with the two higher doses performed poorly when compared to controls and the latency of the positive conditioned response was lengthened significantly. Our results show a dose-dependent behavioral teratogenicity of this organomercurial fungicide. The so called no effect level--as far as the neurobehavioral impairments due to prenatal exposure are concerned--is 0.02 mg/kg daily.

Polycyclic aromatic hydrocarbon exposure and burden of outdoor workers in Budapest.

Polycyclic aromatic hydrocarbons exposure (PAHs: (benz[a]anthracene, benzo[a]pyrene, dibenz[a,h]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, indeno[1,2,3-cd]-pyrene, fluoranthene, chrysene, pyrene) of policemen on street duty in downtown Budapest and workers repairing the road (asphalting) at a traffic junction and their excretion of PAH metabolites (1-hydroxypyrene, 3-hydroxybenz[a]anthracene, and 3-hydroxybenzo[a]pyrene) were determined. As controls, health-care workers were investigated. In addition PAH pollution of the air of a factory processing asphalt was also measured. The measurements were performed on air samples gained using personal samplers and from urine of end-shift samples using a high-performance liquid chromatography method. It was found that PAH pollution of the most crowded and busy center of Budapest was similar to that of several other cities in the world. PAH exposure of road builders was actually not higher than that of policemen; the slight difference resulted from diverging life-styles. PAH metabolite excretion of smoking health-care workers, road builders, or policemen significantly exceeded that of the nonsmokers. The PAH metabolite values of the three groups engaged in various activities did not show any difference. It was concluded that cancer-related risk due to PAH compounds in the case of policemen on street duty and road builders (asphalting) does not exceed significantly that of workers not exposed occupationally to PAHs in the ambient air, but that smoking is a decisive factor.

Hemodynamic effect of indium chloride in pregnant rats.

Daily indium chloride doses of control (0) or 200 mg/kg were administered orally to pregnant Sprague-Dawley (SD) rats by gavage, on d 6-15 of gestation. On d 16 of gestation hemodynamic tests were performed; Arterial blood pressure, cardiac output (CO), and volume organ blood flow were determined with radioactive microspheres using the reference sample method (McDevitt & Nies, 1976). Indium chloride increased the cardiac index (CI), but did not change arterial blood pressure and total peripheral resistance (TPR). Indium decreased the organ fractions of the cardiac output to kidneys, ovaries, uterus, and placenta, while those to brain, lungs, and liver were not affected. In the placenta the blood flow was reduced significantly while the vascular resistance increased. The blood flow and vascular resistance did not change in the rest of the organs studied. The changes in arterial blood pressure, CO, Cl, TPR, organ fraction of cardiac output, blood flow, and vascular resistance in most of the organs displayed normal responsiveness to noradrenaline (NA) infusion. The reduction of uterine and placenta fractions and placental blood flow, produced by NA infusion were significantly greater in control than in the indium-treated group. Data indicate that the hemodynamic changes induced by indium are detrimental to the fetus. Indium chloride exposure modifies the maternal effect of noradrenaline such that there is maternal survival at the expense of fetal mortality.

The effect of prenatal indium chloride exposure on chondrogenic ossification.

Daily indium chloride doses of control (0) or 400 mg/kg were administered orally to pregnant Sprague-Dawley (SD) rats by gavage, on d 20 of gestation. Indium concentration was determined in the maternal and fetal blood, livers, kidneys, skulls, and femurs by atomic absorption spectrometry. Further groups of pregnant rats were treated with control (0) or 400 mg/kg indium chloride orally, during the whole gestation period. The fetuses were examined on d 21 of gestation, using histological and histochemical methods. Four hours after the administration indium concentration was found to be significant in the blood, liver, and kidneys of the dams. Twenty-four hours later it increased in the blood but not in the liver and kidney. Fetal indium concentrations were 40-50% of the maternal levels due to a barrier of the placenta. In the skull and the femur, indium was already detectable at 4 h after the administration, and by the end of 24 h, metal concentration was several times higher than that at 4 h, indicating accumulation. Furthermore, it was found that the birefringency of collagen detectable by picrosirius red staining in polarized light around the chondrocytes disappeared and became irregular. In the matrix of the epiphyseal cartilage, the regular, birefringent network demonstrable by Rivanol reaction became irregular and hardly recognizable. In the cytoplasm of the chondrocytes, the diffuse, evenly distributed positive Ricinus communis agglutinin reaction became irregular or disappeared. Similar but much weaker changes were observed with concanavalin A and wheat germ agglutinin stainings. It was concluded that the missing femur and micromelia diagnosed by alizarin staining is the consequence of a specific toxic effect of indium that inhibits chondrogenic ossification. No similar histochemical changes were observed in the bones of the skull developing by desmogenic ossification, despite the presence of indium. Data indicate that the mechanisms of the effects of indium causing retardation and/or malformation differ in the bones developing through desmogenic or chondrogenic ossification.

Effects of cobalt sulfate on prenatal development of mice, rats, and rabbits, and on early postnatal development of rats.

The effects of cobalt sulfate administered to pregnant C57BI mice, OFA-SD rats, and New Zealand rabbits was studied on fetal and postnatal offspring. Cobalt concentration in the maternal blood was increased in proportion to the administered doses. Cobalt crossed the placenta and appeared in the fetal blood and amniotic fluid. Regardless of the administered dose of cobalt sulfate, cobalt concentration in the blood peaked 2 h after administration. Cobalt produced dose-dependent maternal toxicity and was found to be embryotoxic in all three species, as evidenced by elevated frequency of fetuses with body weight or skeletal retardation and embryolethality. Cobalt increased the frequency of major anomalies significantly in mice and rats, with anomalies of the eyes, kidneys, skull, spine, and sternum in mice, and anomalies of the urogenital system in rats. Cobalt sulfate was not teratogenic in rabbits. Intra-amnial administration of cobalt sulfate produced a dose-dependent increase of the frequency of dead fetuses, and weight retardation of the live fetuses. The direct cytotoxic effect probably plays a role in the embryotoxic and teratogenic effects of cobalt. The postnatal examinations revealed a decrease of the perinatal index in the treated group. The body weight of the pups in the treated group was lower during wk 1 of life, but no difference was found between the control and treated by the end of wk 2. Eye opening was completed in the usual time period in both groups, while time of appearance of the teeth, descending of the testes, shaping of ears, and development of hearing was delayed in the treated group. The development of muscle strength and of the locomotor system was delayed. All the functions studied (forward movement, swimming, righting reflex) normalized by postnatal d 21, with the exception of muscle strength. It was concluded that cobalt sulfate exposure decreases the perinatal viability of the fetuses, but the functions of the surviving fetuses with perinatal retardation become compensated by postnatal wk 2-3. The development of fetuses is undisturbed thereafter.

Study of inflammatory responses to crocidolite and basalt wool in the rat lung.

The subacute effects of crocidolite and basalt wool dusts were studied by nmeans of biochemical, morphological. and histological methods 1 and .3 mo after intrabronchial instillation. The cell count, protein and phospholipid contents, and lactate dehydrogenase (LDH) activity were determined in the bronchoalveolar lavage (BAL). Both types of fibers induced a prolonged inflammatory reaction in the lung. All the parameters studied in the experimental groups were more markedly elevated after 3 mo. Relative to the control, the protein and LDH values were increased three- to fivefold, the phospholipid content twofold, and the number of free cells in the BAL exceeded the control level up to ninefold. The inflammatory responses to crocidolite and basalt wool in the lung did not differ significantly. In spite of this, basalt wool is recoinmended as an asbestos substitute, as the use of this man-nade fiber may result in a significantly lower release of dust than that from crocidolite.

Effects of sodium diethyldithiocarbamate on type II pulmonary epithelial cells in vitro.

Dithiocarbamates (DDTC) are chemicals widely used in the form of pesticides, therapeutic and chelating agents, and scavengers. Since DDTC interfere with SH, Cu, and Zn enzymes due to chelating properties, it was of interest to clarify, in primary culture of type II alveolar pneumocytes, the effect of this compound upon enzymes of glutathione cycle, Cu, Zn-superoxide dismutase, and the membrane structure of cells. DDTC significantly inhibited the activity of superoxide dismutase and the activity of gamma-glutamyl transpeptidase, glutathione reductase, and alkaline phosphatase, whereas an increase in the activity of glutathione peroxidase was found. The membranes of pneumocytes type II were injured. Data show that DDTC adversely affected type II pneumocyte function and structure.

Embryotoxic and teratogenic effects of indium chloride in rats and rabbits.

Daily indium chloride doses of control (0), 50, 100, 200, or 400 mg/kg were administered orally to Sprague-Dawley rats by gavage, on d 6-15 of gestation, and daily metal doses of control (0), 50, 100, or 200 mg/kg were administered to New Zealand rabbits on d 6-20 of gestation. Further groups of pregnant rats were treated with control (0) or 400 mg/kg indium chloride orally on one of d 8, 9, 10, 11, 12, 13, 14, or 15 of gestation. The dams and fetuses were examined on d 21 (rats) and 30 (rabbits) of gestation, using standard teratological methods. Indium concentration was determined in the maternal and fetal blood, as well as in the amniotic fluid, by atomic absorption spectrometry. Indium was found to cross the placenta and appeared in fetal blood in proportion to the metal concentration of the maternal blood. In the amniotic fluid, indium concentrations remained below the detection limit. In rats, indium chloride produced dose-dependent maternal toxic effects, with a dose of 400 mg/kg inducing embryotoxicity (embryolethality) and teratogenicity. Doses of 200 and 100 mg/kg were embryotoxic (retarding) and teratogenic, causing skeletal and visceral anomalies in addition to external anomalies (rudimentary or missing tail, syndactylia, clubfoot, exencephalia) in rats. In rabbits, 200 mg/kg indium chloride was lethal for the dams and the embryos (some of the animals died, and the number of abortions and full resorptions increased). This dose was found to be teratogenic (caused gross renal anomalies) and increased the frequency of fetuses with skeletal retardation. In rats, the effects of indium chloride causing fetal retardation was found to be independent of exposure time. The teratogenic effects were the highest on d 11 and 12 of gestation, when indium chloride caused gross external malformations. Data suggest that the teratogenic effects of indium chloride can be attributed primarily to a direct cytotoxic action of indium resulting from placental transfer, but the effect is not a selective one, as it appears only in the presence of maternal toxic effects.

The pulmonary toxicity of cinnamon dust in rats.

The histopathological effect of a single intratracheal dose of respirable cinnamon dust, cinnamon dust extract, and cellulose dust on the lungs of rats was studied sequentially one, seven days and one month after treatment. Exposure to respirable cinnamon and cellulose dusts resulted in alveobronchiolitis at the end of the first and seventh day, and fibrotic changes by the end of the first month. As the extract of cinnamon dust caused no histopathological alterations, it is assumed that the cellulose content of cinnamon dust was responsible for the histological reactions.

On the structural differences in the membranes between ciliated bronchial and non-ciliated lymphoepithelium in rats.

The membrane structure of bronchial ciliated epithelium and lymphoepithelium was studied in rats by lectin histochemistry. The lymphoepithelium, contrary to bronchial ciliated epithelium, did not contain terminal beta-D-galactose residues. Moreover L-fucose and beta-D-Gal (1-3)-D-GalNAc residues, being masked, could be visualized only after enzymatic digestion of terminal sialic acid. These structural differences in membranes provide a basis for the different functions of bronchial lymphoepithelium.

The effect of cardiac lymphostasis on the microcirculation of the heart: effect of cardiac lymphoedema on the development of an arteriovenous shunt circulation.

The effect of cardiac lymphostasis on the microcirculation of the heart was studied in 18 dogs. By ligation of the main lymph trunks and regional lymph nodes of the heart, cardiac lymphoedema--lymphogenic cardiomyopathy--was induced in 9 dogs, while 9 served as control animals. For microcirculatory investigations: 1) gelatin Indian ink injection, 2 benzidine reaction, 3) PVC injection corrosion preparation was applied. Characteristic changes were demonstrated in the microcirculation and capillary circulation of the heart in cardiac lymphostasis. In some capillaries-mainly where the interstitial oedema exists--the capillary circulation decreased: inhomogeneously vessel-free spots were formed in the heart. Around the vessel-free capillaries, elongated capillaries were found including very dilated pre- and post-capillary vessel sections. Arteriovenous shunts can be revealed in the heart in consequence of lymphoedema. The pathogenesis of the microcirculatory circulation changes caused by cardiac lymphostasis was discussed.

Risk assessment of chemicals--a central European perspective.

During the last four decades in all the Central and East European countries it was intended that prevention of the adverse health effects of chemicals in occupational and environmental settings, including the drinking water and food basket of populations, be achieved by determination and compulsory observance of hygienic limit values (MAC, TLV, ADI). The authors have tried to demonstrate some specific features of risk assessment of exposure to chemicals in environmental and occupational settings. Although the approach to risk assessment and management was similar in many respects in the CMEA countries, implementation and hygienic practice was different in the individual countries in terms of many details and effectiveness. Due to long lasting experience with environmental pollution including health impact on humans, such as in the "Dirty Triangle of Europe" and other heavily contaminated areas a considerable knowledge has been gained. The authors recommend to analyse critically and evaluate the knowledge and experience and present it to the international scientific community and international institutions such as UNEP, ILO, IPCS, IRPTC and last but not least, OECD.

[Effect of acute alcohol intake on certain cardiovascular functions in healthy young males]. / Akut alkoholbevitel hatása egyes cardiovascularis funkciókra fiatal egészséges férfiakon.

.15, 0.25 and 0.5 g/kg alcohol in the form of 40% brandy in one week intervals was consumed by eight healthy, regularly trained young men volunteers. Blood alcohol level, blood pressure and ECG were registered before and 30, 60 and 90 min after, each alcohol consumption. The cardiac output was measured with a radiocirculographic method before and 45 min after alcohol consumption. The cardiac index, stroke volume, stroke index, and total peripheral resistance (TPR) were calculated. With increase of the alcohol dose the blood alcohol level increased, while cardiac output, cardiac index, stroke volume, stroke index, and the systolic blood pressure fell. The other parameters examined--heart rate, diastolic blood pressure, TPR among others--remained unchanged. The ECG was normal. The highest no effect alcohol dose was less than 0.15 g/kg (0.1, k/kg). It is concluded that, depending on the dose, alcohol has practically no effect on the majority of the heart-functions, however, in the range of 0.1 to 0.5 g/kg it has a depressive influence, i.e. lowers the pump-function of the heart and, at 0.5 g/kg the arterial blood pressure.