Mobilization of mercury by DMPS in occupationally exposed workers and in model experiments on rats: evaluation of body burden.

The aim of the study was to evaluate the efficacy of DMPS (sodium-2,3-dimercapto-1-propane sulfonate) (Dimaval) administration for mobilizing mercury from the body in occupationally exposed people and experimental animals. Two doses of DMPS were administered at a 24-h interval to: (a) groups of people occupationally exposed to merkury--workers of the chloralkali industry (n = 43), and dentists (n = 12), (b) non-exposed individuals (n = 20), and (c) rats chronically exposed to mercury vapour at the concentration of 0.8 mg/m3 Hg degree (6 h/day, 5 days/week) for 15 weeks. In an out-patient mobilizing test, the urinary excretion of mercury 48 h after the administration of the first dose reached 1513 micrograms in the group of industrial workers, 132.6 micrograms in dentists, and 3.78 micrograms in controls. In rats, two consecutive doses of DMPS decreased kidney content of mercury by about 30% and 50% after oral and intraperitoneal administration, respectively. Kidney mercury burden was calculated on the basis of the data from animal and human studies of the mobilization of mercury via urine after DMPS treatment: 61, 2800 and 28,000 ng/g in controls, dentists and workers, respectively. It was estimated that two doses of DMPS mobilized 17-20% (after oral administration) and 25-30% (after intramuscular administration) of kidney mercury burden, both in the control and exposed subjects.

Biliary iron excretion in rats following treatment with analogs of pyridoxal isonicotinoyl hydrazone.

Iron overload is a major life-threatening complication of thalassemia major and other iron-loading anemias treated by regular blood transfusions. Although the clinical manifestations of iron overload may be prevented by desferrioxamine, the only iron-chelating drug in routine clinical use, this treatment requires subcutaneous infusion of desferrioxamine for 12 hours each day. New orally effective iron chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective iron chelator in vitro and subsequently in vivo, shows promise for the treatment of iron overload. More recently, over 40 analogs of PIH were synthesized, and some of them proved to be very potent in mobilizing 59Fe in vitro from 59Fe-labeled cells. In this study, we show that PIH analogs such as pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone (PMBH), pyridoxal m-fluorobenzoyl hydrazone (PFBH), and pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to mobilize iron from cells in vitro, are also effective in vivo. All of these chelators significantly enhanced biliary excretion of iron (measured by atomic absorption spectrophotometry) following their intraperitoneal (IP) and/or oral administration to rats. The most effective was PFBH, which increased iron concentration in the bile about 150-fold, as compared with basal biliary iron concentration, within 1 hour following a single IP dose of 0.2 mmol/kg body weight. In contrast, desferrioxamine increased the biliary iron concentration only 20-fold to 30-fold under the same conditions. Moreover, while control rats excreted approximately 0.8 microg Fe in 2 hours, treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative excretions of 87, 59, and 22 microg Fe, respectively, in the same period of time. Interestingly, PMBH was also quite effective following gastric administration, resulting in a 6-hour cumulative value of 34 microg Fe. These compounds are nontoxic and are inexpensive and easy to make. Their further evaluation as candidate drugs for the treatment of iron overload is warranted.

Biological monitoring of child lead exposure in the Czech Republic.

The area around the Pribram lead smelter has been recognized to be heavily contaminated by lead (Pb). In the early 1970s, several episodes of livestock lead intoxication were reported in this area; thereafter, several epidemiological and ecological studies focused on exposure of children. In contrast to earlier studies, the recent investigation (1992-1994) revealed significantly lower exposure to lead. From 1986-1990, recorded average blood lead levels were about 37.2 micrograms lead (Pb)/100 ml in an elementary school population living in a neighborhood close to the smelter (within 3 km of the plant). The present study, however, has found mean blood lead levels of 11.35 micrograms/100 ml (95% CI = 9.32; 13.82) among a comparable group of children. In addition to blood lead, tooth lead was used to assess exposure among children. Statistically significant differences (p < 0.05) were observed between the geometric mean tooth lead level of 6.44 micrograms Pb/g (n = 13; 95% CI = 3.95; 10.50) in the most contaminated zone and 1.43 micrograms Pb/g (n = 35; 95% CI = 1.11; 1.84) in zones farther away from the point source. Both biomarkers, blood and tooth lead levels, reflect a similar pattern of lead exposure in children. This study has attempted a quantitative assessment of risk factors associated with elevated lead exposure in the Czech Republic. Content of lead in soil, residential distance from the smelter, consumption of locally grown vegetables or fruits, drinking water from local wells, the mother's educational level, cigarette consumption among family members, and the number of children in the family were factors positively related (p < 0.05) to blood lead levels. The resulting blood lead level was found to be inversely proportional to the child's age.

Exposure to lead and human health in the Czech Republic.

The aim of presented review is to address the most relevant issues related to the health effects caused by the human exposure to lead, as they have been recognized in Czech Republic in the period of 1992-1994 within the framework of the National Integrated Programme on Environment and Health (NIPEH) approved in 1992 and supported by WHO-European Centre for Environment and Health (WHO-ECEH), Bilthoven, The Netherlands and by the Government of the Netherlands. Basic sources of environment exposure to lead are identified and the fate of lead in the individual compartments of the environment is discussed. Relevant methods used for the exposure evaluation are summarized and the highest-risk group of population is defined. Attention is being paid to the effects of the long-term exposure to low lead levels, while other exposure settings are intentionally omitted. Interventional measures developed in the Czech Republic in attempt to reduce the environmental exposure are introduced. Instead of presenting specific data, current state-of-art and general trends are presented; list of references tries to combine the internationally recognized studies with those coming from national sources.

Hazardous wastes in Eastern and Central Europe [meeting report].

The countries of Eastern and Central Europe have emerged from a political system which for decades has ignored protection of human health from hazardous wastes. While the economies of the countries in this region are stretched, awareness and concern about hazardous waste issues are a part of the new realities. At a recent conference sponsored in part by the National Institute of Environmental Health Sciences, representatives of seven countries in the region described the status of hazardous waste programs, issues of major concern, and steps being taken to protect human health. This report summarizes the deliberations, outlines some of the problems remaining in dealing with the legacy of the past, addressing the problems of the present, and providing a framework for future research and collaborative efforts.

[Motivation for preventive care]. / Motivace k preventivní práci.

This article outlines those psychological characteristics of preventive and prophylactic work that qualify it as an efficient and effective skill. The transactional analysis model is used for explaining some peculiarities of everyday contact and communication between medical professionals and patients.

In vivo and in vitro efficacy of a new carbodithioate for the mobilization of cadmium.

Female Wistar rats with chronic cadmium intoxication (oral exposure to low dosages of CdCl2 in drinking water over a period of 90 d) were used to examine the in vivo ability of a newly developed chelator, sodium N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N- carbodithioate (MeBLDTC), singly and in combination with sodium 4-carboxy-amidopiperidine-N-carbodithioate (INADTC) as agents to induce the biliary and urinary excretion of cadmium. The combined administration of the two dithiocarbamates, which differ greatly in molecular weight and structural features, led to a synergistic increase in the biliary excretion of cadmium and an enhanced reduction of renal cadmium levels. The use of such a coadministration produced an increase in the biliary excretion of cadmium that was more than double that expected if the compounds acted in an additive fashion. Such mixed-chelation therapy has potential utility in the treatment of human chronic cadmium intoxication. The hepatocytes isolated from chronically Cd-intoxicated rats were used as an in vitro screening model system for the new chelator. The plasma membrane integrity study with MeBLDTC at 0.48 mmol/20 ml of hepatocyte incubate using the trypan blue exclusion test and lactate dehydrogenase (LDH) leakage test revealed no differences in the cell viability with or without chelator. The cellular metabolic competence measured as the rate of urea synthesis also did not show any marked deviation from that of controls when incubated with MeBLDTC at three different concentrations. In the hepatocyte cultures, MeBLDTC induced a significant removal of cadmium from the hepatocytes at concentrations as low as 0.04 mmol/20 ml.

The NIPEH network of cooperating countries of central and eastern Europe. National Integrated Programmes on Environment and Health.

The National Integrated Programmes on Environment and Health (NIPEHs) in countries of Central and Eastern Europe (CCEE) are introduced. The NIPEH programme is one of the primary activities of the Bilthoven Division of the World Health Organization's European Centre for Environment and Health (WHO-ECEH). Located in the heart of the Netherlands on the compound of the Dutch National Institute of Public Health and Environmental Protection (RIVM) in Bilthoven, WHO-ECEH's Bilthoven Division has established a small but effective team of highly motivated experts who can draw upon the expertise available both within the Dutch host institution RIVM as well within the ECEH Centre of WHO-EURO. The NIPEHs have striven to lead the way in setting environmental health priorities in cooperation with our partners, taking into account not only what is relevant from the environmental health perspective, but also what is technologically and administratively feasible. The principal goal is to convert the information gathered by cooperating instructions into understandable information for policy and decision-making and for the interested scientific community.

Chemical risk assessment and management in Czech and Slovak Republics.

For more than 40 years, former Czechoslovakia has made minimal efforts to protect the environment. As a result, newly formed republics suffer from some of the worst environmental pollution in Europe. In all stages of a complex process of improving chemical safety both countries are facing tremendous problems: lack of efficient and powerful legislative measures, inadequate and sometimes non-reliable data, shortage of sophisticated equipment, virtual absence of basic knowledge and, generally, persisting distrust between public and governmental institutions in health and environmental issues. These factors have made the beginning of new approaches extremely difficult. However, a great effort of many people in both republics together with a substantial assistance of both international organizations and national institutions from developed countries seem to be promising. It could help to move former position of largely ineffective measures and investments to one where limited funds are spent to achieve public benefits.

Distribution and excretion of cadmium and nickel after simultaneous exposure and the effect of N-benzyl-D-glucamine dithiocarbamate on their biliary and urinary excretion.

A rat model for combined exposure to cadmium and nickel is presented that involves the administration of drinking water containing these elements over a period of 90 d. Coadministration of these two ions in drinking water leads to brain levels of both elements that are significantly higher than results from the administration of equal doses of the metals individually. The enhanced biliary excretion of cadmium in rats given sodium N-benzyl-D-glucamine dithiocarbamate (BGDTC) is almost twice as great in those animals given cadmium and nickel as in those animals given cadmium only. The excretion of nickel is reduced by the administration of this chelating agent. Although equal amounts of nickel and cadmium were administered to these animals, liver and kidney cadmium levels were approximately 100 times greater than the corresponding nickel levels. The results suggest that combined exposure to these elements may lead to enhanced levels of nickel and cadmium in the brain and a level of nervous system damage not predictable from information obtained under conditions of exposure to only one of these elements.

The study of exposure to cadmium in the general population. II. Morbidity studies.

An epidemiological study was performed to assess whether environmental pollution by cadmium as found in cadmium polluted areas of CSFR (Pribram and Frýdek-Mistek) is associated with changes in biological indicators of renal dysfunction in non-occupationally exposed population groups. Polluted areas were chosen on the basis of existing sources of Cd emission. The city of Prague was selected as a control area. Environmental monitoring (Cd in air, dust fall and soil) did not confirm significant contamination of selected areas. It was found that Cd levels in urine (Cd-U) of inhabitants living in areas chosen as Cd-contaminated were significantly higher than in the control area. Differences in concentrations of Cd in blood (Cd-B) levels between individual areas were not significant. No significant differences between the study populations were noted in the urinary excretion of low molecular weight proteins (beta 2-microglobulin, retinol binding protein) and albuminuria. However, total proteinuria and aminoaciduria in persons living in Pribram area was significantly higher. This area suffers from combined contamination by cadmium and lead. In smokers of both sexes the Cd-B levels were significantly higher in all areas, no significant differences were found in Cd-U levels. However, it was found that in smokers there is higher percentage of persons excreting more than 0.9 micrograms Cd.g-1 creatinine in urine. Consumption of home-grown vegetable and fruit in Cd-polluted areas led to significantly higher levels of Cd-B and Cd-U and total proteinuria. The results of the study show that smoking and food seem to be the most important sources of Cd intake in non-occupationally exposed populations. In spite of the fact that environmental monitoring does not reveal a significant contamination of selected areas by Cd, Cd-U levels confirmed that population living in these areas is really exposed to Cd.

Effect of basic oligopeptides on the B-Z transition of poly(dG-dC). poly(dG-dC) in water-methanol solutions.

The effect of basic oligopeptides (Lys-Ala-Ala)n (n = 1-5, 10) and (Lys-Leu-Ala)n (n = 1-4) on the B-Z transition of poly(dG-dC).poly(dG-dC) in water-methanol solutions was investigated using CD and uv spectroscopy. In the absence of peptides, the concentration of methanol at the midpoint of the B-Z transition is 64% at 25 degrees C. The transition is temperature dependent and the B conformation is preferred at higher temperatures. All peptides tested shift the midpoint of the B-Z transition to lower concentrations of methanol. For shorter peptides this effect increases with an increasing number of monomeric units, showing the importance of the number of positive charges in the peptide molecule. Al conditions of low methanol content, the trimer and tetramer of the (Lys-Leu-Ala)n series have a greater effect on the B-Z transition than the corresponding oligomers of the (Lys-Ala-Ala)n series. This indicates an important influence of the presence of hydrophobic groups in the peptide side chains on the binding. In the presence of peptides, the B-Z transition is also temperature dependent and the B conformation is preferred at higher temperatures. The addition of peptides results in an increase of the transition midpoint and of the transition width. These parameters were used for the calculation of the transition enthalpy delta HB-Z in 65% methanol, which is -1.15 +/- 0.25 kcal/base pair. Since the van't Hoff enthalpy delta HVH calculated from the temperature dependence of the B-Z transition in the absence of peptides is -130 kcal/mol, the length of the cooperative unit is about 110 base pairs. The results suggest that the mechanism of Z-DNA induction is similar but not identical with that involved in the action of metal cations in aqueous solution.

Mobilization of aged cadmium from isolated rat hepatocytes by sulfhydryl chelators.

Isolated hepatocytes appear to be a suitable in vitro model for the testing of the efficacy of chelating agents. In this study hepatocytes were isolated from rats exposed to CdCl2 (50 mg Cd2+/l) in drinking water for 3 months. The cells were incubated in a Krebs-Henseleit buffer for 2 hrs and the cytotoxicity was assessed using 5 types of parameters. N-benzyl-D-glucaminedithiocarbamate (BGDTC) and meso-2,3-dimercaptosuccinic acid (DMSA) were tested. Individual chelators in various concentrations were added to the incubation medium at the beginning of the experiment (t = 0). The concentration of Cd in the extracellular fluid was measured every 30 mins using flame AAS. Exposed hepatocytes did not show the signs of damage. Both chelators did not exhibit any cytotoxic effect. BGDTC was found to be efficient in the mobilization of Cd, while DMSA was ineffective.

[Chelating agents]. / Chelátotvorné látky.

The problem of chelating agents used as antidotes in intoxications with metals is intensively studied during the past 20 years. Due to the complex nature of the action of these substances in the organism their investigation is a typically interdisciplinary problem. The submitted review gives the theoretical background of the formation of chelate in the organism, the strategy of research of new substances is discussed and findings on the main groups of chelating agents used in human medicine are summarized.

Determination and metabolism of dithiol chelating agents: X. In humans, meso-2,3-dimercaptosuccinic acid is bound to plasma proteins via mixed disulfide formation.

meso-2,3-Dimercaptosuccinic acid (DMSA) is orally effective for the treatment of chronic lead intoxication in humans. Earlier studies have shown that the majority of DMSA, given p.o. to normal humans, is excreted in the urine as mixed disulfides with L-cysteine. We have developed an assay for the determination of DMSA that has made possible the determination of the form of DMSA in blood and plasma. After p.o. administration of 10 mg DMSA/kg to four normal young men, no unaltered DMSA (unaltered DMSA is the unbound, parent compound; total DMSA consists of unaltered DMSA plus oxidized (disulfide) DMSA and is determined after reduction with dithiothreitol) was found in the blood over an 8-hr period. Only after treatment of blood or plasma with the disulfide-reducing agent, dithiothreitol, was DMSA detected. This indicates that DMSA is in disulfide linkage with plasma proteins and/or non-protein sulfhydryl compounds. Most of the DMSA in the plasma (92-95%) was found to be bound to plasma proteins, mainly albumin. The remaining DMSA may be bound to small molecular weight (less than 10,000 MW) nonprotein sulfhydryl compounds such as cysteine. Plasma protein appears to serve as a depot and reservoir of DMSA, which can exchange for cysteine. The urinary excretion of unaltered DMSA and DMSA mixed disulfides with L-cysteine suggests that this exchange takes place at the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

The study of exposure to cadmium in the general population. I. Autopsy studies.

From 1982 to 1986 samples of materials (liver tissue, kidney cortex) were collected from 438 autopsies in Prague. The age of persons was over 50 years and residence time in the area was at least 10 years Concentrations of Cd and Zn were determined in the kidney cortex and the liver tissue using the AAS method. On the basis of the Questionnaire for Relatives, data on smoking habits, and occupational history of the investigated persons were obtained. The results of the study confirmed that the concentration of Cd in analyzed tissues did not exceed values reported in the literature for people of similar age living in Cd uncontaminated areas. In smokers significant increase of Cd in the kidney cortex was found in all age and sex groups. The body burden of Cd in smokers is significantly higher.

Conformational transitions of leucine-containing isomeric sequential basic polytripeptides.

Conformational transitions of basic sequential polytripeptides (Lys-Ala-Leu)n, (Arg-Ala-Ala)n, (Arg-Leu-Ala)n, and (Arg-Ala-Leu)n, induced by elevated salt concentrations and/or temperatures in aqueous solutions, were investigated by CD, sedimentation equilibrium, and viscometry. The behavior of (Lys-Ala-Leu)n was compared with that of the sequential isomer (Lys-Leu-Ala)n, studied previously. It was found that both polypeptides are highly helical with a tendency to aggregate in high salt solutions. Although the hydrophobic interactions between Lys and Leu residues play an important role in both cases, the final effect on helix stabilization and aggregation is different. The Arg-containing polypeptides were found to assume the alpha-helical conformation. Compared to the Lys-containing polypeptides (Lys-Ala-Leu)n and (Lys-Leu-Ala)n, a very low tendency to aggregate was observed.

Synergistic enhancement of the biliary excretion of cadmium by the simultaneous administration of two dithiocarbamates.

The simultaneous i.p. administration of the two chelating agents bis(2-hydroxyethyl)dithiocarbamate (DEDTC) and 4-carboxamidopiperidinedithiocarbamate (INADTC) to rats given cadmium in their drinking water at a level of 50 mg cadmium/liter for 39 days led to a large synergistic effect on the biliary excretion of cadmium. A much smaller synergistic effect on the urinary excretion of cadmium was also noted. When treated with a similar mixture of chelating agents after a similar cadmium-drinking water exposure of 180 days, rats showed significant decreases in both renal and brain cadmium levels.

Immunogenicity of a synthetic peptide corresponding to a portion of the heavy chain of H3N2 influenza virus haemagglutinin.

Rabbits were immunized with a synthetic octadecapeptide corresponding to the sequence ser-91 to leu-108 of the haemagglutinin heavy chain of H3N2 influenza A viruses. They developed antibodies reactive in solid-phase radioimmunoassay (SPRIA) with the peptide and with haemagglutinins of various H3N2 viruses but not of heterotypic H1N1 and H2N2 viruses. The antibodies were also non-reactive in the haemagglutination-inhibition or neutralization test. Influenza H3N2 virus replicated in the lungs of mice immunized with the peptide to the same extent as in the control mice. Of 27 human sera possessing anti-H3N2 activity or seven sera from rabbits immunized with either virions or haemagglutinins of various influenza A viruses, none was reactive with the peptide in SPRIA.