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Tungsten and tungsten compounds are considered toxicologically relatively safe. Concern regarding the potential health and environmental effects of depleted uranium and lead in military applications has lead many countries to explore the possibility of applying toxicologically safer metals. Heavy metal tungsten alloy-based munitions have been therefore introduced as a replacement in munitions and as kinetic energy penetrators. Although the toxicological profiles of all these metals are well known, their internalization as embedded shrapnel may be considered a new route for long-term exposure. Studies in experimental animals and cell culture indicate that pellets based on heavy metal tungsten alloy possess carcinogenic potential previously unseen for depleted uranium and/or lead. Other metals in the tungsten alloy such as nickel or cobalt may contribute to such a risk. Accordingly, the long-term tungsten-related health risk is reason for concern. This article reviews toxicological and clinical literature and provides new perspectives on tungsten and tungsten-based alloys. [ABSTRACT FROM AUTHOR]

Background: The majority of modern war wounds are characterized by high-energy blast injuries containing a wide range of retained foreign materials of a metallic or composite nature. Health effects of retained fragments range from local or systemic toxicities to foreign body reactions or malignancies, and dependent on the chemical composition and corrosiveness of the fragments in vivo. Information obtained by chemical analysis of excised fragments can be used to guide clinical decisions regarding the need for fragment removal, to develop therapeutic interventions, and to better anticipate future medical problems from retained fragment related injuries. In response to this need, a new U.S Department of Defense (DoD) directive has been issued requiring characterization of all removed fragments to provide a database of fragment types occurring in combat injuries., Objectives: The objective of this study is to determine the chemical composition of retained embedded fragments removed from injured military personnel, and to relate results to histological findings in tissue adjacent to fragment material., Methods: We describe an approach for the chemical analysis and characterization of retained fragments and adjacent tissues, and include case examples describing fragments containing depleted uranium (DU), tungsten (W), lead (Pb), and non-metal foreign bodies composed of natural and composite materials. Fragments obtained from four patients with penetrating blast wounds to the limbs were studied employing a wide range of chemical and microscopy techniques. Available adjacent tissues from three of the cases were histologically, microscopically, and chemically examined. The physical and compositional properties of the removed foreign material surfaces were examined with energy dispersive x-ray fluorescence spectrometry (EDXRF), scanning electron microscopy (SEM), laser ablation inductively-coupled plasma mass-spectrometry (LA-ICP-MS), and confocal laser Raman microspectroscopy (CLRM). Quantitative chemical analysis of both fragments and available tissues was conducted employing ICP-MS., Results: Over 800 fragments have been characterized and included as part of the Joint Pathology Center Embedded Fragment Registry. Most fragments were obtained from penetrating wounds sustained to the extremities, particularly soft tissue injuries. The majority of the fragments were primarily composed of a single metal such as iron, copper, or aluminum with traces of antimony, titanium, uranium, and lead. One case demonstrated tungsten in both the fragment and the connected tissue, together with lead. Capsular tissue and fragments from a case from the 1991 Kuwait conflict showed evidence of uranium that was further characterized by uranium isotopic ratios analysis to contain depleted uranium., Conclusions: The present study provides a systematic approach for obtaining a full chemical characterization of retained embedded fragments. Given the vast number of combat casualties with retained fragments, it is expected that fragment analysis will have significant implications for the optimal short and long-term care of wounded service members.

In our previous study in rats acutely exposed to As, we observed an effect of As on neurofilaments in the sciatic nerve. This study deals with the effects of inorganic As in Wistar rats on the cytoskeletal protein composition of the sciatic nerve after subchronic intoxication. Sodium meta-arsenite (NaAsO2) dissolved in phosphate-buffered saline (PBS) was administered daily in doses of 0, 3 and 10 mg/kg body weight/day (n=9 rats/group) by intragastric route for 4, 8 and 12 week periods. Toxicokinetic measurements revealed a saturation of blood As in the 3- and 10-mg/kg dose groups at approximately 14 microg/ml, with an increase in renal clearance of As at increasing doses. After exsanguination, sciatic nerves were excised and the protein composition was analyzed. Analysis of the sciatic nerves showed compositional changes in their proteins. Protein expression of neurofilament Medium (NF-M) and High (NF-H) was unchanged. Neurofilament protein Low (NF-L) expression was reduced, while mu- and m-calpain protein expression was increased, both in a dose/time pattern. Furthermore, NF-H protein was hypophosphorylated, while NF-L and microtubule-associated protein tau (MAP-tau) proteins were (hyper)-phosphorylated. In conclusion, we show that expression of mu- and m-calpain protein is increased by exposure to As, possibly leading to increased NF-L degradation. In addition, hyperphosphorylation of NF-L and MAP-tau by As also contribute to destabilization and disruption of the cytoskeletal framework, which eventually may lead to axonal degeneration.

The use of dietary supplements has grown dramatically in the last decade. A large number of dietary and herbal supplements escape regulatory and quality control; components of these preparations are poisonous and may contain, among other toxins, heavy metals. Uncontrolled use of dietary and herbal supplements by special populations, such as the military, may therefore pose a health risk. Clinical symptoms are not always properly attributed to dietary supplements; patients often do not mention supplement use to their health care provider. Therefore, a health risk estimate is hard to make on either the individual or the population level. The literature on this issue was reviewed and discussed in the light of a representative clinical-chemical case study. This case study was performed on a host of preparations that were used by one single individual in the military. Both essential (chromium, copper, zinc, and iron) and poisonous (arsenic, lead, and nickel) trace elements were determined using inductively coupled plasma combined with optical emission spectrometry (ICP-OES) or with mass spectrometry (ICP-MS). Arsenic and lead were detected at exposure levels associated with health risks. These health risks were detected predominantly in hormone-containing supplements and the herbs and botanicals used for performance enhancement. To the extent that this is a representative sample, there is an underestimation of supplement use and supplement risk in the US military, if not in the general population. Since clinical symptoms may be attributed to other causes and, unless patients are specifically asked, health care providers may not be aware of their patients' use of dietary supplements, a strong support of laboratory diagnostics, such as a toxicological screening of blood or urine, is required. In addition, screening of the preparations themselves may be advised.

Arsenic (As) has been shown to alter one or more DNA repair processes. Excision repair cross-complementing 1 and 2 (ERCC1 and ERCC2) have shown to be associated with arsenic-induced toxicity and carcinogenicity. In this study, we investigated cytotoxic effects of various As metabolites in relation to two nucleotide excision repair genes: ERCC1 and ERCC2. Various arsenate (pentavalent) and arsenite (trivalent) metabolites were tested in ERCC1, ERCC2 deficient and wild type cells. Our results showed that in the selected concentration range pentavalent As metabolites; iAs(V), MMA(V) and DMA(V) were not cytotoxic, unlike the trivalent As metabolites; iAs(III), MMA(III) and DMA(III). The measured LC(50) demonstrated a significant difference (p<0.01) for iAs(III) between the three cell lines, while MMA(III) and DMA(III) are more cytotoxic to all three cell lines. UV5 (ERCC2 deficient) cells also showed a lower resistance to iAs(III) in comparison to AA8 (wild type) and UV20 (ERCC2 deficient) cells. This might be explained through the generation of hydrogen peroxide (H(2)O(2)), which is generated by increase of intracellular Ca(2+) level. Generation of H(2)O(2) in UV5 cells after incubation with iAs(III) is significantly higher than AA8 and UV20 cells (p<0.01). In conclusion, absence of ERCC2 leads to a increased generation of H(2)O(2) by iAs(III) in UV5 cells, which is in contrast to AA8 and UV20 cells.

In recent studies we have demonstrated that arsenic (As) metabolites change the composition of neuronal cytoskeletal proteins in vivo and in vitro. To further examine the mechanism of arsenic-induced neurotoxicity with various arsenate metabolites (iAsV, MMAV and DMAV) and arsenite metabolites (iAsIII, MMAIII and DMAIII), we investigated the role of the proteolytic enzyme calpain and its involvement in the cleavage of p35 protein to p25, and also mRNA expression levels of calpain, cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta (gsk3ss). A HeLa cell line transfected with a p35 construct (HeLa-p35) was used as a model, since all other proteins such as calpain, CDK5 and GSK3beta are already present in HeLa cells as they are in neuronal cells. HeLa-p35 cells were incubated with various As metabolites and concentrations of 0, 10 and 30 microM for duration of 4 h. Subsequently the cells were either lysed to study their relative quantification levels of these genes or to be examined on their p35-protein expression. P35-RNA expression levels were significantly (p<0.01) increased by arsenite metabolites, while p35 protein was cleaved to p25 (and p10) after incubation with these metabolites. The cleavage of p35 is caused by calcium (Ca2+) induced activation of calpain. Inhibition of calpain activity by calpeptin prevents cleavage of p35 to p25. These results suggest that cleavage of p35 to p25 by calpain, probably As-induced Ca2+-influx, may explain the mechanism by which arsenic induces its neurotoxic effects.

Background: The Epidemiological Study Air Disaster in Amsterdam (ESADA) aimed to assess long-term health effects in professional assistance workers involved in the 1992 air disaster in Amsterdam. As part of ESADA indications of nephrotoxicity due to exposure to uranium from the balance weights of the crashed aircraft were assessed., Methods: Data of a historically defined cohort of 2499 (exposed and non-exposed) firefighters, police officers and hangar workers were collected 8.5 years after the disaster. Urinary uranium concentrations were determined by sector field inductively coupled plasma mass spectrometry. Urine albumin-creatinine ratio and fractional excretion of beta(2)-microglobulin were calculated from a single-spot urine specimen and simultaneous blood sample. Exposed assistance workers were compared with their non-exposed colleagues, and associations between uranium and kidney function parameters were explored., Results: Median uranium concentrations were around 2 ng/g creatinine. Median values of albumin-creatinine ratio and fractional excretion of beta(2)-microglobulin were well below the level for microalbuminuria and for tubular damage, respectively. No statistically significant differences between exposed and non-exposed workers were found in uranium concentrations and kidney function parameters, although exposed hangar workers had lower uranium concentrations. No statistically significant associations were found between uranium concentrations and kidney function parameters in the total cohort., Conclusions: Occupational exposure to the air disaster in Amsterdam was neither significantly associated with higher uranium concentrations, nor with disturbed kidney function parameters. In this large cohort of professional assistance workers, urinary uranium concentrations were in the low range compared with previously published reference populations. No indications of nephrotoxicity were found at urinary uranium concentrations around 2 ng/g creatinine.

Arsenic (As) is one of the oldest poisons known to men. Its applications throughout history are wide and varied: murder, make-up, paint and even as a pesticide. Chronic As toxicity is a global environmental health problem, affecting millions of people in the USA and Germany to Bangladesh and Taiwan. Worldwide, As is released into the environment by smelting of various metals, combustion of fossil fuels, as herbicides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of As in groundwater. The environmental fate of As is contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by World Health Organization (WHO). Arsenic exists in both organic and inorganic species and either form can also exist in a trivalent or pentavalent oxidation state. Long-term health effects of exposure to these As metabolites are severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases. Neurological effects of As may develop within a few hours after ingestion, but usually are seen in 2-8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barré syndrome. The predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet. Electrophysiological studies performed on patients with As neuropathy have revealed a reduced nerve conduction velocity, typical of those seen in axonal degeneration. Most of the adverse effects of As, are caused by inactivated enzymes in the cellular energy pathway, whereby As reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation. These changes may lead to disorganization of the cytoskeletal framework, which is a potential mechanism of As-induced neurotoxicity.

Tungsten and tungsten compounds are considered toxicologically relatively safe. Concern regarding the potential health and environmental effects of depleted uranium and lead in military applications has lead many countries to explore the possibility of applying toxicologically safer metals. Heavy metal tungsten alloy-based munitions have been therefore introduced as a replacement in munitions and as kinetic energy penetrators. Although the toxicological profiles of all these metals are well known, their internalization as embedded shrapnel may be considered a new route for long-term exposure. Studies in experimental animals and cell culture indicate that pellets based on heavy metal tungsten alloy possess carcinogenic potential previously unseen for depleted uranium and/or lead. Other metals in the tungsten alloy such as nickel or cobalt may contribute to such a risk. Accordingly, the long-term tungsten-related health risk is reason for concern. This article reviews toxicological and clinical literature and provides new perspectives on tungsten and tungsten-based alloys.

Neurological studies indicate that the central (CNS) and peripheral nervous system (PNS) may be affected by arsenic (As). As-exposed patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison to healthy subjects. As may play a role in the disruption of neuroskeletal integrity, but the mechanisms by which it exerts a toxic effect on the peripheral and central nervous system are still unclear. In the present study, we examined the neurotoxic effects of various arsenic metabolites (iAs(III), iAs(V), MMA(V) and DMA(V)) on two different cell lines derived from the peripheral (ST-8814) and central (SK-N-SH) nervous system. The effects of the arsenic metabolites were examined on the relative quantification levels of the cytoskeletal genes, neurofilament-light (NEFL), neurofilament-medium (NEF3), neurofilament-heavy (NEFH) and microtubule-associated protein-tau (MAPT), using real-time PCR. Our results show that iAs(III) and iAs(V) have no significant effects on either cell lines. On the other hand, MMA(V) and DMA(V) cause significant changes in expression levels of NEF3 and NEFL genes, while the expression level of the NEFH gene is significantly increased in both cell lines.

Exposure to arsenic compounds may lead to skin and lung cancer and various disorders such as vascular disease and peripheral neuropathy in humans. Peripheral arsenic neurotoxicity has been demonstrated clinically and in electrophysiological studies. Patients intoxicated with arsenic show neurological symptoms in their feet and hands. These patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison with controls. The mechanism of arsenic peripheral nervous system (PNS) toxicity, however, has never been described before. This is the first study to investigate the toxicity of arsenic on the PNS. Male Wistar rats were exposed to arsenite given as a single dose i.v. After sacrifice, sciatic nerves were excised and the protein composition was analysed. Protein analysis of sciatic nerves showed disappearance of neurofilament and fibroblast proteins in rats treated with arsenite doses of 15 and 20 mg/kg in comparison with the control groups. Some fibroblast protein bands had disappeared in the 20-mg/kg dose group. The analysed neurofilament-M and -L proteins decreased dose dependency over time. arsenic affects the composition of proteins in the rat sciatic nerve, especially the neurofilaments. The reduction of signals in Western blot analysis reveals changes in cytoskeletal composition, which may well lead to neurotoxic effects in vivo.

We describe a fetus with a hypoplastic right ventricle detected by prenatal ultrasound examination. A possible causal relationship with prenatal valproate exposure is discussed., (Copyright 2005 John Wiley & Sons, Ltd.)

Nephrotoxicity is the most important dose-limiting factor in cisplatin based anti-neoplastic treatment. Pretreatment with bismuth salts, used as pharmaceuticals to treat gastric disorders, has been demonstrated to reduce cisplatin-induced renal cell death in clinical settings and during in vivo and in vitro animal experiments. To investigate the genomic basis of this renoprotective effect, we exposed NRK-52E cells, a cell line of rat proximal tubular epithelial origin, to 33 microM Bi3+ for 12 hours, which made them resistant to cisplatin-induced apoptosis. Differentially expressed genes in treated and untreated NRK-52E cells were detected by subtraction PCR and microarray techniques. Genes found to be down regulated (0.17-0.31-times) were cytochrome c oxidase subunit I, BAR (an apoptosis regulator), heat-shock protein 70-like protein, and three proteins belonging to the translation machinery (ribosomal proteins S7 and L17, and S1, a member of the elongation factor 1-alpha family). The only up-regulated gene was glutathione S-transferase subunit 3A (1.89-times). Guided by the expression levels of these genes, it may be possible to improve renoprotective treatments during anti-neoplastic therapies.

The population of Curaçao, Netherlands Antilles (133,000) shows a very high prevalence of end-stage renal disease (approximately 1 per 1,000). These patients are often treated chronically with haemodialysis. As the drinking water on the island is prepared by distillation of sea water, the haemodialysis fluid used to be prepared with tap water without further treatment. In 1996, the 27 patients of one of the dialysis centers on the island presented with nausea, vomiting, and hypercalcaemia in a short time span, which was initially diagnosed as 'hard water syndrome'. In spite of treatment with low-calcium dialysate, microcytic anaemia and neurological symptoms developed. Ten patients died of convulsions, sepsis, and coma. As aluminum (Al) intoxication was suspected, Al in serum (AlS) was measured. Ante mortem AlS was 808 microg/l (n = 7; range 359-1189); in the survivors AlS was 255 microg/l (n = 17; range 113-490). Normal AlS is < 10 microg/l, and <50 microg/l in asymptomatic dialyzed patients. The court requested post-mortem toxicological analysis of four patients. Al concentrations in liver, bone, and cerebral cortex were significantly increased as compared with background levels. Al intoxication was, therefore, considered to be the most likely cause of death in these patients. Investigations of the tap water supply revealed that a few weeks before the onset of the symptoms, a water conduit pipe to the dialysis unit had been replaced, which was lined with Al- and Ca-rich cement mortar. These ions leached into the distilled water and caused both Ca- and Al-intoxication through uptake from the dialysate into the patients' circulation. The symptoms of the latter were initially not recognized as they were masked by the symptoms of hypercalcaemia.

Colloidal bismuth subcitrate (CBS), a drug for treatment of peptic ulcers, has been reported in the literature to be nephrotoxic in humans when taken in high overdoses. To investigate the mechanism of bismuth nephropathy, we developed an animal model by feeding rats single doses of CBS containing 3.0 mmol Bi/kg body weight. Terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling assay, immunostaining for active caspase-3, and electron microscopy showed that proximal tubular epithelial cells die by necrosis and not by apoptosis within 3 h after CBS administration. Exposure of the renal epithelial cell lines NRK-52E and LLC-PK1 to Bi(3+) in citrate buffer served as an in vitro model of bismuth nephropathy. NRK-52E cells exposed to 100 microM Bi(3+) or more died by necrosis, as was demonstrated by nuclear staining with Hoechst 33258 and flow cytometry using Alexa(488)-labeled Annexin-V and the vital nuclear dye TOPRO-3. Bismuth-induced cell death of NRK-52E cells was not prevented by the caspase-3 inhibitor z-VAD-fmk, whereas this inhibitor did prevent cisplatinum-induced apoptosis. Mitochondrial dysfunction and induction of free radicals were shown not to be involved in bismuth nephrotoxicity. The early time point of damage induction in vitro as well as in vivo and the early displacement of N-cadherin, as found in previous studies, suggest that bismuth induces cell death by destabilizing the cell membrane. In conclusion, we showed that high overdose of bismuth induced cell death by necrosis in vivo as well as in vitro, possibly by destabilization of the cell membrane., ((c) 2002 Elsevier Science (USA).)

The nephrotoxicity of single high doses of bismuth (Bi)-containing therapeutic drugs is characterized morphologically by detachment of proximal tubular epithelial cells (PTECs) from each other, followed by cell death. We investigated whether Bi nephrotoxicity is mediated by changes in the distribution of proteins involved in intercellular adhesion. A nephrotoxic dose of colloidal bismuth subcitrate (CBS; 3.0 mmol Bi/kg) was orally administrated to 10 female Wistar rats. After 1 h, N-cadherin had disappeared from the adherence junctions of vital PTECs, whereas ZO-1, a tight junction marker, remained present at the cell-cell border until cell death occurred after 3 h. E-Cadherin, absent in PTECs, remained absent. Exposure of the renal epithelial cell lines NRK-52E and LLC-PK1 to 400 microM Bi(3+) also resulted in the disappearance of N-cadherin expression after 1 h, whereas ZO-1, E-cadherin, and Desmoplakin expression did not resolve before cell death at 24 h, thus confirming in vivo results. Our results are the first to indicate that Bi-induced death of PTECs is preceded by redistribution of N-cadherin and the disruption of homotypic cell adhesion., (Copyright 2001 Academic Press.)

Overdosing of colloidal bismuth subcitrate (CBS), used to treat peptic ulcers and Helicobacter pylori infections, has been reported to result in serious, though reversible, nephrotoxicity in humans. However, little is known about the nature of the renal damage induced by bismuth (Bi), and no well-described experimental model exists. Single large oral CBS doses (0.75, 1.5, and 3.0 mmol Bi/kg) were administered to three groups of 20 female Wistar rats. A control group (n = 20) received only the vehicle. Standard kidney function parameters, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and the Bi content were monitored in blood, urine, liver, and kidneys for 14 days. A dose of 3.0 mmol Bi/kg, 100 times the daily therapeutic dose, caused kidney damage within 6 h as detected by proteinuria, glucosuria, and elevated plasma urea and plasma creatinine levels. The kidneys of all animals, except two that died, recovered functionally within 10 days. At a dose of 1.5 mmol Bi/kg, clinical parameters changed less and normalized within 48 h, whereas a dose of 0.75 mmol Bi/kg induced no changes. Histological evaluation revealed that the S3 tubular segment necrotized first with additional necrotization of the S1/S2 segment when more Bi was absorbed. The lesions were accompanied by interstitial infiltrates of CD45+ leukocytes. In summary, we developed a rat model for Bi-induced reversible nephropathy. A large single oral overdose of CBS administered to Wistar rats led to damage to the proximal tubule, especially in the last segment.

Bismuth induced nephrotoxicity has been reported to occur after acute overdoses of Bi-containing therapeutic drugs. We studied the development of bismuth induced nephropathy and bismuth biokinetics in rats. Bismuth nephropathy was induced in 33 young adult female Wistar rats weighing ca. 175 g by feeding them a single overdose of colloidal bismuth subcitrate containing 3.0 mmol Bi/kg at (t = 0). Control animals (n = 7) were fed the vehicle only. The animals were sacrificed after 1-48 h. Plasma creatinine increased from 51 +/- 6 micromol/l at t = 0 to 550 +/- 250 micromol/l after 48 h in the experimental group. The S3 segment of the proximal tubule showed epithelial cell vacuolation after 1 h and necrosis after 3 h. Cells of the S1/S2 segment demonstrated vacuolation after 6 h and necrosis after 12 h. Biokinetics of bismuth in blood could best be described with a one-compartment model characterized by an absorption half-life of 0.32 h and an elimination halflife of 16 h. The peak concentration of about 7.0 mg Bi/l was reached after 2 h. In conclusion, cells of the S3 segment of the proximal tubule necrotized first after an oral colloidal bismuth subcitrate overdose and biokinetics of Bi in blood was best described by a one-compartment model.

The role of fluoride in aluminium neurotoxicity was studied using an in vitro system of cultured hippocampal neurons from foetal rats. Sodium fluoride (50 microM) and aluminium chloride (12.5 microM) were administered alone or in a specific combination (50 + 12.5 microM) in a 14-day culture in a chemically defined medium before staining of neurofilaments. Neuronal aggregates interconnected by neuritic fibers were detected light microscopically in control cultures. The aggregates and the fibers stained positive for neurofilament proteins. In cultures treated with aluminium chloride the development of the interconnecting fibers was affected, resulting in a fusion pattern of the aggregates. This phenomenon was enhanced when sodium fluoride was given together with aluminum chloride. It was concluded that aluminium interferes with the metabolism of the neuronal cytoskeleton and that this interference is potentiated by fluoride.

Suriname is experiencing a revival of small scale gold mining activities, with about 10,000 to 15,000 workers involved in 1996. The estimated production in 1995 is at least 10,000 kg crude gold. Gold is extracted with mercury and methods used are comparable with those described for gold mining in the Amazon Basin. Since no data exist on the internal mercury exposure of workers in Suriname a study was performed. A group of mercury-exposed Maroons, who are principally involved in the mining located in the tropical rainforest, is compared with nonexposed Maroons living in a non-gold mining area. Blood and urine samples of both groups were analyzed for total mercury using an atomic absorption spectrometer with an FIAS hydride system. In the study 28 exposed and 17 controls with a comparable mean age (P=0.544; exposed 27+/-7.2 years, n=26; controls 26+/-7.7 years, n=17), all males, participated. The urine levels for both groups differ statistically significantly from each other (P<0.001; exposed mean 27.5+/-21.1 microg/g creatinine; controls mean 5. 2+/-2.9 microg/g creatinine). This is, however, not the case with the blood levels (P=0.036: exposed mean 18.1+/-11.0 microg/L, n=25; controls mean 26.8+/-14.6 microg/L, n=16). In contrast with blood the urine total mercury levels in this study confirm, on a group basis, exposure to mercury as described for individuals working in the gold mining in the Amazon Basin., (Copyright 1998 Academic Press.)

Two groups of 12 human volunteers, who had been treated with colloidal bismuth subcitrate, because of Helicobacter pylori-associated gastritis, participated in the study. The patients received a single dose of meso-2,3-dimercaptosuccinic acid (DMSA) or D,L-2,3-dimercaptopropane-1-sulfonic acid (DMPS) at a dose of 30 mg kg-1 in a randomized single blind study. In contrast to DMPS, increasing concentrations of bismuth in blood were observed during the first 4 h after intake of DMSA. In urine, both chelators induced a 50-fold increase in urinary bismuth excretion compared with the control urines. The treatment was well tolerated. The results indicate that both DMSA and DMPS effectively increase the elimination of bismuth in human urine. Consequently, both chelators may be of benefit in the treatment of patients with bismuth intoxication.

Aluminum (Al) is recognized as a toxin in patients with deficient renal function. Moreover, Al may play a role in some neurodegenerative diseases. It is hypothesized that more than one intestinal absorption mechanism exists for Al, related to various intraluminal chemical species, and that Al shares intestinal transport routes for essential inorganic substances due to similarities in their chemical speciation characteristics. The purpose of the present investigation was to study the effects of ionic Na (0-120 mmol/l) and Ca (0-10 mmol/l), alone and in combination, on the intestinal absorption of ionic Al (20 and 30 mmol/l). A previously standardized method of perfusion of rat small intestine was used, combined with serial blood sampling. Mucosal uptake and systemic appearance of Al in the blood were monitored during 1 h perfusion, together with Na and Ca; the metals were given as the chloride. The intestinal absorption of Na and Ca was taking place according to previously reported mechanisms. A one-sided negative interaction was shown to exist between Ca and Al resp. Al and Na during both mucosal uptake and systemic appearance; Ca interacts negatively with Na during systemic appearance, but enhances mucosal uptake of Na. It may be speculated that Al mimicks Ca in its Na-dependent intestinal passage.

Background/objective: Aluminium is produced from the mineral bauxite. Occupational exposure is reported during the industrial processing of aluminium and is associated with pulmonary and neurotoxicity. However, data on exposure and toxicity of workers in the open bauxite mining industry do not exist. Therefore, a study was performed to explore aluminium exposure in employees involved in this bauxite mining process in a Surinam mine., Methods/design: A group of workers occupationally exposed to aluminium in an open bauxite mine were compared with a group of nonexposed wood processors. Serum aluminium was analyzed using atomic absorption spectrometry Data from the clinical chemistry of the blood and a questionnaire were used to explore determinants for aluminium exposure., Results: No significant difference between serum aluminium in the exposed (4.4 +/- 2.0 micrograms/L, n = 27) and control group (5.1 +/- 1.5 micrograms/L, n = 27) was detected. For the serum concentration of the clinical chemical variables (calcium, citrate, and creatinine), a statistically significant difference was computed (p < or = 0.02) between the exposed and control group. All levels were slightly higher in the exposed group; no statistically significant correlations with serum aluminium were found., Conclusions: In this study, serum aluminium values were in the normal range, no significant difference between the groups could be detected despite long-term occupational exposure.

Objective: The detection of low levels of iron overload by magnetic resonance imaging., Methods: Eight consecutive patients suspected of having idiopathic haemochromatosis. Comparison of signal intensity ratios and absolute iron content of liver., Results: There was a good correlation between the signal intensity ratios and iron content in the range 2-30 micrograms Fe/mg dry weight., Conclusions: The ability of a non-invasive technique to detect low levels of iron overload could be useful in the assessment of therapy and in the screening of relatives of probands with idiopathic haemochromatosis.

Evaluation of the amount of bismuth (Bi) absorbed from the gastrointestinal tract is important for assessment of the possible risks associated with the use of Bi compounds in the treatment of gastrointestinal disorders. We compared the absorption of Bi from media containing the equivalent of 1 g of elemental Bi from either Bi subnitrate (BSN), Bi subsalicylate (BSS), colloidal Bi subcitrate (CBS), Bi chloride (BiCl3), or Bi citrate (BCit) by an in vivo perfusion system of rat small intestine. The intestinal absorption was < 1% for all compounds, but higher from BCit and CBS than from BSN, BSS, and BiCl3. The dose dependency of Bi absorption from both CBS and BiCl3 in citrate buffer showed a nonlinear relationship between the concentration of Bi in perfusate and the concentration of Bi in blood after 60 min.

Deposition of aluminum in the body is responsible for the development of dialysis-related diseases in patients with renal dysfunction and may play a role in the development of certain neurodegenerative disorders. Although citric acid is known to be a strong enhancer of gastrointestinal absorption of aluminum, its effect on aluminum distribution and accumulation is not yet clear. Maltol has been shown to increase the neurotoxicity of aluminum, but little is known about its effect on aluminum deposition in the body. To elucidate the role of citric acid and maltol in aluminum accumulation and toxicity, rats were loaded intraperitoneally during a 7-day period with different amounts of aluminum chloride in absence or presence of citric acid or maltol before analysis of aluminum in serum, brain, bone, and urine. Coadministration of citric acid led to relatively reduced serum levels, as compared with aluminum and aluminum-maltol treatment. This is explained by both tissue elimination and enhanced renal elimination. Only at the highest aluminum dose (8 mg/kg body weight) was an enhancing effect of citric acid on accumulation of aluminum in brain observed; no effect on bone aluminum was seen. Furthermore, it was seen that citric acid alters the distribution pattern of aluminum. This may be explained by the postulation of a characteristic aluminum citrate species in serum. Administration of citric acid may increase this aluminum fraction in serum, thereby inducing an alteration of the distribution pattern. Maltol was shown to be a strong enhancer of aluminum accumulation in serum, brain, and bone. The rise of aluminum in these target tissues was dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum (Al) has been observed to cause neurofilament protein accumulation in both experimental animals and cultured cells. Impairment of axonal transport is thought to be a mechanism of toxicity. Inhibition of the degradation of neurofilament proteins, however, resulting in accumulation of these proteins may be an alternative mechanism for Al toxicity. In the present study, the effect of calcium (Ca) on the proteolysis of the neurofilament triplet proteins by calcium-activated neutral proteases (CANP) was studied in the isolated sciatic nerve explants. The extent of the degradation was found to be dependent on the Ca concentration. The effect of Al chloride, -citrate and -maltol on the calcium-induced degradation was studied. No effect of any of the Al compounds was observed, suggesting that the metal may exert its neurotoxic effect via a mechanism other than impairment of neurofilament proteolysis. Maltol itself was found to enhance the effect of Ca on the degradation of neurofilament proteins, probably by facilitating the movement of Ca across the neuronal membrane.

Aluminium (Al) accumulation occurs in the liver of renal patients and in patients on parenteral nutrition. Human hepatotoxicity is not proven. The role of the liver in storage and biotransformation of Al and in development of osteo- and neurotoxicity is not clarified as yet. The aim of the present investigation was to study the storage of Al in total liver and in subcellular liver fractions, and its association with soluble cytosolic molecular species. Therefore, rats were loaded with Al prior to liver fractionation by ultracentrifugation, and equilibrium gel filtration chromatography of the cytosol, using a previously described method for Al speciation in serum. Al accumulated dose-dependently in liver and subcellular liver fractions, the lowest levels occurring in the cytosol. A dose-dependent elevation of Al in the blood was also observed. Gelfiltration of the cytosol indicated that Al was associated with a low molecular weight form which was not a citrate complex, and a high molecular weight form, which was larger than transferrin. No induction of and association with metallothionein occurred.

The intestinal absorption of aluminium can contribute significantly to systemic exposure to this element. Aluminium can be absorbed not only from oral pharmaceuticals but also from solid food and drinking water. The absorption process is not restricted to patients with kidney disorders; other groups of patients and healthy subjects are not excluded. Details of the absorptive mechanism are mainly obtained from in vitro (everted gut sac) and animal studies (intestinal perfusion) rather than from controlled human studies and case reports. The process of absorption depends on the intraluminal speciation, the intraluminal quantity, the presence of competing (iron, calcium) or complexing (citrate) substances and the intraluminal pH. The condition of the exposed organism with respect to the gut also determines intestinal absorption (iron status, calcium [vitamin D, parathyroid hormone] status, age and kidney function). Various absorption sites and passage routes, both transcellular and paracellular, have been reported, each apparently related to a different aluminium species (hydrated ionic species, aluminium citrate complex etc.). No uniform mechanistic model allowing extrapolation to the clinical situation has yet emerged.

Bismuth-containing medicines have been used for years, but there is a lack of clinically applicable methods for measuring bismuth in body fluids. We describe a sensitive, accurate and precise method for analysis of bismuth in blood and serum, which is suitable both for monitoring purposes and for further investigations into the biokinetics and safety of bismuth. Bismuth was quantitated with electrothermal atomic absorption spectrometry with Zeeman background correction. In the furnace programme a cool-down step was introduced and platinum was used as a matrix modifier. Recovery for 40 micrograms/l is 93.7 +/- 4.6% (mean +/- SD) from serum and 92.8 +/- 5.4% from blood; within-day precision (n = 10) at 40 micrograms/l is 3.2% for serum and 4.2% for blood. Day-to-day precision at 40 micrograms/l (n = 10) was 4.5% for serum and 4.0% for blood. The detection limit is 0.7 microgram/l for serum and 1.0 microgram/l for blood. Blood samples have to be collected in glass tubes and stored at -20 degrees C.

Doses of 4-6 mg kg-1 c-DDP given 6 months before renal irradiation caused only a modest increase in functional radiation damage (DEF 1.1). These effects could be explained by additive toxicities and the damage was much less than when c-DDP was given 3-6 months after irradiation. Pharmacokinetic studies did not demonstrate any decrease in the rate of platinum elimination after previous low-dose renal irradiation.

A two-year-old male Barsoi dog was presented after a two-week period of muscle twitching and convulsions during exercise, which worsened to a state of tetraparesis and coma. Removal of a gastric foreign body, containing aluminium, resolved the presenting signs. Parallel with this clinical recovery the elevated serum levels of aluminium decreased to values of two normal control dogs, suggesting that the neurological signs were due to A1 intoxication.

The binding of aluminium in rat serum was studied. Rats were loaded intraperitoneally with different doses of aluminium(III)chloride 4 times during one week, before being killed by cardiac puncture. One ml of serum was applied to a Sephacryl S-200 SF column and 70 fractions were collected. In the collected fractions, the distribution of aluminium was measured and compared with the concentrations of total protein, transferrin, and citrate. The presence of a high molecular weight aluminium-complex in serum is confirmed. Although a possible role for albumin cannot be excluded, it is most likely that transferrin plays a role as a carrier for biological transport of aluminium in plasma. In addition to transferrin, aluminium was shown to be associated with citrate in serum, resulting in a low-molecular weight complex. It is postulated that citrate acts as a chelator for aluminium, and that the Al/citrate complex in serum may play an important role in intracellular accumulation, and hence the toxicity, of aluminium.

To improve the accuracy and precision of the assay of aluminum in brain tissue, we modified for application to brain samples from rats and humans the wet-digestion method of Trapp et al. (Biol Psychiatry 1978; 13:709-18), established the contribution of contamination, and examined the effect of precipitation of nonoxidizable fatty residues on the analysis. Specifications of the modified assay are a detection limit of 5 ng of aluminum per gram wet weight of brain tissue, a within-day CV of 4.8% (24.3 microgram/L; n = 10), and a day-to-day CV of 5.5% (27.8 micrograms/L; n = 5). Contamination, a systematic error in the analysis of aluminum, was established to be 13 ng (SD = 7.9 ng; n = 8) per tube. The presence of indestructible fatty residues did not affect the accuracy of the method. Application of the method to brain hemispheres of nonexposed rats revealed an aluminum content of 0.041 mg/kg wet weight of tissue (SD = 0.032 mg/kg; n = 8). The aluminum content in human cortex samples, consisting of gray and white matter, ranged from 0.14 to 0.22 mg/kg. Modification of the wet-digestion method resulted in a reliable, simple sample pretreatment before analysis for aluminum in brain tissue. The extent of the aluminum contamination must be controlled by including appropriate blanks.

The antibacterial activity of mecillinam and ampicillin, alone and in combination, against Escherichia coli was quantitated and compared in vitro and in vivo. Minimum inhibitory concentrations (MICs) were determined for both antibiotics individually and combined. Two-hour growth curves were established in vitro. A quadratic fit to these growth curves provided quantitative concentration-dependent growth characteristics. The antibacterial activity in vivo was determined by applying a short-term thigh muscle infection model to normal and irradiated granulopenic mice. The effects in vivo were also quantitated as dose-dependent or concentration-dependent parameters. Mecillinam showed activity in vitro, but none in vivo. Combinations of mecillinam with ampicillin showed a strong potentiation, as judged from MICs and from short-term experiments in vitro and in the normal and irradiated granulopenic mice. The potentiating activity in vivo was not influenced by host factors (i.e. granulocytes). However, the degree of potentiation indicated by the MICs led to strong overestimation of the effect of the combination of the two antibiotics on short-term in vitro growth. Furthermore, the combined activity in vitro overestimated the potentiating effect of the two antibiotics in vivo.

The effects of citric acid and dinitrophenol on the mucosal uptake of aluminum (Al) and its appearance in the portal and systemic blood were investigated to establish the energy dependence of these processes. Therefore, the rat small intestine was perfused in situ with media containing 20 mmol Al/liter, with or without 5 mmol citric acid/liter, and with or without 0.1 mmol/liter of the metabolic inhibitor DNP. It is concluded that (1) the appearance of Al in systemic blood depends on the mucosal Al uptake after perfusion and the systemic blood level before perfusion and (2) citric acid stimulates and DNP inhibits both mucosal uptake and Al absorption in situ.

To investigate the association of serum copper and zinc with mortality from cancer and cardiovascular disease, the authors performed a case-control analysis of data obtained in a Dutch prospective follow-up study. Cancer (n = 64) and cardiovascular disease (n = 62) deaths and their matched controls were taken from a cohort of 10,532 persons examined in 1975-1978. Trace elements were measured in baseline serum samples, which had been stored during the six to nine years of follow-up. The adjusted risk of death from cancer and cardiovascular disease was about four times higher for subjects in the highest serum copper quintile (greater than 1.43 mg/liter) compared with those with normal levels. The excess mortality observed in subjects with low copper status suggests a U-shaped relation. No significant change in the risk of death from cancer and cardiovascular disease was found for subjects with low or high baseline levels of serum zinc. However, a protective effect of a high zinc status on the risk of cancer and cardiovascular disease is compatible with the data. For definitive conclusions, analysis of larger prospective data sets is recommended.

The intestinal absorption of aluminium (Al) from the antacid hydrotalcite (Ultacit) was compared with that from algeldrate (Algeldratum des-acidans) in 8 healthy human subjects in a cross-over study. The level of Al in serum (AlS) was increased in 7 out of 8 subjects 7 hr after intake of 6 g algeldrate while AlS did not rise after intake of 8 g hydrotalcite--a dose with at least comparable acid-neutralizing capacity--in any of the subjects.

The relative antibacterial efficacy of amoxycillin ampicillin was compared in vitro and in vivo against a strain of Escherichia coli in short-term experiments (hours). The quadratic fit to the growth curves in vitro in the presence of the antibiotic gave concentration dependent parameters. The concentration effect curves for both antibiotics showed that amoxycillin varied between equipotent (at 2 mg/l) and twice as potent (at higher concentrations) as ampicillin. The relative efficacy in vivo was determined in a thigh muscle infection in irradiated as well as normal mice. Numbers of colony forming units 3 h after infection were dose (or concentration) dependent, the slopes for amoxycillin and ampicillin being parallel. Slopes in irradiated and non-irradiated mice differed significantly. In both kinds of animals the average potency ratio was 1.5 in favour of amoxycillin. Thus, no difference was found between the in vitro and in vivo situation regarding relative efficacy.

We are presenting a quantitative determination of the effect of granulocytes, monocytes and lymphocytes on the course of infection during antibiotic treatment. The animal model was a short-term infection of the thigh muscle in normal or irradiated mice. Two kinds of antibiotics were used: tobramycin for Pseudomonas aeruginosa infections and ampicillin for Escherichia coli infections. The number of granulocytes was changed by irradiating the mice before they were infected. The dose-effect relations for both combinations of bacteria and antibiotics were determined on various days after irradiation. Analysis of the results shows that the effect of an antibiotic was predominantly potentiated by granulocytes. This means that under the conditions of granulopenia, the dose of an antibiotic must be increased to obtain the same antibacterial effect. The present results indicate that the interrelation between host factors, bacterial proliferation and antibiotic treatment can be quantitated and may offer a useful model for screening antimicrobial drugs before they are clinically applied.

Aluminium (Al) intoxication in dialysis patients is held to be caused not only by Al in the dialysis fluid but also by Al from orally administered phosphate binders. Studies on Al absorption in patients and healthy individuals as well as in animals are still scarce, and do not provide sufficient data to characterize the absorption process. This paper presents a method of studying the process of Al absorption in a perfusion system of rat small intestine in vivo, in combination with a cannulation system of the portal vein for serial blood sampling. Determination of concentrations of an absorbed substance in samples of both the perfusion medium and the portal blood, collected during the perfusion medium and the portal blood, collected during the perfusion period, may clarify the nature of the absorption process. Although this method appears to be useful for the study of the intestinal absorption of any substance, it was adapted for the study of the intestinal absorption of Al compounds. The usefulness of this method for studying Al absorption was demonstrated in an experiment in which Al chloride (0.5 g/l) in buffered media of pH 7.0, 7.5, and 8.0 was perfused through the rat small intestine over a period of at least 30 min. The results of this experiment indicate that a decrease in pH of the perfusion medium leads to an increase in absorption of Al in the portal blood.

The effect of aluminum (Al) was studied in an in vitro system of cultured hippocampal neurons from fetal rats in a chemically defined medium. Neuronal aggregates interconnected by neurites were detected light and electron microscopically in control and Al-treated cultures. In the Al-treated cultures disruptions of the fibers were observed proximal to the aggregates; the number of disruptions increased with The Al concentration applied. It is concluded that interference of intracellular Al with the neuronal skeleton occurs, leading to an enhanced fragility of the interconnecting neurites. The concentration-dependent Al-induced disruption of interconnecting neurites may serve as an in vitro model for further research in Al neurotoxicity.

The effect of iron (Fe) on the intestinal absorption of aluminum (A1) was studied in an in situ perfusion system of rat small intestine in combination with systemic and portal blood sampling. The gut was perfused with media containing 0.0, 10.0, 15.0, 20.0, and 25.0 mmol/liter Al chloride and 5 mmol/liter Fe(II) or Fe(III) chloride at pH 3.0. Neither luminal disappearance nor intestinal absorption of A1 were affected by Fe(III). Fe(II), however, enhanced luminal disappearance and reduced absorption of Al.