Biomarkers of cadmium and arsenic interactions.

Advances in proteomics have led to the identification of sensitive urinary biomarkers of renal dysfunction that are increasingly used in toxicology and epidemiology. Recent animal data show that combined exposure to inorganic arsenic (As) and cadmium (Cd) gives rise to more pronounced renal toxicity than exposure to each of the agents alone. In order to examine if similar interaction occurs in humans, renal dysfunction was studied in population groups (619 persons in total) residing in two metal contaminated areas in China: mainly a Cd contaminated area in Zhejiang province (Z-area) and mainly a As contaminated area in Guizhou province (G-area). Nearby control areas without excessive metal exposure were also included. Measurements of urinary beta(2)-microglobulin (UB2MG), N-acetyl-beta-glucosaminidase (UNAG), retinol binding protein (URBP) and albumin (UALB) were used as markers of renal dysfunction. Urinary Cd (UCd) and total As (UTAs) were analyzed by graphite-furnace atomic absorption spectrometry. Urinary inorganic As and its mono- and di-methylated metabolites (UIAs) were determined by Hydride generation. Results. As expected, the highest UCd values occurred in Z-area (Geometric mean, GM 11.6 microg/g crea) while the highest UTAs values occurred in G-area (GM = 288 microg/g crea). Statistically significant increases compared to the respective control area were present both for UTAs, UCd and for UB2MG, UNAG and UALB in Z-area as well as in G-area. UIAs was determined only in Z area. In G-area, there was a clear dose-response pattern both in relation to UTAs and UCd for each of the biomarkers of renal dysfunction. An interaction effect between As and Cd was demonstrated at higher levels of a combined exposure to As and Cd enhancing the effect on the kidney. In Z-area an increased prevalence of B2MG-uria, NAG-uria and ALB-uria was found in relation to UCd, but no relationship to UTAs was found. A statistically significant relationship between UIAs and UB2MG was found among women in this area and an interaction between As and Cd was indicated for B2MG. Conclusion. The present studies, which employed sensitive biomarkers of renal dysfunction, give support to the idea that human co-exposure to Cd and inorganic arsenic gives rise to more pronounced renal damage than exposure to each of the elements alone, but further studies are needed to establish and clarify this interaction.

Survival after a lethal dose of arsenic trioxide.

A case of a 27-year-old woman who ingested 9000 mg arsenic trioxide (As2O3) is reported. Classical symptoms of an acute arsenicum (As) poisoning such as gastrointestinal cramps, vomiting, diarrhea, ECG changes and disturbed liver function tests were observed. The absorption of the ingested As was minimalized by a continuous gastric irrigation with highly concentrated NaHCO3 and intestinal cleansing with NaHCO3 and polyethyleneglycol was performed. Forced diuresis, BAL (2,3-dimercaptopropanol) and DMSA (meso-2,3-dimercaptosuccinic acid) were started and therapy to enhance the formation of methylated As derivatives, which are potentially less toxic and which can be excreted more easily, was then administered. The patient survived this massive dose of ingested inorganic As with only polyneuropathy one year later.

Lung hyperpermeability and asthma prevalence in schoolchildren: unexpected associations with the attendance at indoor chlorinated swimming pools.

AIMS: To study whether exposure to nitrogen trichloride in indoor chlorinated pools may affect the respiratory epithelium of children and increase the risk of some lung diseases such as asthma. METHODS: In 226 healthy children, serum surfactant associated proteins A and B (SP-A and SP-B), 16 kDa Clara cell protein (CC16), and IgE were measured. Lung specific proteins were measured in the serum of 16 children and 13 adults before and after exposure to NCl(3) in an indoor chlorinated pool. Relations between pool attendance and asthma prevalence were studied in 1881 children. Asthma was screened with the exercise induced bronchoconstriction test (EIB). RESULTS: Pool attendance was the most consistent predictor of lung epithelium permeability. A positive dose-effect relation was found with cumulated pool attendance and serum SP-A and SP-B. Serum IgE was unrelated to pool attendance, but correlated positively with lung hyperpermeability as assessed by serum SP-B. Changes in serum levels of lung proteins were reproduced in children and adults attending an indoor pool. Serum SP-A and SP-B were already significantly increased after one hour on the pool side without swimming. Positive EIB and total asthma prevalence were significantly correlated with cumulated pool attendance indices. CONCLUSIONS: Regular attendance at chlorinated pools by young children is associated with an exposure dependent increase in lung epithelium permeability and increase in the risk of developing asthma, especially in association with other risk factors. We therefore postulate that the increasing exposure of children to chlorination products in indoor pools might be an important cause of the rising incidence of childhood asthma and allergic diseases in industrialised countries. Further epidemiological studies should be undertaken to test this hypothesis.

Direct experimental evidence for a negative heat capacity in the liquid-to-gas phase transition in hydrogen cluster ions: backbending of the caloric curve.

By selecting specific decay reactions in high-energy collisions (60 keV/amu) of hydrogen cluster ions with a helium target (utilizing event-by-event data of a recently developed multicoincidence experiment) and by deriving corresponding temperatures for these microcanonical cluster ensembles (analyzing respective fragment distributions), we are able to construct caloric curves for H+3(H2)(m) cluster ions (6

Urinary homovanillic acid and serum prolactin levels in children with low environmental exposure to lead.

Current evidence suggests that the neurotoxic effects of lead may partially be mediated through interference with the dopaminergic system. The aim of this study was to assess the levels of two peripheral dopaminergic markers--serum prolactin (Pro-S) and urinary homovanillic acid (HVA-U)--in children living around two lead smelters, who are presumed to be exposed to high environmental lead pollution (n = 200), and compare their results with 200 age- and sex-matched controls living in an area unpolluted by heavy metals, giving a total of 400 children (200 boys and 200 girls). The influence of lead exposure on HVA-U and Pro-S was assessed by stepwise multiple regression, testing lead concentrations in blood (Pb-B), age, sex and area of residence as predictors. Though lead levels were significantly higher in boys and in the lead-polluted environment, mean Pb-B values were relatively low, indicating a low uptake of lead in the contaminated environment (39.5 micrograms l-1, range 4.6-165 micrograms l-1, n = 200), and no significant correlation could be found with either Pro-S or HVA-U. However, when the subgroup of 121 children with Pb-B levels above 50 micrograms l-1 were considered, a weak positive correlation was found between Pb-B and HVA-U (r2 = 0.04, p = 0.03), whilst in the even smaller subgroup of 15 children with Pb-B levels above 100 micrograms l-1, Pro-S appeared to be positively correlated with Pb-B, though the numbers of children were too small for the correlation to reach statistical significance (p = 0.095). These weak associations, probably not important in biological terms, indicate that Pro-S and HVA-U are not useful biomarkers at present exposure levels to lead in the environment. Nevertheless, the finding of subtle biochemical alterations in the dopaminergic system at Pb-B levels of around 100 micrograms l-1 supports the recommended setting of the action level at this value.

Probing the liquid-to-gas phase transition in a cluster via a caloric curve.

High-energy collisions ( 60 keV/amu) of hydrogen cluster ions with a helium target have been completely analyzed on an event-by-event basis. By selecting specific decay reactions we can start after the energizing collision with a microcanonical cluster ion ensemble of fixed excitation energy and we derive corresponding temperatures of the decaying cluster ions. The relation between the temperature and the excitation energy (caloric curve) exhibits the typical prerequisites of a first-order phase transition in a finite system, in the present case signaling the transition from a bound cluster to the gas phase.

Insertion polymorphism of CYP2E1 and urinary N-methylformamide after N,N- dimethylformamide exposure in Japanese workers.

OBJECTIVES: This study examined whether consideration of the *1C/*1D CYP2E1 insertion polymorphism is important for interpreting the biological monitoring of exposure to N,N-dimethylformamide (DMF) in Japanese workers. METHODS: The insertion genotype, airborne DMF exposure on the last day of a work week, and NMF in urine sampled just after the last workshift of the week were determined in 44 male and female Japanese workers. RESULTS AND CONCLUSIONS: The allelic frequency of this CYP2E1 polymorphism was 0.261 in this Japanese population of workers. The CYP2E1 insertion polymorphism did not contribute to NMF levels even after consideration of BMI or alcohol intake. The results indicate that CYP2E1 insertion polymorphism does not appear to be an important determinant for the interpretation of biological exposure to DMF by the measurement of urinary NMF.

Investigations on the liver toxicity of a blend of HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-124 (2-chloro-1,1,1,2-tetrafluoroethane) in guinea-pigs.

2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Male Hartley guinea-pigs were exposed for 4 h to 5,000 ppm HCFC-123 alone or blended with 5,000 ppm HCFC-124, either once (single exposure) or on 5 consecutive days (repeated exposure). The animals were killed either 24 or 48 h after the last exposure. A transient cytolytic action of HCFC-123 was evident by increased mean serum levels of alanine aminotransferase at 24 h and isocitrate dehydrogenase at 24 and 48 h, both after a single or repeated exposure. The liver toxicity of HCFC-123 was confirmed by pathological examination of liver tissue, which showed mild (foci of necrotic hepatocytes) to moderate (multifocal random degeneration and necrosis) damage. Steatosis was also observed and was more pronounced after repeated exposure than after single. One animal out of 6 that were repeatedly exposed to the blend and sacrificed at 24 h showed liver lesions similar to halothane hepatitis. Although a few other animals responded markedly in the blend-treated group, on average, no significant difference in the biochemical or pathological lesions was found between the groups treated with HCFC-123 alone or with the blend. Urinary excretion of trifluoroacetic acid and chlorodifluoroacetic acid increased dose-dependently upon exposure to HCFC-123 and indicated accumulation after repeated exposure. No difference in metabolite excretion was found between animals treated with HCFC-123 alone or blended with HCFC-124. Treatment with HCFC-123 depleted hepatic glutathione levels by about 40 and 25% after single and repeated exposure, respectively; the amplitude of this reduction was not modified by co-exposure to HCFC-124. In conclusion, this study confirmed the hepatotoxicity of HCFC-123, based on biochemical, histopathological and metabolite studies, and found only very limited indication of a potentiation by HCFC-124 of this hepatotoxic effect.

Event-by-event analysis of collision-induced cluster-ion fragmentation: sequential monomer evaporation versus fission reactions.

The most abundant decay channels have been studied quantitatively for high-energy (60 keV/amu) cluster ions H (3) (+)(H (2))(m = 1-14) colliding with He atoms employing a recently developed multicoincidence technique for the simultaneous detection of the correlated fragments on an event-by-event basis. This allows us to identify decay reactions and their underlying decay mechanisms responsible for the occurrence of the U-shaped fragmentation pattern.

Determination of germanium in urine and its usefulness for biomonitoring of inhalation exposure to inorganic germanium in the occupational setting.

The present study aimed to assess whether urinary germanium concentration can be used as a biomarker of inhalation exposure to airborne dust from metallic germanium (Ge) or GeO2 in the occupational setting. A novel hydride generation-based method coupled with fow-injection graphite furnace atomic absorption spectrometry (HG/FI-GFAAS) was developed for the determination of urinary germanium. It was found that urinary germanium concentration could be reliably determined by a standard additions method after thorough digestion of the urine and careful pH adjustment of the digest. The limit of detection (LOD) in urine for the HG/FI-GFAAS method was 0.25 microg Ge L(-1). In Belgian control male subjects, the urinary germanium concentration was below this LOD. In 75 workers currently exposed to inorganic germanium compounds, respirable and inhalable concentrations of germanium in the aerosols were measured on Monday and Friday at the job sites using personal air samplers. Spot-urine samples were collected on the same days before and after the work shift. The germanium concentrations of respirable dust correlated very well with those of inhalable dust and represented 20% of the inhalable fraction. Workers exposed to metallic Ge dust were on average ten times less exposed to germanium than those whose exposure involved GeO2 (3.4 versus 33.8 microg Ge m(-3)). This difference was reflected in the urinary germanium concentrations (3.4 versus 23.4 microg Ge g(-1) creatinine). Regression analysis showed that the concentration of germanium in the inhalable fraction explained 42% of the post-shift urinary germanium concentration either on Monday or on Friday, whereas in a subgroup of 52 workers mainly exposed to metallic germanium dust 57% (r = 0.76) of the Monday post-shift urinary germanium was explained. Urinary elimination kinetics were studied in seven workers exposed to airborne dust of either metallic Ge or GeO2. The urinary elimination rate of germanium was characterised by half-times ranging from 8.2 to 18.1 h (on average 12 h 46 min). The present study did not allow discrimination between the germanium species to which the workers were exposed, but it showed fast urinary elimination kinetics for inhalation exposure to dust of metallic Ge and GeO2. It pointed out that urine samples taken at the end of the work shift can be used for biological monitoring of inorganic germanium exposure in the occupational setting.

Importance of genetic polymorphisms of drug-metabolizing enzymes for the interpretation of biomarkers of exposure to styrene.

The objective of this study was to test the infiuence of genetic polymorphisms for metabolic enzymes (CYP2E1, mEH, GSTM1 and GSTT1) implicated in the biotransformation of styrene in humans on the interpretation of urinary biomarkers of exposure. Thirty workers from a fibreglass-reinforced plastics factory took part in the study. Ambient styrene concentration was determined during the whole workshift by passive sampling. Urine was collected at the end of the shift for the determination of mandelic acid (MA) and phenylglyoxylic acid (PGA) (major biotransformation pathway), N-acetyl-S-(1-phenyl-2-hydroxy)ethyl-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxy)ethyl-L-cysteine (M2) (minor metabolic pathway) and creatinine. The average airborne styrene concentration of 18.2 ppm (range: 0.9-68.9 ppm) was very close to the current threshold limit value (TLV-TWA) recently adjusted by ACGIH from 50 to 20 ppm. There was a better correlation between external and internal exposure as estimated by urinary MA + PGA (r=0.92; p<0.0001) compared with urinary M1 + M2 (r=0.74; p<0.0001). To investigate to what extent genetic polymorphisms in metabolic enzymes could explain interindividual variations observed in the concentration of urinary biomarkers related to a given external exposure, two 'metabolic indexes' (derived from the ratio between the sum of urinary metabolites for a specific pathway and ambient styrene concentration) were calculated for each worker and compared for different allelic combinations. Monovariate analyses showed that GSTM1 polymorphism was clearly the most significant parameter infiuencing urinary concentrations of mercapturic acids. Based on GSTM1 allelic status, two different biological exposure indexes (BEIs) for M1 + M2 in post-shift urinary samples corresponding to a 20 ppm styrene concentration are proposed (GSTM1null: 1330 µg g(-1) creatinine, GSTM1+: 2878 µg g(-1) creatinine). Multivariate regression analyses were also performed and revealed that the presence of the rare CYP2E1*1B allele linked to TaqI polymorphism (A1/A2) was associated with increased urinary concentrations of metabolites from both pathways. Two previously described polymorphisms for the EPHX gene were also tested but seemed not really relevant for interpretation of biomarkers. In conclusion, while CYP2E1 genotyping, particularly assessment of the CYP2E1*1B allelic status, is useful for a more accurate interpretation of the concentration of urinary biomarkers, GSTM1 genotyping is absolutely necessary when considering a biological monitoring programme based on determination of urinary mercapturic acids.

Absence of significant genotoxicity in lymphocytes and urine from workers exposed to moderate levels of cobalt-containing dust: a cross-sectional study.

Mortality studies have shown that, in the past, lung cancer occurred after exposure to mixtures of cobalt metal and metallic carbide particles, the main constituents of hard metals, but apparently not when exposure was to cobalt alone. The major objective of this biomonitoring study was to assess genotoxic effects as a measure for carcinogenic risk in workers from cobalt refineries and hard metal plants currently exposed to the threshold limit value/time-weighted average (TLV-TWA) for cobalt-containing dust. The study comprised three groups of workers: 35 workers exposed to cobalt dust from three refineries, 29 workers exposed to hard metal dust from two producing plants, and 35 matched control subjects recruited from the respective plants. The study design integrated complementary methodologies to assess biomarkers of effects that represent both initial DNA damage (8-hydroxydeoxyguanosine [8-OHdG] in urine and comet assay on lymphocytes) and definitive chromosome breakage/loss (micronuclei in lymphocytes). Cobalt and cotinine were determined in urine as a measure for cobalt exposure and recent smoking, respectively. No significant increase of genotoxic effects was detected in workers exposed to cobalt-containing dust as compared to controls. No difference in any genotoxicity biomarker was found between workers exposed to cobalt and hard metal dusts. Multiple regression analysis indicated that workers who smoked and were exposed to hard metal dusts had elevated 8-OHdG and micronuclei values. Because this observation is in line with a previous epidemiological study of an increased risk of dying from lung cancer in workers from the hard metal industry who smoked, it is concluded that this specific occupational group needs closer medical surveillance.

Repetitive endoscopy and continuous alkaline gastric irrigation in a case of arsenic poisoning.

BACKGROUND: The poor prognosis of patients with persistent gastrointestinal radio-opacities after oral arsenic poisoning supports efficient gastrointestinal decontamination as critical for survival. In a case of massive arsenic ingestion, we performed repetitive gastric endoscopy and a continuous alkaline irrigation of the stomach over several days. CASE REPORT: A 41-year-old woman was admitted 4 hours after intentional ingestion of trivalent arsenic powder 5 g. The admission abdominal X-ray confirmed the presence of multiple gastric opacities. Initial treatment was gastric lavage with normal saline, dimercaprol chelation, and supportive therapy. Since gastric opacities persisted on the abdominal X-ray at 34 hours despite repeated gastric lavage, a gastroscopy was performed showing nonremovable agglomerates. In an attempt to achieve further gastric decontamination, we performed a continuous gastric alkaline irrigation. After 3 days of alkaline irrigation, the abdomen was normal on X-ray but the gastroscopy still showed arsenic concretions. Alkaline irrigation was continued for another 3 days until total disappearance of arsenic agglomerates at the gastroscopy. Admission urinary arsenic was 3663 microg/L. A total of 46.2 mg of inorganic arsenic, or less than 1% the ingested dose, was extracted from the stomach by this technique. The patient was discharged from the intensive care unit 20 days after admission without sequelae.

Epidemiological survey of workers exposed to inorganic germanium compounds.

OBJECTIVES: To assess occupational exposure to inorganic germanium (Ge) in workers from a producing plant, and to assess the health of these workers, with a special focus on respiratory, kidney, and liver functions. METHODS: Cross sectional study of 75 workers exposed to Ge and 79 matched referents. Exposure was characterised by measuring air and urine concentrations of the element during a typical working week, and health was assessed by a questionnaire, clinical examination, lung function testing, chest radiography, and clinical chemistry in serum and urine, including high and low molecular weight urinary proteins. RESULTS: Airborne concentrations of Ge (inhalable fraction) ranged from 0.03 to 300 micrograms/m, which was reflected by increased urinary excretion of Ge (0.12-200 micrograms/g creatinine, after the shift at the end of the working week). Lung, liver, and haematological variables were not significantly different between referents and workers exposed to Ge. A slightly higher urinary concentration of high molecular weight proteins (albumin and transferrin) was found in workers exposed to Ge, possibly reflecting subclinical glomerular changes. No relation was found between the intensity or duration of exposure and the urinary concentration of albumin. No difference between referents and workers exposed to Ge was found for other renal variables. CONCLUSIONS: Measurement of urinary Ge can detect occupational exposure to inorganic Ge and its compounds. It is prudent to recommend the monitoring of renal variables in workers exposed to Ge.

Renal effects of low-level environmental cadmium exposure: 5-year follow-up of a subcohort from the Cadmibel study.

BACKGROUND: The clinical relevance of renal effects of cadmium in people exposed in the environment remains uncertain. This study examined the evolution of renal effects observed in a population exposed to cadmium in the environment. METHODS: 208 men and 385 women surveyed in 1985-89 (Cadmium in Belgium study [Cadmibel]; baseline) were re-examined on average 5 years later (Public health and environmental exposure to cadmium study [PheeCad]; follow-up). Urinary and blood cadmium and markers of renal tubular dysfunction and glomerular effects were measured. The association between cadmium body burden and renal factors was examined by multivariate logistic and linear regression. FINDINGS: In men, mean urinary cadmium excretion and blood cadmium concentration measured at follow-up were 7.5 nmol/24 h (SD 1.9) and 6.1 nmol/L (2.2), reductions of 16% and 35% from baseline, respectively. In women, the corresponding values were 7.6 nmol/24 h (1.9) and 7.8 nmol/L (2.1), reductions of 14% and 28% from baseline. No indication of progressive renal damage was found and the overall results suggest that the effects of low environmental exposure to cadmium on the kidney are weak, stable, or reversible. INTERPRETATION: Subclinical renal effects that have been reported in Belgium in patients with increased cadmium body burden are not associated with progressive renal dysfunction and most likely represent non-adverse manifestations.

Increased serum and urinary concentrations of lung clara cell protein in rats acutely exposed to ozone.

Clara cell protein (CC16) is a 16-17-kDa protein secreted by Clara cells in the bronchial lining fluid of the lung from which it passively diffuses into serum before being eliminated by the kidneys. The concentration of CC16 in serum has recently been proposed as a peripheral marker of the integrity of Clara cells and/or of the bronchoalveolar/blood barrier. To evaluate the sensitivity of this new lung marker to acute epithelial damage induced by ozone (O(3)), CC16 was determined in the serum of rats after a single 3-h exposure to 0.3, 0.6, or 1 ppm O(3). The urinary excretion of the protein was also studied in rats repeatedly exposed to 1 ppm O(3), 3 h/day, for up to 10 days. The concentrations of CC16 in the lung or trachea homogenates, the lung CC16 mRNA levels, and classical markers of lung injury in bronchoalveolar lavage fluid (BALF) were also determined. O(3) produced a transient increase of CC16 concentration in serum that reached values on average 13 times above normal 2 h after exposure to 1 ppm O(3). The intravascular leakage of CC16 was dose-dependent and correlated with the extent of lung injury as assessed by the levels of total protein, LDH, and inflammatory cells in BALF. This effect was most likely responsible for the concomitant marked reduction of CC16 concentrations in BALF and lung homogenate, since the CC16 mRNA levels in the lungs were unchanged and the absolute amounts of CC16 leaking into serum or lost from the respiratory tract were similar. These changes were paralleled by an elevation of the urinary excretion of CC16 resulting from an overloading of the tubular reabsorption process. These results demonstrate that the assay of CC16 in serum and even in urine represents a new noninvasive test to detect the increased lung epithelial permeability induced by O(3).

Lung fibrosis induced by silica particles in NMRI mice is associated with an upregulation of the p40 subunit of interleukin-12 and Th-2 manifestations.

Interleukin (IL)-12 is a cytokine produced principally by activated macrophages which is involved in control of the T-helper 1/T-helper 2 cell (Th1/Th2) polarization of immune responses. To examine its potential involvement in the development of lung fibrosis, we examined the expression (protein, messenger RNA [mRNA]) of IL-12 (p70) and of its subunits (p40 and p35) in lung homogenates, bronchoalveolar lavage fluid (BALF), and bronchoalveolar lavage (BAL) cell cultures in mouse models of resolutive alveolitis (RA) and fibrosing alveolitis (FA) induced by inorganic particles (manganese dioxide [MnO2] and crystalline silica, respectively). The administration of tungsten carbide (WC), which behaved as an innocuous dust for the lung, served as a negative control condition. The FA was specifically accompanied by a Th2-like polarization characterized by high levels of immunoglobulin (Ig)G1 in BALF and by a protracted overproduction of both p40 protein and mRNA, but not by the biologically active form of IL-12 (p70). In the RA model, the p40 response was only transient, and a Th1-like response was reflected by increased levels of interferon (IFN)-gamma and dominant levels of IgG2a in BALF. Taken together, these findings suggest that production of the p40 subunit of IL-12 and Th2 polarization play important roles in lung inflammatory and fibrotic responses to inhaled inorganic particles.

Coal fly ash- and copper smelter dust-induced modulation of ex vivo production of tumor necrosis factor-alpha by murine macrophages: effects of metals and overload.

The objective of this study was to assess the effect of two arsenic-containing particles, coal fly ash (FA) and copper smelter dust (CU), on lung integrity and on the ex vivo release of tumor necrosis factor alpha (TNF-alpha) by alveolar phagocytes. Particle effects were compared in nonoverload condition on the basis of a low but identical volume load and arsenic content intratracheally instilled in the mouse lung (273 nl/mouse and 186 ng arsenic/mouse; FAL and CUL groups). Other mice received 600 ng arsenic/mouse in amounts of particles leading to different volume loads (FAH and CUH groups: 880 and 273 nl/mouse, respectively). Animals were sacrificed at 1, 6, 30, or 120 d (FAL and CUL groups) or at 6 and 120 d posttreatment (FAH and CUH groups). Biochemical markers and inflammatory cell number and type were analyzed in bronchoalveolar lavage, ex vivo TNF-alpha production by alveolar phagocytes was assessed, and measurement of arsenic lung content and histopathological examinations were performed. Our results show that coal fly ash and copper smelter dust bear distinct inflammatory properties. At the end of the observation period (d 120), the high CU dose (CUH) produced a fibrotic reaction whereas the high dose of FA particles (FAH) generated a delayed and persistent lung inflammatory reaction associated with lymphoid noduli. Marked differences in TNF-alpha production were observed within the CU and FA groups. CU particles, conceivably through their metal content, decreased TNF-alpha production by alveolar phagocytes. Due to their low arsenic content, considerably higher FA particle doses needed to be administered to produce an inhibition of TNF-alpha production. Since high doses of FA (FAH) caused an overload condition, our results do not allow us to decide whether FA-mediated TNF-alpha reduction is due to the load administered or to the metallic content.

Effects of vanadium complexes with organic ligands on glucose metabolism: a comparison study in diabetic rats.

1. Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non-ketotic, streptozotocin-diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3-ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorganic vanadium salt, vanadyl sulphate (VS) was also studied. 2. Oral administration of the three organic vanadium compounds (125 mg vanadium element 1(-1) in drinking fluids) for up to 3 months induced a faster and larger fall in glycemia (VAc being the most potent) than VS. Glucosuria and tolerance to a glucose load were improved accordingly. 3. Activities and mRNA levels of key glycolytic enzymes (glucokinase and L-type pyruvate kinase) which are suppressed in the diabetic liver, were restored by vanadium treatment. The organic forms showed greater efficacy than VS, especially VAc. 4. VAc rats exhibited the highest levels of plasma or tissue vanadium, most likely due to a greater intestinal absorption. However, VAc retained its potency when given as a single i.p. injection to diabetic rats. Moreover, there was no relationship between plasma or tissue vanadium levels and any parameters of glucose homeostasis and hepatic glucose metabolism. Thus, these data suggest that differences in potency between compounds are due to differences in their insulin-like properties. 5. There was no marked toxicity observed on hepatic or renal function. However, diarrhoea occurred in 50% of rats chronically treated with VS, but not in those receiving the organic compounds. 6. In conclusion, organic vanadium compounds, in particular VAc, correct the hyperglycemia and impaired hepatic glycolysis of diabetic rats more safely and potently than VS. This is not simply due to improved intestinal absorption, indicating more potent insulin-like properties.

Epidemic of fatal encephalopathy in preschool children in Burkina Faso and consumption of unripe ackee (Blighia sapida) fruit.

BACKGROUND: On March 21, 1998, the Regional Health Authority of Bobo-Dioulasso, Burkina Faso, asked the Centre Muraz to investigate an unexplained outbreak of epidemic fatal encephalopathy (EFE). We aimed to identify the cause of this epidemic. METHODS: We identified cases retrospectively through review of health-service records and interviews of family members, village chiefs, and local healers. Active surveillance was started in administrative divisions within the study area in April, 1998, to identify further EFE cases. We did a case-control study of households to investigate the risk from various environmental and health factors. Blood and urine samples were collected if possible and urine dicarboxylic acid concentrations measured by gas chromatography. FINDINGS: 29 cases of EFE were identified from January to May, 1998. Estimated age-specific attack rates (2-6 years) ranged from 31 to 847 per 100,000 population (p<0.001). The most common symptoms were hypotonia, vomiting, convulsions, and coma. All children died in 2-48 h. The only factor associated with EFE was the presence of ackee trees (Blighia sapida) within 100 m of households (odds ratio 5.1 [95% CI 1.8-14.7] p=0.001). Poisoning with unripe ackee fruits was suggested by urine concentrations of dicarboxylic acids four to 200 times higher in cases (n=2) than in controls (n=3). CONCLUSION: Consumption of unripe ackee fruit probably caused this epidemic and may lead to a substantial number of unexplained deaths in preschool children in west Africa every year. Educational campaigns have the potential to prevent these deaths.