Biomedical subjects
R Lauwerys
Publications and source records attributed to R Lauwerys.
The impact of nonwork-related impairments of organ functions on the toxicokinetics and toxicodynamics of industrial chemicals.
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In vitro effect of mercury and vanadium on superoxide anion production and plasminogen activator activity of mouse peritoneal macrophages.
The in vitro effects of mercuric chloride and vanadate were examined on two functions of mouse peritoneal macrophages, i.e., the superoxide anion production and the plasminogen activator (PA) activity. Vanadate, at concentrations which do not affect the viability of the cells, does not seriously alter any of these functions. High concentrations of mercury depress the respiratory burst; this effect results from loss of the reducing properties of cellular NADPH. Low concentrations of mercury stimulate the effect of phorbol 12-myristate 13-acetate on PA activity. The mechanism of this stimulation does not involve the protein kinase C system. It is hypothesized that mercury could enhance the synthesis of PA, its translocation to the cell surface, or its binding to the membrane receptors.
The renal uptake of proteins: a nonselective process in conscious rats.
The selectivity of the renal reabsorption of proteins has been investigated by competition experiments in conscious rats. The animals were intravenously injected with increasing doses of proteins over a wide range of net charge and size, including lysozyme, cytochrome C, metallothionein, beta 2-microglobulin, retinol-binding protein, albumin and IgG. The urinary excretion of exogenous proteins injected concomitantly (human beta 2-microglobulin, retinol-binding protein, albumin and/or egg white lysozyme depending on the experiment) and of rat beta 2-microglobulin, albumin and IgG was determined with specific immunoassays. The results show that low molecular weight cationic proteins and low or high molecular weight anionic proteins can increase each other's urinary excretion. Several observations strongly suggest that these effects result from a competitive inhibition of renal uptake. The phenomenon is dose-related in most cases and, as evidenced by cytochrome C injection, transient, reproducible and saturable. In addition, the injected proteins induce a tubular type proteinuria irrespective of their net charge and size. In the case of cationic proteins, this finding excludes the possibility of an enhanced glomerular permeability due to a partial neutralization of the glomerular polyanion which, as demonstrated with protamine sulfate, entails a glomerular type proteinuria. These quantitative data on the mutual inhibition of renal uptake of a wide spectrum of specific proteins lead us to challenge the concept of charge- and size-selective tubular reabsorption of proteins, and to postulate that proteins filtered through the glomeruli are taken up by common tubular endocytotic sites irrespectively of their physicochemical features. As demonstrated by the ability of beta 2-microglobulin and IgG to inhibit the uptake of lysozyme, the affinity of a protein for reabsorption sites is not simply related to its size and net positive charge. Evidence is also presented that proteins, when administered intravenously at high doses, induce a lysosomal enzymuria most likely reflecting a stimulated exocytosis.
Lack of relationship between urinary glycosaminoglycans and indices of tubular or glomerular renal damage. Urinary GAG are an unreliable nephrotoxicity index.
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Red blood cell electric charge and microalbuminuria in diabetes mellitus.
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The relationship between blood pressure and environmental exposure to lead and cadmium in Belgium.
The question whether in the general population environmental exposure to lead and cadmium influences blood pressure after controlling for confounding factors remains debated. The environmental exposure of the Belgian population to both lead and cadmium is high as compared with other countries. The Cadmibel Cooperative Study was therefore designed to elucidate whether environmental exposure to lead and cadmium has any effect on blood pressure and renal function in the population at large. Before embarking on the large Cadmibel project, a small study was conducted. Blood pressure and the 24-hr urinary excretion of cadmium (CdU) and lead (PbU) were determined in a random 4% sample of the population of a small Belgian town. CdU averaged 0.27 micrograms/24 hr in 46 youths (mean age 14 +/- 3 years, +/- SD), increased with age, and was higher in 57 adult men (age 41 +/- 14 years), as compared with 59 adult women (age 39 +/- 14 years) (1.05 vs. 0.81 micrograms/24 hr; p less than 0.01). PbU averaged 5.8 micrograms/24 hr in youths and similarly increased with age; adult men excreted more lead than women (13.3 vs. 8.3 micrograms/24 hr; p less than 0.001). Among men, manual workers excreted more cadmium (1.4 vs. 0.8 micrograms/24 hr; p less than 0.05) but a similar amount of lead (7.0 vs. 6.9 micrograms/24 hr) as compared with office workers. In simple regression analysis, CdU was positively correlated with both systolic (r = 0.30; p less than 0.05) and diastolic (r = 0.38; p less than 0.01) blood pressure in women.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological monitoring of exposure to benzene, toluene and xylene.
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Abnormal methylation capacity in human liver cirrhosis.
To investigate the influence of liver cirrhosis on the capacity of methylation, the urinary excretion of the methylated forms of arsenic was measured by atomic absorption spectrometry after the administration of a small dose of inorganic arsenic. The study was carried out in 13 normal controls, 18 patients with various clinical conditions, but without evidence of parenchymal liver disease, and 38 with cirrhosis of varied aetiology and severity. In normal controls, the percentage of arsenic excreted as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) averaged 12.3 +/- 2.8% and 23.3 +/- 6.4%, respectively, and was not significantly different from that obtained in disease controls. The presence of liver cirrhosis did not affect the percentage of the injected dose excreted within 24 h. However, cirrhotic patients excreted significantly less MMA (4.7 +/- 3.3, p less than 0.001) and more DMA (40.4 +/- 16.6%, p less than 0.001). The amount of MMA correlated with the 14C aminopyrine breath test (r = 0.43) and was invariably lower than the normal range in patients with severe liver disease. These findings indicate that liver cirrhosis is associated with profound abnormalities of the methylation pathway, which might have potential consequences in the metabolism of endogenous amines and xenobiotics.
Development of a method to monitor low molecular mass hydrocarbons in exhaled breath of man: preliminary evaluation of its interest for detecting a lipoperoxidation process in vivo.
Low molecular mass hydrocarbons, particularly ethane and pentane, have been measured in expired air of man. The air is collected into 5-10 l polyamide bags. After removal of water vapour and CO2, the hydrocarbons are concentrated on a silicagel column kept at 0 degree C. The column desorption is carried out at 290 degrees C, and the gases are analysed by gas chromatography. A slight but statistically significant increased pentane production was detected in cirrhotic patients.
A cross-sectional survey of kidney function in refinery employees.
We examined sensitive biochemical and immunological markers of kidney function and damage in 53 male oil refinery workers exposed to hydrocarbons and compared their results with those of a control group of 61 age-matched nonexposed males. The mean duration of employment of exposed males was 11 years. The current levels of exposure to a variety of aliphatic and aromatic hydrocarbons, as determined by personal monitoring, were well below the current threshold limit values. No difference was found in the urinary tubular parameters beta-N-acetyl-D-glucosaminidase, beta 2-microglobulin (beta 2-m) and retinol-binding protein. Similar serum beta 2-m levels indicated no impairment of the glomerular filtration rate in the exposed workers. The levels of circulating immune complexes were also identical in both groups. The mean albuminuria was slightly higher (p less than .005) in the exposed group in a quantitative assay but was not dipstick-detectable. The mean urinary excretion of a renal antigen was also higher (p less than .05) in the exposed group and correlated with the excretion of albumin. Finally, slightly higher titers of anti-laminin antibodies were found in five exposed employees, but this was not accompanied by an increased albuminuria. We conclude that chronic low-level hydrocarbon exposure in these refinery workers does not lead to clinically significant renal abnormalities. Nevertheless, some findings are consistent with the possible role of hydrocarbon exposure in the induction of renal disturbances.
Relationship between external and internal parameters of exposure to manganese in workers from a manganese oxide and salt producing plant.
In a plant producing manganese (Mn) oxides and salts, 11 different workplaces were identified. The current exposure to airborne Mn (total dust, personal sampling, n = 80) varied from 0.07 to 8.61 mg/m3. The geometric mean and median values amounted approximately to 1 mg/m3 and the 95th percentile was 3.30 mg/m3. The concentration of Mn in blood (Mn-B) in a group of 141 Mn-exposed male workers ranged from 0.10-3.59 micrograms/100 ml compared to 0.04-1.31 micrograms/100 ml in a group of 104 control subjects. The ranges of the concentrations of Mn in urine (Mn-U) were 0.06-140.6 and 0.01-5.04 micrograms/g creatinine for the exposed and control groups, respectively. The average level of Mn-B in the Mn group was more than twice as high as in the control group (arithmetic mean, 1.36 vs 0.57 microgram/100 ml) and that of Mn-U was ten times higher in the Mn group (geometric mean, 1.56 vs 0.15 microgram/g creatinine). The Mn-B level did not change significantly after 8 h of Mn exposure, whereas the Mn-U level dropped rapidly when exposure ceased (half-life less than 30 h). On an individual basis, neither Mn-B nor Mn-U correlated with the current levels of Mn-air or duration of Mn exposure. There was also no relationship between Mn-B and Mn-U. On a group basis, there was no correlation between the mean Mn-B levels and the current levels of Mn-air at each workplace.(ABSTRACT TRUNCATED AT 250 WORDS)
Epidemiological survey among workers exposed to manganese: effects on lung, central nervous system, and some biological indices.
A cross-sectional epidemiological study was carried out among 141 male subjects exposed to inorganic manganese (Mn) in a Mn oxide and salt producing plant (mean age 34.3 years; duration of exposure, mean 7.1 years, range 1-19 years). The results were compared with those of a matched control group of 104 subjects. The intensity of Mn exposure was moderate as reflected by the airborne Mn levels and the concentrations of Mn in blood (Mn-B) and in urine (Mn-U). A significantly higher prevalence of cough in cold season, dyspnea during exercise, and recent episodes of acute bronchitis was found in the Mn group. Lung ventilatory parameters (forced vital capacity, FVC; forced expiratory volume in one second, FEV1; peak expiratory flow rate, PEFR) were only mildly altered in the Mn group (smokers) and the intensity and the prevalence of these changes were not related to Mn-B, Mn-U, or duration of exposure. There was no synergistic effect between Mn exposure and smoking on the spirometric parameters. Except for a few nonspecific symptoms (fatigue, tinnitus, trembling of fingers, increased irritability), the prevalence of the other subjective complaints did not differ significantly between the control and Mn groups. Psychomotor tests were more sensitive than the standardized neurological examination for the early detection of adverse effects of Mn on the central nervous system (CNS). Significant alterations were found in simple reaction time (visual), audioverbal short-term memory capacity, and hand tremor (eye-hand coordination, hand steadiness). A slight increase in the number of circulating neutrophils and in the values of several serum parameters (ie, calcium, ceruloplasmin, copper, and ferritin) was also found in the Mn group. There were no clear-cut dose-response relationships between Mn-U or duration of Mn exposure and the prevalence of abnormal CNS or biological findings. The prevalences of disturbances in hand tremor and that of increased levels of serum calcium were related to Mn-B. The response to the eye-hand coordination test suggests the existence of a Mn-B threshold at about 1 microgram Mn/100 ml of whole blood. This study demonstrates that a time-weighted average exposure to airborne Mn dust (total dust) of about 1 mg/m3 for less than 20 years may present preclinical signs of intoxication.
Evaluation of the nephrotoxic potential of styrene in man and in rat.
The urinary excretion of beta 2-microglobulin, retinol-binding protein and albumin was measured in 65 workers exposed to styrene at levels averaging 50 percent of the current threshold limit value (215 mg/m2) for 1-13 years (mean: 6 years). By comparison with a control group matched for age and socioeconomic status, no significant difference was observed in the urinary excretion of proteins. In rats, styrene was weakly nephrotoxic. No functional or morphological renal change could be disclosed in rats exposed to 565 mg of styrene/m3, 5 days/week for 13 weeks. The repeated i.p. injection of 1 g styrene/kg (1/5 of oral LD50) for 10 days induced only a slight tubular dysfunction as evidenced by a 5-fold increase in beta 2-microglobulinuria. Altogether, these epidemiological and experimental data suggest that the current threshold limit value for styrene (215 mg/m3) proposed by the American Conference of Governmental and Industrial Hygienists does not entail any risk of renal toxicity.
Study of factors influencing the in vivo methylation of inorganic arsenic in rats.
Previous studies have shown that several factors may influence the methylation of inorganic arsenic by rat liver in vitro (Buchet and Lauwerys, 1985). The present study attempts to assess the relevance of these observations in vivo. Like man, rat inactivates inorganic arsenic by methylation to monomethylarsonic (MMA) and dimethylarsinic (DMA) acids which are excreted in urine along with unchanged inorganic arsenic (Asi). The administration of S-adenosylmethionine alone or in association with reduced (GSH) or oxidized glutathione or acetylcysteine and the increase of hepatic GSH level by butylated hydroxytoluene pretreatment do not stimulate the urinary excretion of the methylated arsenic metabolites following a challenge dose of inorganic arsenic. Conversely a reduction of the hepatic GSH level by phorone pretreatment greatly modifies the metabolism of inorganic arsenic in vivo. A reduction exceeding 90% of the control value leads to a decreased urinary excretion of MMA and DMA and an increased urinary excretion of inorganic arsenic. This is also associated with an increased accumulation of inorganic arsenic in the liver. This suggests that a drastic reduction of GSH level in liver not only impairs the methylation of inorganic arsenic but also impairs its biliary excretion. When GSH depletion is less severe, the total amount of arsenic excreted in urine after a challenge dose of NaAsO2 is not significantly different from that found in unpretreated animals but the proportion of the three metabolic forms is different: MMA is reduced whereas Asi and DMA tend to increase. These changes resemble those found in patients with liver insufficiency (J.P. Buchet, A. Geubel, S. Pauwels, P. Mahieu, and R. Lauwerys (1984). The influence of liver disease on the methylation of arsenite in humans. Arch. Toxicol. 55, 151-154). Long-term pretreatment of rats with CCl4 slightly reduces the amount of MMA and DMA excreted in urine following a challenge dose of inorganic arsenic. This effect may result from a reduction of GSH transferase activity by CCl4. This study demonstrates the important role of liver GSH in the metabolism of inorganic arsenic in vivo.
Mutagenicity, carcinogenicity and teratogenicity of beryllium.
The carcinogenicity of a number of beryllium compounds has been confirmed in experiments on laboratory animals and this metal has to be treated as a possible carcinogenic threat to man. These carcinogenic properties are associated with mutagenic activity as shown by the results of short-term tests performed in vitro with beryllium chloride and beryllium sulfate. These soluble beryllium compounds can produce some infidelity of in vitro synthesis, forward gene mutations in microorganisms and in mammalian cells. They are also able to induce cell transformation. In addition to the positive results obtained in several short-term assays beryllium compounds have been found to bind to nucleoproteins, to inhibit certain enzymes needed for DNA synthesis, to bind nucleic acids to cell membranes and to inhibit microtubule polymerization. The teratogenicity of beryllium salts is relatively unknown and needs additional investigation.
A comparative study, with 40 chemicals, of the efficiency of the Salmonella assay and the SOS chromotest (kit procedure).
A comparison was made, for 40 compounds belonging to different chemical classes, of the mutagenicity as measured by the Salmonella assay and of the SOS-inducing potency as measured by the SOS chromotest kit procedure. It was found that most (78%) of the chemicals described as mutagens/carcinogens (14 compounds) were detected with a simplified Ames test procedure, using 3 strains (TA 97, TA 98, TA 100) and 3 concentrations of the tested material. The SOS chromotest, carried out following the recommendations of the commercially available kits, revealed that only 4 Ames test-positive compounds were mutagenic towards E. coli strain PQ 37.
Relationships between the concentrations of mercury in air and in blood or urine in workers exposed to mercury vapour.
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