Harry Roels

Comparison of the Urinary-excretion of Arsenic Metabolites After a Single Oral Dose of Sodium Arsenite, Monomethylarsonate, Or Dimethylarsinate in Man

SummaryThe urinary elimination of the metabolites of arsenic has been followed up as a function of time in volunteers who ingested a single oral dose of arsenic (500 μg As) either as sodium arsenite (Asi), monomethylarsonate (MMA), or cacodylate (DMA). The excretion rate increased in the order Asi < DMA < MMA. After 4 days, the amount of arsenic excreted in urine represents 46, 78, and 75% of the ingested dose in the case of Asi, MMA and DMA, respectively. With regard to the in vivo biotransformations, it is concluded that DMA is excreted unchanged; MMA is slightly (13%) methylated into DMA while roughly 75% of the arsenic excreted after ingestion of Asi is methylated arsenic (about 1/3 as MMA and about 2/3 as DMA).

Renal effects of cadmium body burden of the general population.

In a cross-sectional population study to assess whether environmental exposure to cadmium is associated with renal dysfunction, 1699 subjects aged 20-80 years were studied as a random sample of four areas of Belgium with varying degrees of cadmium pollution. After standardisation for several possible confounding factors, five variables (urinary excretion of retinol-binding protein, N-acetyl-beta-glucosaminidase, beta 2-microglobulin, aminoacids, and calcium) were significantly associated with the urinary excretion of cadmium (as a marker of cadmium body burden), suggesting the presence of tubular dysfunction. There was a 10% probability of values of these variables being abnormal when cadmium excretion exceeded 2-4 micrograms/24 h. Excretion reached this threshold in 10% of non-smokers. There was also evidence that diabetic patients may be more susceptible to the toxic effect of cadmium on the renal proximal tubule.

Assessment of the permissible exposure level to manganese in workers exposed to manganese dioxide dust.

The prevalence of neuropsychological and respiratory symptoms, lung ventilatory parameters, neurofunctional performances (visual reaction time, eye-hand coordination, hand steadiness, audioverbal short term memory), and several biological parameters (calcium, iron, luteinising hormone (LH), follicle stimulating hormone (FSH), and prolactin concentrations in serum, blood counts, manganese (Mn) concentration in blood and in urine) were examined in a group of workers (n = 92) exposed to MnO2 dust in a dry alkaline battery factory and a matched control group (n = 101). In the battery plant, the current exposure of the workers to airborne Mn was measured with personal samplers and amounted on average (geometric mean) to 215 and 948 micrograms Mn/m3 for respirable and total dust respectively. For each worker, the lifetime integrated exposure to respirable and total airborne Mn dust was also assessed. The geometric means of the Mn concentrations in blood (MnB) and in urine (MnU) were significantly higher in the Mn exposed group than in the control group (MnB 0.81 v 0.68 microgram/100 ml; MnU 0.84 v 0.09 microgram/g creatinine). On an individual basis, MnU and MnB were not related to various external exposure parameters (duration of exposure, current exposure, or lifetime integrated exposure to airborne Mn). On a group basis, a statistically significant association was found between MnU and current Mn concentrations in air. No appreciable difference between the exposed and the control workers was found with regard to the other biological measurements (calcium, LH, FSH, and prolactin in serum). Although the erythropoietic parameters and serum iron concentration were in the normal range for both groups, there was a statistically significant trend towards lower values in the Mn exposed workers. The prevalences of reported neuropsychological and respiratory symptoms, the lung function parameters, and the audioverbal short term memory scores did not differ between the control and exposed groups. The Mn workers, however, performed the other neurofunctional tests (visual reaction time, eye-hand coordination, hand steadiness) less satisfactorily than the control workers. For these tests, the prevalences of abnormal results were related to the lifetime integrated exposure to total and respirable Mn dust. On the basis of logistic regression analysis it may be inferred that an increased risk of peripheral tremor exists when the lifetime integrated exposure to Mn dust exceeds 3575 or 730 micrograms Mn/m3 x year for total and respirable dust respectively. The results clearly support a previous proposal by the authors to decrease the current time weighted average exposure to Mn dust.

Urinary-excretion of Inorganic Arsenic and its Metabolites After Repeated Ingestion of Sodium Metaarsenite By Volunteers

SummaryArsenic (125, 250, 500 or 1000 μg as NaAsO2) was administered orally once a day for five consecutive days to 4 volunteers who refrained from eating marine organisms during the experiment. Urine was collected during 24-h periods starting one day before the first administration and up to 14 days later. The following determinations were performed: total arsenic, inorganic arsenic (As;), monomethyl arsenic (MMA) and dimethylarsinic (DMA) acids. In each case, the sum of As;, MMA and DMA approximated very closely the urinary concentration of total arsenic determined after mineralisation of the urine sample. It was concluded that these arsenicals are the only metabolic forms of arsenic following absorption of inorganic arsenic. Since a steady state in the urinary excretion of arsenic is reached within 5 days, our results demonstrated that at equilibrium, the total amount of arsenic excreted in urine per day amounts to 60% of the ingested dose. Speciation of the arsenic metabolites in urine indicated that the arsenic methylation capacity of the human body was not yet saturated, even with an oral daily dose of 1000 μg As for 5 days. However, when the administration of arsenic was stopped, the biological half life of arsenic in urine increased slightly with the dose (from 39 h at 125 μg to 59 h at 1000 μg). Determination of inorganic arsenic, MMA and DMA in urine appears to be the method of choice for the biological monitoring of workers exposed to inorganic arsenic since these measurements are not influenced by the presence of organoarsenicals from marine origin. From the linear relationship found in this study between arsenic administered and that excreted in urine, it was estimated that a time-weighted average exposure of 50 μg As/m3 would lead to an average urinary excretion of 220 μg As (sum of Asi, MMA and DMA) per gram creatinine.

Placental transfer of lead, mercury, cadmium, and carbon monoxide in women: I. Comparison of the frequency distributions of the biological indices in maternal and umbilical cord blood

500 pregnant women living in different areas in Belgium were surveyed to evaluate the extent of environmental exposure to heavy metals (lead, cadmium, and mercury) during fetal life, possible biological effects of such exposure, and various epidemiological significances which may influence such exposure. In addition carboxyhemoglobin level was determined. And frequency distributions of these various hematological indexes were compared. Maternal and umbilical cord blood levels of these hematological parameters indicate that the 3 metals do cross the placenta, but the transfer rate differs for each heavy metal. No barrier was demonstrated for mercury transfer. A slight barrier seemed present for lead. A barrier of some importance was demonstrated for cadmium. Statistical correlations bear out these contentions; there was a lower correlation between maternal blood cadmium and umbilical blood cadmium concentrations (r + .38) than for the other 2 metals (r .6). Carboxyhemoglobin levels of mother and newborn are highly correlated (P .001), and in mothers carboxyhemoglobin levels are also associated with cadmium concentration in blood, suggesting that the source of these pollutants is the same, namely smoking. There were no significant correlations observed between blood lead concentrations and erythrocyte prophyrin level; rather, because of its high sensitivity to lead, the erythrocyte enzyme ALAD was negatively correlated with blood lead in mother and newborn.

Markers of early renal changes induced by industrial pollutants. II. Application to workers exposed to lead.

The present study has been carried out in the framework of a collaborative research project on the development of new markers of nephrotoxicity. A battery of more than 20 potential indicators of renal changes has been applied to 50 workers exposed to lead (Pb) and 50 control subjects. After application of selection criteria 41 exposed and 41 control workers were eventually retained for the final statistical analysis. The average blood Pb concentration of exposed workers was 480 micrograms/l and their mean duration of exposure was 14 years. The battery of tests included parameters capable of detecting functional deficits (for example, urinary proteins of low or high molecular weight), biochemical alterations (for example, urinary eicosanoids, glycosaminoglycans, sialic acid) or cell damage (for example, urinary tubular antigens or enzymes) at different sites of the nephron or the kidney. The most outstanding effect found in workers exposed to Pb was an interference with the renal synthesis of eicosanoids, resulting in lower urinary excretion of 6-keto-PGF1 alpha and an enhanced excretion of thromboxane (TXB2). The health significance of these biochemical alterations, detectable at low exposure to Pb is unknown. As they were not associated with any sign of renal dysfunction, they may represent reversible biochemical effects or only contribute to the degradation of the renal function from the onset of clinical Pb nephropathy. The urinary excretion of some tubular antigens was also positively associated with duration of exposure to Pb. Another effect of Pb that might deserve further study is a significant increase in urinary sialic acid concentration.

Renal excretion of proteins and enzymes in workers exposed to cadmium

Abstract. The proteinuria rate and the relative clearances of β2‐microglobulin, orosomucoid, albumin, transferrin and IgG were measured in forty‐two workers exposed to cadmium and in seventy‐seven control workers. A tubular type proteinuria with an increased excretion of β2‐microglobulin and often also a glomerular type proteinuria with an increased excretion of orosomucoid, albumin, transferrin and IgG were observed mainly in workers exposed to cadmium for more than 25 years and whose cadmium concentration in blood exceeded 1 μg Cd/100 ml and that in urine 10 μg Cd/g creatinine. The glomerular dysfunction was also suggested by an increased plasma level of β2‐microglobulin and creatinine. Both tubular and glomerular impairments occurred with the same prevalence and were not necessarily associated. The increased release of β‐galactosidase by the kidney suggested that cadmium can damage some epithelial cells.

Influence of the route of administration and the chemical form (MnCl2, MnO2) on the absorption and cerebral distribution of manganese in rats.

Abstract  The absorption and cerebral distribution of manganese (Mn) have been studied with respect to the route of administration and the chemical form of the Mn compound. Different groups of adult male rats received either MnCl2 · 4H2O or MnO2 once a week for 4 weeks at a dose of 24.3 mg Mn/kg body wt. (b.w.) by oral gavage (g.) or 1.22 mg Mn/kg b.w. by intraperitoneal injection (i.p.) or intratracheal instillation (i.t.). Control rats were treated with 0.9% saline. Four days after the last administration the rats were killed and the concentration of Mn measured in blood, hepatic and cerebral tissues (cortex, cerebellum, and striatum). The liver Mn concentration was not affected by the treatments whatever the chemical form or the route of administration of the Mn compound. Administration of MnCl2 by g., i.p., and i.t. routes produced equivalent steady-state blood Mn concentrations (about 1000 ng Mn/100 ml), representing increases of 68, 59, and 68% compared with controls, respectively. Mn concentrations were significantly increased in the cortex but to a lesser extent (g., 22%; i.p., 36%; i.t., 48%) and were higher in the cerebellum after i.p. and i.t. administrations than after oral gavage. Rats treated i.t. with MnCl2 showed an elective increase of the striatal Mn concentration (205%). In contrast, MnO2 given orally did not significantly increase blood and cerebral tissue Mn concentrations; the low bioavailability is most likely due to the lack of intestinal resorption. Administration of MnO2 i.p. and i.t., however, led to significant increases of Mn concentrations in blood and cerebral tissues. These increments were not significantly different from those measured after MnCl2 administration, except for striatal Mn after i.t. which was markedly less (48%) after MnO2 administration. A comparison of the blood Mn kinetics immediately after g. and i.t. treatment with MnCl2 or MnO2 indicated that the higher elevation of blood Mn concentration ( > 2000 ng Mn/100 ml) after i.t. administration of MnCl2 could account for the elective uptake of Mn in the striatum observed in repeated dosing experiments. It is concluded that the modulation of Mn distribution in brain regions according to the route of administration and the chemical form of the Mn compound may be explained on the basis of different blood Mn kinetics and regional anatomic specificities of the striatal region.

Comparison of several methods for the determination of arsenic compounds in water and in urine

SummarySeveral arsenic species (inorganic tri- or pentavalent arsenic, mono-and dimethylated arsonic acids) can be determined in water samples by electrothermal atomic absorption spectrometry after appropriate acidification procedures (concentrated HCl or a mixture HCl/HClO4/HBr) and extraction by toluene in the presence or absence of KI; the determination of aromatic derivatives and of arsenic thiol complexes needs a wet or dry ashing step. The procedures for water analysis are not directly applicable to urine samples; in the best conditions, total inorganic plus 85% on the average of the methylated arsenicals present in urine are measured after acidification with concentrated HCl and extraction by toluene in the presence of KI. Total arsenic content (including arsenic from marine origin) is measured only after a drastic mineralization step like MgO treatment at 600°C. The results obtained by the electrothermal atomic absorption technique and those obtained by neutron activation analysis are in excellent agreement.When the presence of arsenic of marine origin is suspected in urine, the analysis of inorganic arsenic and its metabolites is preferably performed by an arsine generation technique. The sum of inorganic arsenic and of its mono and dimethylated derivatives determined by such a technique is identical with the results obtained by electrothermal atomic absorption spectrometry after complete mineralization of the samples as long as no arsenic from marine origin is present.After oral ingestion of As2O3 by man, the urinary excretion of inorganic arsenic and its metabolites is important and rapid (approximately 60% are eliminated by the oral route with a half life of 30 h).While the excretion occurs in the form of inorganic species during the first hours following the ingestion, a methylating process is rapidly triggered and leads to a preponderant excretion of dimethylarsinic acid 1 day after ingestion. In the case of ingestion of seafood containing arsenic, the urinary excretion occurs at a higher rate (half life 18 h) apparently without transformation.The absence of interference of arsenic from marine origin and the capacity of measuring separately inorganic arsenic and its main urinary metabolites makes the arsine generation technique the best suited for the monitoring of workers exposed to inorganic arsenic. However, since the technique may sometimes be too elaborate and time-consuming for routine work, the biological monitoring of workers can be performed by determining total arsenic concentration in urine after mineralization with MgO. Samples with high arsenic content are then re-analyzed to distinguish between occupational exposure and ingestion of the organic arsenic present in marine organisms. This is carried out either by the arsine generation method or, if this technique is not available, by a direct extraction procedure in the presence of KI of a sample acidified with HCI. With the latter procedure, 85% of the methylated arsenic is measured on average without interference of arsenic from marine origin.

Markers of early renal changes induced by industrial pollutants. I. Application to workers exposed to mercury vapour.

Several markers of renal changes have been measured in a cohort of 50 workers exposed to elemental mercury (Hg) and in 50 control workers. After application of selection criteria 44 exposed and 49 control workers were retained for the final statistical analysis. Exposed workers excreted on average 22 micrograms Hg/g creatinine and their mean duration of exposure was 11 years. Three types of renal markers were studied--namely, functional markers (creatinine and beta 2-microglobulin in serum, urinary proteins of low or high molecular weight); cytotoxicity markers (tubular antigens and enzymes in urine), and biochemical markers (eicosanoids, thromboxane, fibronectin, kallikrein, sialic acid, glycosaminoglycans in urine, red blood cell membrane negative charges). Several bloodborne indicators of polyclonal activation were also measured to test the hypothesis that an immune mechanism might be involved in the renal toxicity of elemental Hg. The main renal changes associated with exposure to Hg were indicative of tubular cytotoxicity (increased leakage of tubular antigens and enzymes in urine) and biochemical alterations (decreased urinary excretion of some eicosanoids and glycosaminoglycans and lowering of urinary pH). The concentrations of anti-DNA antibodies and total immunoglobulin E in serum were also positively associated with the concentration of Hg in urine and in blood respectively. The renal effects were mainly found in workers excreting more than 50 micrograms Hg/g creatinine, which corroborates our previous estimate of the biological threshold of Hg in urine. As these effects, however, were unrelated to the duration of exposure and not accompanied by functional changes (for example, microproteinuria), they may not necessarily represent clinically significant alterations of renal function.