Robert Lauwerys

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.

Carcinogenicity and mutagenicity of chromium

Occupational exposure represents the main source of human contamination by chromium. For non-occupationally exposed people the major environmental exposure to chromium occurs as a consequence of its presence in food. Chromium must be considered as an essential element. Its deficiency impairs glucose metabolism. Trivalent chromium salts are poorly absorbed through the gastro-intestinal and respiratory tracts because they do not cross membranes easily. Hexavalent chromium can be absorbed by the oral and pulmonary routes and probably also through the skin. After its absorption, hexavalent chromium is rapidly reduced to the trivalent form which is probably the only form to be found in biological material. Epidemiological studies have shown that some chromium salts (mainly the slightly soluble hexavalent salts) are carcinogens. Lung cancers have, indeed, often been reported among workers in chromate-producing industry and, to a lesser extent, in workers from the chrome-pigment industry. The first attempts to produce cancers in experimental animals by inhalation or parenteral introduction gave negative or equivocal results but, from 1960, positive results have been obtained with various chromium compounds. As for the carcinogenic activity, the mutagenicity of chromium has mainly been found with hexavalent salts. In the majority of assay systems used, trivalent chromium appears inactive. It can be considered as evident, however, that the ultimate mutagen which binds to the genetic material is the trivalent form produced intracellularly from hexavalent chromium, the apparent lack of activity of the trivalent form being due to its poor cellular uptake.

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.

Carcinogenicity, Teratogenicity and Mutagenicity of Arsenic

Arsenic may be released into the environmental through industrial processes and through the generation of power from coal. It is also widely used in agriculture and was formerly used extensively in medicine. For the general population, exposure to arsenic occurs mainly through the ingestion of foodstuffs containing inorganic and organic arsenicals. Trivalent arsenicals are regarded as being primarily sulfhydryl reagents with the result they inhibit a number of thiol-dependent enzymic systems in various tissues. Arsenite also has an effect on DNA synthesis and DNA repair. Owing to its lower affinity for hydroxy and thiol groups, pentavalent arsenate inhibits fewer enzymic systems. Although there is no reliable evidence that arsenic produces tumors in experimental animals, epidemiological studies show that the incidence of epidermoid carcinomas of the skin and lungs, and of pre-cancerous dermal keratoses, is significantly increased in human subjects who have been chronically exposed to arsenic compounds by oral or respiratory routes. Arsenic appears to be one of the only teratogenic members of the Group V metals. Most of the studies performed on the mutagenic activity of arsenic have provided positive results. They involve experiments on microorganisms, plant material and Drosophila as well as observations on the ability of this metal to induce, in vitro and in vivo, chromosomal aberrations in mammalian cells.

Exposure To Lead By the Oral and the Pulmonary Routes of Children Living in the Vicinity of a Primary Lead Smelter

Abstract Yearly from 1974 to 1978, a medical survey was carried out among 11-year-old children attending schools situated less than 1 and 2.5 km from a lead smelter. Age-matched control children from a rural and urban area were examined at the same time. The blood lead levels (PbB) of the children living in the smelter area (mainly those attending schools located less than 1 km from the smelter) were higher than those of rural and urban children. The mean PbB levels were usually lower in girls than in boys, especially in the smelter area. Despite a slightly decreasing trend in the annual mean airborne lead concentration at less than 1 km (mean PbA: from 3.8 μg/m3 in 1974 to 2.3 μg/m3 in 1978) the PbB levels there did not improve, whereas 2.5 km from the plant a significant tendency to normalization of PbB became apparent. Therefore, in the third survey, the medical examination was combined with an environmental study which demonstrated that lead in school-playground dust and in air strongly correlated. Lead on the childrens hands (PbH) was also significantly related to lead in air or lead in dust. Less than 1 km from the factory boys and girls had on the average 436 and 244 μg Pb/hand, respectively, vs 17.0 and 11.4 μg Pb/hand for rural boys and girls, respectively. Partial correlations between PbB, PbA, and PbH indicated that in the smelter area the quantitative contribution of PbA to the childrens PbB is negligible compared to that of PbH. Thus, the control of airborne lead around the lead smelter is not sufficient to prevent excessive exposure of children to environmental lead. In view of the importance of lead transfer from dust and dirt via hands to the gastrointestinal tract remedial actions should be directed simultaneously against the atmospheric emission of lead by the smelter and against the lead particulates deposited on soil, dust, and dirt.

Impairment of Renal Function with Increasing Blood Lead Concentrations in the General Population

BACKGROUND Nephropathy is known to occur in persons with heavy exposure to lead. Whether exposure to lead in the general population leads to impaired renal function is not known. METHODS We studied renal function and indexes of lead exposure in a random population sample of 965 men and 1016 women (age range, 20 to 88 years). In all the subjects we measured creatinine clearance and blood concentrations of lead and zinc protoporphyrin (an indirect measure of blood lead level). RESULTS The mean (+/- SD) creatinine clearance rate was 99 +/- 30 ml per minute in the men and 80 +/- 25 ml per minute in the women. In the men the geometric mean blood lead concentration was 114 micrograms per liter (0.55 mumol per liter) (range, 23 to 725 micrograms per liter [0.11 to 3.5 mumol per liter]), and in the women 75 micrograms per liter (0.36 mumol per liter) (range, 17 to 603 micrograms per liter [0.08 to 2.9 mumol per liter]); the zinc protoporphyrin values in blood averaged 1.0 and 1.1 micrograms per gram of hemoglobin, respectively. The creatinine clearance rate was inversely correlated with blood lead and zinc protoporphyrin values in the men and the women both before and after adjustments for age, bodymass index, and diuretic treatment. A 10-fold increase in blood lead concentration was associated with a reduction of 10 to 13 ml per minute in creatinine clearance. We also found a positive correlation between serum beta 2-microglobulin (which is inversely related to the glomerular filtration rate) and blood lead in men, between serum beta 2-microglobulin and zinc protoporphyrin in both sexes, and between serum creatinine and zinc protoporphyrin in men. CONCLUSIONS Exposure to lead may impair renal function in the general population. The alternative hypothesis that renal impairment may lead to an increase in the blood lead concentration cannot be excluded, however.

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.

Study of inorganic arsenic methylation by rat liver in vitro: relevance for the interpretation of observations in man

The biotransformation of inorganic arsenic by rat liver in vitro leads to the production of a monomethylated and a dimethylated arsenic derivative, measured by flameless atomic absorption as monomethylarsonic (MMA) and dimethylarsinic (DMA) acids respectively. The methylating activity is localized in the cytosol and accepts only As3+ as substrate. Its optimum pH lies between 7.5 and 8.0, and reduced glutathione (10−2M) is required for full activity. S-Adenosylmethionine is the essential methyl group donor and corrinoïd derivatives act synergistically.An excess of substrate and the addition of mercuric ions prevent the formation of the dimethylated arsenic derivative without affecting that of the monomethylated compound. This indicates that two different enzymatic activities are involved in the methylation of inorganic arsenic in mammals. Previous observations in man (Buchet et al. 1981 b, 1984) and the results of the present study suggest that DMA production results from the subsequent methylation of the MMA precursor, although the possibility that metabolites are also produced by two completely independent pathways cannot yet be conclusively rejected. The kinetics of MMA and DMA production provide an explanation for the observations that in volunteers given increasing amounts of As3+, the urinary excretion of DMA levels off faster than that of MMA and in patients acutely intoxicated with As3+, several days may elapse before DMA becomes the preponderant metabolite. The results of the present study also suggest that the reduction of MMA production associated with an increased synthesis of DMA found in patients with liver diseases given a standard dose of As3+ might be due to a reduction of As3+ uptake by the liver cells.