Control biológico humano de una serie de compuestos químicos industriales : Benceno

Traducción de la obra en inglés \"Human biological monitoring of industrial chemicals series\" (EUR 8476 EN) publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: propiedades químicas y físicas del benceno, cambios biológicos relacionados con la toxicidad crónica del benceno, metabolismo, indicadores biológicos...

Indicadores biológicos para la valoración de la exposición humana a compuestos químicos industriales : Xileno

Traducción de la obra en inglés \"Biological indicators for the assessment of human exposure to industrial chemicals\" (EUR 8903 EN) publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: propiedades químicas y físicas del xileno, efectos en los humanos, metabolismo e indicadores biológicos.

Indicadores biológicos para la valoración de la exposición humana a compuestos químicos industriales : Aminas Aromáticas y Compuestos Nitrogenados Aromáticos

Traducción de la obra en inglés \"Biological indicators for the assessment of human exposure to industrial chemicals\" (EUR 11478 EN) publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: metabolismo, indicadores biológicos de exposición, pruebas que reflejan la exposición a sustancias mutagénicas y potencialmente carcinogénicas...

Indicadores biológicos para la valoración de la exposición humana a compuestos químicos industriales : Dimetilformamida

Traducción de la obra en inglés \"Biological indicators for the assessment of human exposure to industrial chemicals\" (EUR 10704 EN) publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: propiedades químicas y físicas de la dimetilformamida, efectos en los humanos, metabolismo, indicadores biológicos...

Indicadores biológicos para la valoración de la exposición humana a compuestos químicos industriales : Estireno

Traducción de la obra en inglés \"Biological indicators for the assessment of human exposure to industrial chemicals\" (EUR 8903 EN) publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: propiedades químicas y físicas del estireno, efectos en los humanos, factores que influyen en el metabolismo del estireno e indicadores biológicos.

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.

Adverse effects of chronic low level lead exposure on kidney function--a risk group study in children.

BACKGROUND: Children have been considered a risk group for lead (Pb) toxicity, mainly because of neurophysiological or neuro-cognitive deficits following Pb exposure. Blood Pb levels (b-Pb) of 100 microg/l currently have been defined as the lowest adverse effect level. The aim of this study was to compare, with the help of urinary markers, the kidney function of children with b-Pb just above this threshold with that of unexposed children, to assess from a nephrological point of view whether the current threshold is justified and whether children really are a particularly vulnerable risk group in terms of Pb-induced kidney damage. METHODS: In a cross-sectional study, 112 children, either from unexposed areas (controls, n=50) or Pb-contaminated areas (n=62), the latter partly with a known history of elevated b-Pb, were examined. Twenty nine urinary or serum markers mostly related to the function or integrity of specific nephron segments were determined (e.g. filtered plasma proteins, tubular enzymes, tubular antigens, eicosanoids). RESULTS: b-Pb were 39+/-13 microg/l in controls and 133+/-62 microg/l in exposed children. The main findings were increased excretion rates of prostaglandins and thromboxane B2, epidermal growth factor, beta2-microglobulin and Clara cell protein in the exposed children. A relationship between b-Pb and the prevalence of values above the upper reference limits was observed. CONCLUSIONS: With the help of urinary markers, nephron segment-specific effects of chronic low-level Pb exposure could be detected in children. The pattern of effects on glomerular, proximal and distal tubular and interstitial markers was similar to that previously observed in adults. The changes, however, occur at lower b-Pb levels than in adults. The current threshold appears to be justified also from a nephrological point of view, and children can indeed be considered a special risk group.

Interleukin 1 alpha hematological examination in mechanics exposed to low benzene concentrations.

OBJECT: To examine the hypothesis of Renz and Kalf relative to the involvement of interleukin 1 alpha (IL-1 alpha) in the development of anemia in benzene-exposed workers. According to this hypothesis, benzene inhibits the cleavage of the IL-1 alpha precursor (proIL-1 alpha) to mature IL-1 alpha and the lack of this cytokine is responsible for benzene-induced bone marrow suppression. This inhibition of the processing of proIL-1 alpha is attributed to an inhibition of calpain. METHOD: Selection of a population of mechanics exposed to low levels of benzene from fuels, assessment of usual exposure and lifetime exposure duration, and measurements of concentrations of workplace-air benzene and urinary benzene metabolites. Determination of IL-1 alpha concentrations was done by a whole-blood assay after lipopolysaccharide stimulation and a hematological examination was carried out. Statistical analysis considered several possible confounding factors, particularly smoking and drinking habits. DESIGN: Cross-sectional study. RESULTS: The level of exposure of the mechanics to benzene from fuels was mostly well below 1 ppm. IL-1 alpha production was not decreased in mechanics exposed to benzene from fuels, and no correlation between IL-1 alpha concentrations and red blood cell counts appeared. With the exception of a slight decrease in red blood cell counts in mechanics, no hint of a toxic effect of exposure on hematological parameters was found. CONCLUSIONS: The hypothesis of Renz and Kalf could not be confirmed. Although the low level exposure of the study population and methodological factors are possible explanations, it cannot be excluded that the hypothesis of Renz and Kalf is not generalizable to benzene-exposed humans. Presently, one cannot advise the measurement of IL-1 alpha production for biological effect monitoring of workers exposed to low concentrations of benzene.

The assessment of biomarkers to detect nephrotoxicity using an integrated database.

Groups of industrial workers exposed to heavy metals (cadmium, mercury, and lead) or solvents were studied together with corresponding control groups. The cohorts were collected from several European centers (countries). Eighty-one measurements were carried out on urine, blood, and serum samples and the results of these analyses together with questionnaire information on each individual were entered into a central database using the relational database package Rbase. After the completion of the database construction phase, the data were exported in a format suitable for analysis by the statistical package SAS. The potential value of each test as an indicator of nephrotoxicity was then assessed. Rigorous exclusion criteria were applied which resulted in the elimination of some tests and samples from the dataset. The measurable contributions of smoking, gender, metal exposure, and site were either singly or in combination assessed by biomarkers for nephrotoxicity. The parameters measured included three urinary enzymes, six specific proteins, total protein, two extracellular matrix markers, four prostaglandins and anti-GBM antibodies, and beta 2-microglobulin in serum. The most sensitive renal tests included the urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and intestinal alkaline phosphatase (IAP), brush border antigens, and urinary low-molecular-weight proteins. Of the newer tests investigated the prostaglandins were the most promising. Different patterns of biomarker excretion were observed following exposure to lead, cadmium, or mercury. The dataset provides a unique repository of data which could provide the basis of an enlarging source of information on normal human reference ranges and on the effects of exposure to toxins and the use of biomarkers for monitoring nephrotoxicity.

Hematopoietic and lymphatic malignancies in vehicle mechanics.

Although it is generally acknowledged that benzene causes leukemia, especially acute myeloid leukemia, considerable divergences persist in the assessment of the leukemia risk due to occupational low-level benzene exposure. Specifically, the risk for vehicle mechanics is considered by some authors as being nondetectable with epidemiologic methods, whereas others calculated that the incidence rate of leukemia (all types) in vehicle mechanics is increased more than 60 times. The purpose of this review is to examine the publications on this topic in light of criteria for causal inference and to discuss the possible role of bias, confounding factors, and chance. The results of this analysis reveal that there are surprisingly few epidemiologic observations supporting an increased incidence of leukemia in vehicle mechanics. Apparently, publications suggesting a leukemogenic effect of low-level benzene exposure in garage mechanics are more often quoted than their negative counterparts, although they are not better designed.

Relationships between smoking habits, smoking-associated hematological changes, and urinary benzene metabolites.

It has been suggested that benzene metabolites might be good indicators of smoking. Moreover, benzene could stimulate the neutrophil lineage while depressing the lymphocytic and erythroid lineages, possibly by an interference with cytokines. The effect on the neutrophil lineage could explain the smokers' leukocytosis, the mechanism of which is presently unknown. Therefore, the usefulness of benzene metabolites as indicators of smoking was compared to that of cotinine and thiocyanate, and the relationships between benzene metabolites, the hematological parameters of smokers, and interleukin 1 alpha production were examined. The results show that benzene metabolites are not better indicators of smoking status than cotinine or thiocyanate. Furthermore, it seems unlikely that the smokers' leukocytosis is benzene induced.

Urinary neutral endopeptidase in workers exposed to cadmium: interaction with cigarette smoking.

OBJECTIVES: Structural impairment of the renal proximal tubular epithelium induced by cadmium (Cd) was investigated by measuring the concentration of neutral endopeptidase 24.11 (NEP), an ectoenzyme of the apical brush border, in the urine of 106 male workers employed in a Cd smelter (among whom 52 were occupationally exposed to Cd), and by comparing it with other tubular markers (low molecular weight proteins, lysosomal enzymes). METHODS: NEP (EC 3.4.24.11), beta-N-acetyl-glucosaminidase (NAG) (EC 3.2.1.30), and NAG-B isoenzyme activities were measured by fluorimetric assays, whereas the concentrations of retinol binding protein (RBP), beta 2-microglobulin (beta 2M), and Clara cell protein (CC16) were measured by automated latex agglutination techniques. RESULTS: An increased urinary excretion of NEP as well as microproteins was found only in subjects excreting more than 5 micrograms Cd/g creatinine. In this group, NEP concentrations were significantly higher in the subjects who smoked. This significant interaction could not be found for any other marker tested. CONCLUSIONS: The data suggest that NEP enzymuria is high even at low exposures to Cd (with a threshold of urinary cadmium excretion (U-Cd) at 5 micrograms/g creatinine), indicating early structural alterations. Moreover, its particular sensitivity to smoking could be useful in the detection of new population clusters potentially more susceptible to development of nephrotoxic insult.

Reversibility of microproteinuria in cadmium workers with incipient tubular dysfunction after reduction of exposure.

The study aimed at assessing the evolution of cadmium (Cd)-induced renal tubular dysfunction in Cd workers according to the severity of the microproteinuria observed at the time the exposure was substantially decreased. Male workers employed in the Cd production industry for whom formerly high exposure had markedly decreased by 1984 and for whom standardized medical data were available during two observation periods (1980-1984 and 1990-1992) were eligible for the study. A total of 32 Cd workers fulfilling this profile were divided into two groups on the basis of historical records of urinary Cd concentration (Cd-U) covering the period until 1984. The workers with Cd-U values of > 10 micrograms Cd/g creatinine were subdivided further on the basis of the urinary concentration of beta 2-microglobulin (beta 2 MG-U) measured during the first observation period (1980-1984). In each group, the tubular microproteinuria as reflected by beta 2 MG-U and the concentration of retinol-binding protein in urine as well as the internal Cd dose as reflected by the concentration of Cd in blood and urine were compared between the first and second (1990-1992) observation periods. Increased microproteinuria was often diagnosed in cases with Cd-U values of > 10 micrograms Cd/g creatinine. The evolution of tubular renal function has been found to depend on the extent of the body burden of Cd (as reflected by Cd-U) and the severity of the initial microproteinuria at the time high Cd exposure was reduced or ceased. When reduction of Cd exposure took place while beta 2 MG-U did not exceed the upper reference limit of 300 micrograms/g creatinine, the risk of developing tubular dysfunction at a later stage was likely to be low, even in cases with historical Cd-U values occasionally > 10 but always < 20 micrograms Cd/g creatinine. When the microproteinuria was mild (beta 2 MG-U > 300 and < or = 1,500 micrograms/g creatinine) at the time exposure was reduced, and the historical Cd-U values had never exceeded 20 micrograms Cd/g creatinine, there was indication of a reversible tubulotoxic effect of Cd. When severe microproteinuria (beta 2 MG-U > 1,500 micrograms/g creatinine) was diagnosed in combination with historical Cd-U values exceeding 20 micrograms Cd/g creatinine, Cd-induced tubular dysfunction was progressive in spite of reduction or cessation of Cd exposure.

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

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.

Biological monitoring of vehicle mechanics and other workers exposed to low concentrations of benzene.

It has been suggested that the threshold limit value (TLV) for the time-weighted average (TWA), of benzene be lowered because of its possible leukemogenic effect at low exposure concentrations. This requires the development of new methods of biological monitoring. In this cross-sectional study the diagnostic power of blood and breath benzene and of urinary phenol, catechol, hydroquinone, S-phenylmercapturic acid, and muconic acid were compared in a population of 410 male workers exposed to benzene in garages, in two coke plants, and in a by-product plant. Benzene exposure was assessed by personal air sampling (charcoal tube and passive dosimeter). In all, 95% of the workers were exposed to less than 0.5 ppm benzene. According to the multiple regression equation, the muconic acid and S-phenylmercapturic acid concentrations detected in nonsmokers exposed to 0.5 ppm benzene were 0.3 mg/g and 6 micrograms/g, respectively (range 0.2-0.6 mg/g and 1.2-8.5 micrograms/g, respectively). With muconic acid very few false-positive test results were found, and this determination remained reliable even around a cutoff level of 0.1 ppm benzene. Moreover, the diagnostic power of this test proved to be good even when diluted or concentrated urine samples were not excluded. S-Phenylmercapturic acid (S-PMA) also performed fairly well. Blood and breath benzene as well as urinary phenol (PH) and hydroquinone (HQ) were clearly less suitable biomarkers than muconic acid (MA). Catechol (CA) was not associated with occupational benzene exposure. According to the results of biological monitoring, the skin resorption of benzene from gasoline or other fuels seems negligible. Correlation, multiple regression, and likelihood ratios consistently showed that MA and S-PMA concentrations were fairly good indicators of benzene exposure in the 0.1- to 1-ppm range, even in a population comprising both smokers and nonsmokers. PH, HQ, CA, and blood and breath benzene were less suitable, if at all, in the same exposure range.

Proximal tubular injury in Chinese herbs nephropathy: monitoring by neutral endopeptidase enzymuria.

Neutral endopeptidase (NEP) is a 94 kDa ectoenzyme of the proximal tubule brush border, physiologically released into the urine with apical membrane fragments. As proximal tubular atrophy was a histological hallmark of Chinese herbs nephropathy (CHN), this study firstly determined renal excretion of NEP in healthy control subjects (N = 31), in patients with CHN (N = 26) and in women having consumed Chinese herbs and whose renal function was normal but running the risk of developing CHN (N = 27). Another patient group consisted of female patients with glomerular diseases (N = 12). At the same time, measurements of urinary microproteins (Clara cell protein, retinol binding protein, beta 2-microglobulin and alpha 1-microglobulin) were performed, as indicators of tubular dysfunction. Cell damage was estimated by the excretion of N-acetyl-beta-D-glucosaminidase (NAG). In the control group, the physiological NEP enzymuria was 43.1 micrograms/24 hr (geometric mean). In CHN patients, levels of urinary NEP were significantly decreased in those with moderate renal failure (26.7 micrograms/24 hr; N = 21; P < 0.05) and almost abolished in end-stage renal failure patients (4.35 micrograms/24 hr; N = 5; P < 0.05). In patients at risk as well as in patients with glomerular diseases, urinary NEP levels were not statistically different from those observed in control subjects (40.68 micrograms/24 hr and 48.5 micrograms/24 hr, respectively). Several degrees of tubular dysfunction and injury were noted in patients groups, as attested by increased urinary microproteins and NAG excretions. Considering the data from control and CHN patients, NEP enzymuria positively correlated with individual creatinine clearance values (r = 0.76; P = 0.0001) and negatively correlated with urinary microproteins levels (r = -0.55; P = 0.00001). Finally, NEP was regularly quantitated in the urine of 6 CHN patients for a period ranging from six months to two years and in 19 patients at risk during two years, respectively. In the first group, renal function progressively deteriorated in 3 patients, leading them to renal replacement therapy after 38 to 115 weeks. Stable parameters were observed in the remaining 3 patients. A direct correlation between creatinine clearance and NEP excretion was found longitudinally in each case. In the second group, no significant change of urinary NEP levels was observed (45.9 micrograms/24 hr), in parallel with stable renal function. Taken together, these results indicate that, in CHN patients, NEP enzymuria provides a rapid and noninvasive determination of the degree of structural impairment affecting the proximal tubular population and further reflecting the severity of the renal disease. The interest of this urinary marker in monitoring the progression of other tubulointerstitial diseases remains to be assessed.

Long-term pulmonary and systemic toxicity following intravenous mercury injection.

Long-term pulmonary and systemic toxicity following mercury intravenous injection has rarely been assessed. We present the results of a detailed investigation assessing pulmonary and systemic long-term toxic effects in a subject who had pulmonary and systemic mercury microembolism diagnosed more than 11 years previously. Radiographic examination showed the persistence of mercury microemboli in both lungs and elsewhere in the body. Lung function tests revealed a decreased diffusing capacity for carbon monoxide and PO2 probably indicative of microscopic inflammation of lung interstitium. Electroneuromyography showed signs of mild axonopathy in both legs. At semen analysis, a high proportion of motionless spermatozoa was present. Urinary excretion of mercury was high. Signs of interstitial lung impairment, peripheral axonopathy and asthenozoospermia in a subject who had mercury microembolism persisting for more than 11 years might be evidence of long-term mercury toxicity.