Michèle Berode

Biological monitoring of occupational exposure to toluene diisocyanate

SummaryThe study validated the use of urinary toluene diamine (TDA) in postshift samples as an indicator of preceding 8-h exposure to toluene diisocyanate (TDI). Nine workers exposed in TDI-based polyurethane foam production were studied. Their exposure levels varied in 8-h time-averaged samples from 9.5 to 94 μg/m3. The urinary TDA concentrations varied from 6.5 to 31.7μg/g creatinine and they were linearly related to the atmospheric TDI levels. Approximately 20% of TDI is metabolized to diamines but their specificity is remarkable to the extent that by analysis for the 2,4- and 2,6-diamino isomers an idea of the percutaneous absorption may be had.

Maturation-dependent neurotoxicity of lead acetate in vitro: implication of glial reactions.

Despite a wealth of data on the neurotoxic effects of lead at the cellular and molecular levels, the reasons for its development‐dependent neurotoxicity are still unclear. Here, the maturation‐dependent effects of lead acetate were analyzed in immature and differentiated brain cells cultured in aggregates. Markers of general cytotoxicity as well as cell‐type‐specific markers of glial and neuronal cells showed that immature brain cells were more sensitive to lead than the differentiated counterparts, demonstrating that the development‐dependent neurotoxicity of lead can be reproduced in aggregating brain cell cultures. After 10 days of treatment, astrocytes were found to be more affected by lead acetate than neurons in immature cultures, and microglial cells were strongly activated. Eleven days after cessation of the treatment, lead acetate caused a partial loss of astrocytes and an intense reactivity of the remaining ones. Furthermore, microglial cells expressed a macrophagic phenotype, and the loss of activity of neuron‐specific enzymes was aggravated. In differentiated cultures, no reactive gliosis was found. It is hypothetized that the intense glial reactions (microgliosis and astrogliosis) observed in immature cultures contribute to the development‐dependent neurotoxicity of lead.

Urinary hexane diamine as an indicator of occupational exposure to hexamethylene diisocyanate

The occupational exposure of 19 men to hexamethylene diisocyanate (HDI) vapour was monitored during one 8-h shift. It ranged from 0.30 to 97.7 μg/m3. This was compared with the urinary output of hexane diamine (HDA) liberated by acid hydrolysis from its conjugates in post-shift samples. The excretion varied from 1.36 to 27.7 μg/g creatinine, and there was a linear association of HDI air concentration with urinary HDA excretion. The validity of the urinary analysis was confirmed by simultaneous blind analysis in another laboratory. The results had an excellent linear concordance. Thus, it seems that while the gas chromatographic-mass spectrometric detection method requires sophisticated apparatus, the results are very useful to occupational health practices. A biological exposure index limit of 19 μg HDA/g creatinine in a post-shift urine specimen is proposed as an occupational limit level of HDI monomer (time-weighted average=75 μg/m3). Most importantly, biological monitoring of HDA is sensitive enough to be used at and below the current allowable exposure limit levels.

Evaluation of Concomitant Biological and Air Monitoring Results

Abstract The quantitative estimation of dose in epidemiological studies is characterized by two main types of difficulties. The dose often changes widely over time, making its exact estimation a long and costly process for chronic diseases. Although systematic, long-term changes can be dealt with quite easily, short-term, random fluctuations have to be treated statistically. On the other hand, one must admit that target dose can only be measured directly on rare occasions because the biological receptors are, in most cases, inaccessible in studies on workers. Surrogates of target dose, therefore, have to be used, i.e., air exposure or biological indicators. This paper examines advantages and disadvantages of these two approaches, with respect to the difficulties mentioned. For exposure fluctuations over time, air and biological monitoring are compared, taking into account the half-life of the chemical in the body and also some measure of the biological individual variability. Plots are given to describe h...

Lead acetate toxicity in vitro: Dependence on the cell composition of the cultures.

It is well known that exposure to low doses of lead causes long-lasting neurobehavioural deficits, but the cellular changes underlying these behavioural changes remain to be elucidated. A protective role of glial cells on neurons through lead sequestration by astrocytes has been proposed. The possible modulation of lead neurotoxicity by neuron-glia interactions was examined in three-dimensional cultures of foetal rat telencephalon. Mixed-brain cell cultures or cultures enriched in either neurons or glial cells were treated for 10 days with lead acetate (10(-6) m), a concentration below the limit of cytotoxicity. Intracellular lead content and cell type-specific enzyme activities were determined. It was found that in enriched cultures neurons stored more lead than glial cells, and each cell type alone stored more lead than in co-culture. Moreover, glial cells but not neurons were more affected by lead in enriched culture than in co-culture. These results show that neuron-glia interactions attenuate the cellular lead uptake and the glial susceptibility to lead, but they do not support the idea of a protective role of astrocytes.

Bicarbonate-catalyzed hydrolysis of hexamethylene diisocyanate to 1,6-diaminohexane

The hydrolysis of hexamethylene diisocyanate (HDI) in water was tested in a dynamic and stationary system. Without catalysts, the reaction was very slow (less than 1% in 10 min at 30 degrees C) while the addition of simple carboxylic-acid-containing neutral buffers markedly catalyses the formation of 1,6-diaminohexane as the known hydrolysis product. The catalytic efficiency of formic acid, oxalic acid, acetic acid, lactic acid, citric acid and carbonic acid increased in this order while phosphate, glycine and glutamate were inactive even at very high concentrations. A 20 mM bicarbonate buffer was the optimal catalyst, but below this concentration the rate of HDI hydrolysis was drastically reduced. It is suggested that the hydrolysis of inhaled HDI in the lungs may be catalysed by bicarbonate in the blood, giving rise to amines found as urinary metabolites following occupational exposure.

Effect of Alcohol on the Kinetics of Styrene and its Metabolites in Volunteers and in Workers

Abstract The reliability of mandelic acid (MA) and phenylglyoxylic acid (PGA) in urine as biological indicators of styrene exposure is impaired by the concurrent intake of ethyl alcohol. This has been verified by controlled experiments in the laboratory and in the field. Six males were exposed to styrene at 50 ppm with four concurrent levels of ethyl alcohol intake from 0 to 1 g per kg of body weight during or following exposure. Blood and urine samples were analyzed for MA, PGA, styrene epoxide (SO), and styrene glycol (SG). The MA/SG ratio in blood was found to be the most promising indicator and could be used as a metabolic “check-index.” An MA/SG ratio less than 30 is proposed as a warning level which is indicative of interference by alcohol intake. Similar studies on seven workers in a polyester plant yielded results in agreement with the controlled laboratory findings. Berode, M.; Droz, P. O.; Boillat, M. A.; Guillemin, M. Effect of alcohol on the kinetics of styrene and its metabolites in volunteer...

Sex differences in urinary levels of several biological indicators of exposure: A human volunteer study

The aim of the study was to quantify the variability on biological indicators of exposure between men and women for three well known solvents: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile. Controlled human exposures were carried out in a 12 m³ exposure chamber for each solvent separately, during 6h and at half of the threshold limit value. The human volunteers groups were composed of ten young men and fifteen young women, including ten women using hormonal contraceptive. An analysis of variance mainly showed an effect on the urinary levels of several biomarkers of exposure among women due to the use of hormonal contraceptive, with an increase of more than 50% in metabolites concentrations and a decrease of up to 50% in unchanged substances concentrations, suggesting an increase in their metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Our study suggests that not only physiological differences between men and women but also differences due to sex hormones levels can have an impact on urinary concentrations of several biomarkers of exposure. The observed variability due to sex among biological exposure indices can lead to misinterpretation of biomonitoring results. This aspect should have its place in the approaches for setting limits of occupational exposure.

Exposition professionnelle aux isocyanates et susceptibilité individuelle

Patients with organic diisocyanate-induced pulmonary disease may be specially susceptible to the toxic effects of agent. Among 11 cases diagnosed in one year, the majority (10/11) were slow acetylators. The same patients were different from the control population in terms of alpha-1-antitrypsin phenotypes. Heterozygous combinations were more frequent than among controls. It seems that the combination of low N-acetylation capacity and a heterozygous alpha-1-antitrypsin predisposes to the disease.