Biological monitoring as a valid tool to assess occupational exposure to mixtures of 2,4-:2,6-toluene diisocyanate.

BACKGROUND AND OBJECTIVES: Despite its advantages over environmental monitoring, biological monitoring of exposure to 2,4-:2,6-toluene diisocyanate (TDI) mixtures is still underused. The present study was designed in order to evaluate the feasibility and reliability of biological monitoring in a factory producing polyurethane foam blocks. METHODS: Airborne TDI isomers were sampled by both static and personal pumps and determined by HPLC with fluorimetric detection. Specific metabolites 2,4- and 2,6-toluenediamine (TDA) were determined by gas chromatography-mass spectrometry on hydrolysed urine samples collected from 16 workers at the beginning of the workweek and both before (BS) and at the end (ES) of the 4th workday. Additional samples were collected at the end of the 1st half-shift and at the beginning of the 2nd half-shift in 5 workers. RESULTS: In the foam production shop, TDI values were on average about 20 microg/m3, with higher levels in the 2nd half-shift and peak levels in workers operating along the polymerization tunnel. Average TDI levels were significantly correlated with ES TDA concentrations (p < 0.0001). TDA showed a fast urinary elimination phase leading to progressively higher TDA levels either during the shift (5 workers) and at the end-of-shift. A slower elimination phase with a weekly accumulation was demonstrated by values at the beginning of the workweek (higher than in unexposed subjects) and by their elevation in subsequent BS samples. CONCLUSIONS: The study demonstrates the feasibility and reliability of biological monitoring in workers exposed to 2,4-:2, 6-TDI mixtures. This approach can provide information about both the daily and weekly exposure levels.

Xenobiotic action on steroid hormone synthesis and sulfonation the example of lead and polychlorinated biphenyls.

OBJECTIVES: In the present study, the metabolism of steroid hormones has been investigated to determine whether and how xenobiotics like lead (Pb) and polychlorinated biphenyls (PCBs) interfere with steroid hormone biotransformation in humans. METHODS: Three groups of subjects were tested for concentration of urinary total steroids, 17-ketosteroids (n = 5), pregnane derivates (n = 6), 17-hydroxycorticosteroids (n = 11) and their sulfonated compounds: 14 workers exposed to lead, with a mean Pb blood concentration (PbB) of 29.21 microg/dl; 15 subjects exposed to PCBs, with a mean PCB blood concentration (PCBB) of 61.69 microg/l; a control group (n = 25). RESULTS: The urinary concentrations of 17-ketosteroids and 17-hydroxycorticosteroids were significantly lower in the PCB-exposed groups. There were significantly fewer sulfonated 17-hydroxycorticosteroids in the subjects exposed to PCBs as compared to the controls, while the percentage of sulfonated steroids was lower for both 17-ketosteroids and 17-hydroxycorticosteroids in the PCB-exposed subjects, but only for the 17-hydroxycorticosteroids in the group of subjects exposed to Pb (P < 0.05). Pregnane derivate urinary concentrations did not differ between the three groups. CONCLUSION: Our results suggest that PCBs and Pb act on steroid hormone metabolism with different effects and only partially using the same hormone pathways; they may cause changes in endogenous hormone homeostasis and interfere with the xenobiotic phase II of detoxification. PCBs interfere on a larger number of steroids and cause more significant effects than Pb. It is likely that different mechanisms are involved in steroid hormone metabolism interference.

[Polychloro biphenils (PCBS) and cancer]. / Policlorobifenili (PCB) e cancro.

A lot of studies treat the issue of PCBs and cancer. The weight of evidence in studies of environmental exposure or increased mortality in subjects professionally exposed does not support a causal association for PCBs and human cancer. The main international agencies classified PCB as probable carcinogenicity, limited evidences in humans and sufficient on the animals. The present report would to resume the principals epidemiological and experimental studies with the purpose to show its weak and/or discordant points and to underline the critical aspects of the evaluation of the exposure. Critics are the identification of the congeners more diffused and persistent and therefore more representative and the correlation with early effects or specific metabolic alterations.

[Validity of urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) as biomarker of exposure to very low concentrations of carbon disulphide: preliminary results]. / Validiti dell'acido 2-tiotiazolidin-4-carbossilico (TTCA) urinario quale indicatore biologico dell'esposizione a concentrazioni molto basse di solfuro di carbonio: risultati preliminori.

The possibility to use urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) as biomarker of occupational exposure to very low doses of carbon disulphide (CS2) was evaluated preliminarily in 10 workers employed in a chemical plant where rubber vulcanization accelerators are produced, and in 10 workers, residents in the same geographical area and not occupationally exposed to CS2 and dithiocarbamates (DTC). Exposure to airborne CS2 was assessed, only for exposed workers, by both personal and area samplers. For the determination of TTCA, a spot urine sample was collected for each worker, exposed and non exposed, at the end of work-shift. A questionnaire probing lifestyle and dietary habits and non occupational exposure to CS2 and DTC was administered to all workers involved in the study. Environmental exposure to CS2 in 2007 ranged between 0.21 mg/m3 and 0.73 mg/m3 for personal sampling, and between 0.23 mg/m3 and 0.41 mg/m3 for area sampling. Urinary TTCA levels resulted very low and did not show any significant difference between exposed (Median: 10.8 microg/g creat; Range: 6.1-26.4 microg/g creat) and non exposed workers (Median: 9.3 microg/g creat; Range: 3.0-33.0 microg/g creat), while higher, but not significant concentrations of TTCA were observed in smokers than in non smokers (p = 0.09). No correlation was found between urinary TTCA levels and environmental exposure to CS2, age, body mass index, smoking and dietary habits. In conclusion, the low sensibility and specificity in the assessment of occupational exposure to low doses of CS2 in workers compared to general population subjects, makes urinary TTCA a biomarker with a low usefulness in biological monitoring. ACGIH, besides, should also introduce "B" (background) notation, at present not considered for the BEI indicated for urinary TTCA.

[Environmental and biological monitoring of exposure to polycyclic aromatic hydrocarbons in workers of an electric steel foundry]. / Monitoraggio ambientale e biologico dell'esposizione ad idrocarburi policiclici aromatici in lavoratori di una acciaieria elettrica.

AIMS: To assess and classify exposure to Polycyclic Aromatic Hydrocarbons (PAHs) in some specific working areas of a steel foundry operating with a continuous casting process and evaluate biomonitoring data in different job tasks. METHODS: Exposure to dusts and six PAHs classified as carcinogenic by EU directives was studied in a cohort of 35 male foundry workers (aged 41.1 +/- 6.9 years), who were examined both prior to and at the end of the work-shift (06:00 a.m.-02:00 p.m.) in two different periods. The urinary excretion of 1-hydroxypyrene (1-OH-P) was measured as a biomarker of exposure to pyrene. RESULTS: PAHs concentrations ranged from 461.8 to 935.6 ng/m3 near the continuous casting area, whereas lower values were measured near the ladle furnace. End of shift 1-OH-P values were higher in 11 non-smoking workers involved in continuous casting process as compared to those employed in mantenance and furnace areas (median of the second determination: 5.70 microg/g creatinine--range: 1.24-21.24 vs 1.17 microg/g creatinine--range: 0.23-4.49; p< 0.001). 1-OH-P excretion was significantly correlated with both the sum of six carcinogenic PAHs and pyrene airborne concentrations. In two biomonitoring sessions, 9.1% and 34.3% of the workers respectively showed end-of-shift 1-OH-P values exceeding the occupational exposure limit (OEL) (4.4 microg/g creatinine or 2.3 micromol/mol(-1) creatinine) recommended for coke-oven workers. CONCLUSIONS: 1-OH-P is a useful biomarker in assessing PAH exposure and is associated with job category at a Steelplant. Due to exposure variability, to assess risk associated with PAHs exposure, biological monitoring should be carried out periodically.

[New biomarkers of exposure]. / Nuovi indicatori di esposizione.

In this paper we have defined the new biomarkers of exposure (NBE) as those biomarkers discovered in the last five years and, among previously validated biomarkers, also those applied in different ranges of doses or those determined in biological matrices which differ from matrices originally considered. We examined the results from the surveys carried out by the main Italian research units involved in biological monitoring, i.e. those from the Universities of Brescia, Milan, Naples, Padua, Parma, Pavia, Turin and Verona. The data were collected using a standardized model and included the following: type of element or organic compound, type of biomarker, analytical technique and method, their relationship with environmental monitoring data, their relationship with effect indicators or effects in general, improvement with respect to old biomarkers, reference values. Twenty two NBEs were identified: 14 elements and chemical compounds as such or as metabolites, 4 examples of mixtures, 3 of new matrices, one of speciation. Among the others, aspects such as interest in requiring NBE, quality assurance, availability, cost-benefit ratio were discussed. We conclude that development of this specific field of research appears to be a crucial point for future improvement in risk assessment and health surveillance procedures.

Whole body action of xenoestrogens with different chemical structures in estrogen reporter male mice.

The present work tested the estrogenic activity of three weak environmental estrogens p,p'DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane], p,p'DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] and betaBHC [beta-benzene-hexachloride] in the transgenic estrogen-reporter mouse model (ERE-tK-LUC). By a time dependent analysis of the transgenic reporter expression (luciferase), we showed that all these chemicals modulated the estrogen receptors (ERs) in the whole body, although with a different efficacy and depending upon the tissue analyzed. Peak activity was registered at 16 h of treatment with 5000 microg/kg of each compound. Organochlorines are lipophylic molecules that accumulate in fat. During weight loss they are mobilized and their concentration increases in blood. We tested whether after experimental accumulation in fat tissue, followed by a 48 h period of fasting, these compounds could be modulated to reach sufficient levels to activate the ERs in target tissues. This experimental setting produced results that were different from those obtained following acute treatments. In loaded mice, fasting induced betaBHC mobilization resulted in strong ER activation in the liver, lung, eye, cerebellum, hypothalamus and cortex. p,p'DDT mobilization had no effect in these tissues, but efficiently acted in the testis, where, on the contrary, betaBHC inhibited reporter expression. During fasting, betaBHC, p,p'DDT and the metabolite p,p'DDE increased in blood concentration, from 2.7 +/- 0.36, 0.65 +/- 0.01 and 0.48 +/- 0.06 microg/ml to 9.51 +/- 1.1, 4.98 +/- 0.77 and 6.0 +/- 0.71 microg/ml, respectively. We conclude that these organochlorines modulate differently the expression of estrogen regulated genes in a tissue- and compound-specific manner and that their action is dependent on the energy balance. Moreover, we show that this mouse model is suitable to detect the estrogenic activity of chemicals with variable structures such as alkyl phenols and polychlorobiphenyls.

Metanalytical assessment of reference values for polychlorinated biphenyl in human blood.

Due to their physico-chemical characteristics, polychlorinated biphenyls (PCBs) are highly persistent in the environment and therefore easily measured in the biological matrices of more and more large groups of general population. For these reasons it would be useful to determine suitable Reference Values (RVs) for these xenobiotics. In this paper, a metanalysis to the published data on PCBs values in human blood is presented. This investigation was carried out in order to reach adequate information on their RVs and to focus some specific topics to be taken into account when producing directly RVs for PCBs. The PCBs RVs resulted between 1.2 e 8.28 microg/L for males and between 2.69 e 5.17 microg/L for females the general range varied from 0.9 to 56 microg/L. The main criticisms in the assessment of RVs for PCBs resulted: the number of examined subjects; the inclusion and stratification criteria; the analytical method adopted and their quality assurance; the type and number of congeners to be determined and their specific quantification; the calculation of blood PCBs concentration (weight/volume or weight/lipids); the statistical analysis and in particular the treatment of not detectable data.

Synthesis and anti-aggregatory activity of linear retro-inverso RGD peptides.

Six retro-inverso tri- and tetrapeptide analogues of RGD were prepared and their anti-aggregatory activity was determined by platelet aggregation tests in comparison with the corresponding parent peptides. An efficient method for the introduction of a malonyl-aspartic residue into a peptide chain is described for the first time. A 2-3-fold decrease in potency or total loss of bioactivity was observed with the new peptides; structure-activity relationships are discussed.