Human variability in influx and efflux transporters in relation to uncertainty factors for chemical risk assessment

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Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e. L55M, Q192R, and C-108T) in subgroups from a range of geographical ancestry and PON1 activities in three probe substrates (paraoxon, diazoxon and phenyl acetate). Bayesian meta-analyses were performed to estimate variability distributions for PON1 activities and PON1-related uncertainty factors (UFs), while integrating quantifiable sources of inter-study, inter-phenotypic and inter-individual differences. Inter-phenotypic differences were quantified using the population with high PON1 activity as the reference group. Results from the meta-analyses provided PON1 variability distributions and these can be implemented in generic physiologically based kinetic models to develop quantitative in vitro in vivo extrapolation models. PON1-related UFs in the Caucasian population were above the default toxicokinetic UF of 3.16 for two specific genotypes namely −108CC using diazoxon as probe substrate and, −108CT, −108TT, 55MM and 192QQ using paraoxon as probe substrate. However, integration of PON1 genotypic frequencies and activity distributions showed that all UFs were within the default toxicokinetic UF. Quantitative inter-individual differences in PON1 activity are important for chemical risk assessment particularly with regards to the potential sensitivity to organophosphates' toxicity. Keywords: Human variability, PON1 activity, Polymorphism, Uncertainty facto

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Aluminum determination in biological fluids and dialysis concentrates via chelation with 8-hydroxyquinoline and solvent extraction/fluorimetry

We describe a simple, rapid, and sensitive fluorescence method for measurement of aluminum (Al) in human biological fluids, in dialysis solutions and in tap water, which uses 8-hydroxyquinoline for ion chelation. The fluorescence intensity Of the toluene-extracted metal chelate (excitation wavelength, 380 nm; emission wavelength, 504 nm) remains unchanged for over 48 h at room temperature. Fluorescence intensity is a linear function of the concentration of Al in the 2-1000 mu g/L range with detection limits of 0.7-2 mu g/L. A large excess of other ions normally found in biological fluids does not interfere in Al determination. The method developed was Successfully used in assaying Al in serum and urine of reference Subjects, in serum samples from patients undergoing long-term dialysis, and in dialysis solutions. Al concentrations, measured by this fluorimetric procedure, were compared with those obtained by Zeeman graphite-furnace atomic absorption spectrometry. A correlation coefficient of 0.98 was obtained. The proposed method could be used for routine analysis in clinical laboratories for accurate determination of aluminum in aqueous or biological fluids

Polyurethane foam chips combined with liquid chromatography in the determination of unmetabolized polycyclic aromatic hydrocarbons excreted in human urine

A method suitable for the determination of unmetabolized polycyclic aromatic hydrocarbons (PAHs) excreted at trace levels (ng/L) in human urine for the monitoring of exposure of the general population to PAH contamination was developed. PAHs were determined, after enrichment by solid-phase extraction on polyurethane foam (PUF) chips, by HPLC with fluorescence detection. Different parameters affecting analyte extraction to the PUF, including urine salting-out and organic additives, and optimization of conditions for clean-up and desorption have been investigated. Optimized conditions were 40 mL acidified urine sample, added with magnesium sulfate, tetrahydrofuran and a 2 cm(3) PUF chip, and extracted by shaking at 30 rpm for 1 h at ambient temperature. Desorption was performed, after a clean-up step with diluted sodium hydroxide, using a small amount of diethyl ether. The recovery of PAH congeners from spiked urines was &rt;90% in the 2-100 ng/L range; the detection limit was 0.1-0.5 ng/L, depending on the considered PAH congener; day-to-day precision, at 50 ng/L native PAH content, was CV= 10-20%. The proposed technique provides a simple, economical and effective procedure for the determination of trace amounts of unmetabolized PAHs excreted in human urine spot samples

Difficult hernia repair in the elderly : a particular case

A particular clinical case personally observed is described. On the basis of this case it is evaluated if it can be correct to implant a mesh in potentially contaminated areas, if preperitoneal repair is the best approach in recurrent or difficult hernia repair and if there are specific contraindications in operating elderly patients

Indicatori di esposizione a idrocarburi aromatici policiclici : il paradosso pirene-idrossipirene

Comparison between the inhaled dose of pyrene by non-smoking subjects exposed to urban airborne contamination and the daily urinary excretion of the main metabolite 1-hydroxypyrene highlights a quantitative inconsistency, since the amount of the metabolite is 10-50 times higher than the inhaled dose of the parent compound. It is suggested that the excessive amount of hydroxypyrene may derive from the slow release of pyrene strongly absorbed or chemically embedded in the carbon soot deposited over a lifetime in the lung alveoli of the subject

Il metabonoma e il metaboloma come indicatori di dose e di effetto nella moderna tossicologia industriale

This paper briefly describes the potential of the metabonomic/metabolomic approach in present-day industrial toxicology as a tool for studying the relationship that occupational stressors linked to changed working and living conditions can have on the health status of exposed workers

Assay of urinary alpha-fluoro-beta-alanine by gas chromatography-mass spectrometry for the biological monitoring of occupational exposure to 5-fluorouracil in oncology nurses and pharmacy technicians

The validation of an analytical method for the measurement of the unnatural amino acid alpha-fluoro-beta-alanine (AFBA), the main metabolite of the antineoplastic drug 5-fluorouracil (5FU), in urine for the biological monitoring of the exposure of hospital workers to the drug when preparing the therapeutical doses and administering to cancer patients is described. The method employed a two-step extractive derivatization of the analyte from urine to the N-trifluoroacety-n-butyl ester derivative and detection by selected-ion monitoring gas chromatography-mass spectrometry of structurally specific fragments. The limit of detection was 20 ng/mL with quantification accuracy better than +/-20% and precision (CV%) better than +/-20% in the range 0.020-10 microg/mL. Norleucine was used as the internal standard and the sample-to-sample analysis time was less than 15 min. The validated method has been applied to the biological monitoring of some hospital workers potentially exposed to 5FU and to matched control subjects. On a total number of 65 analyzed urine samples from control and exposed subjects, only three, obtained from exposed subjects, were found to be positive, with values of 20, 30 and 1150 ng/mL, respectively