This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component‐based approaches. Specific considerations are given to component‐based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.
Combined liquid chromatography-mass spectrometry using electrospray or atmospheric-pressure chemical ionization has become an important tool in the quantitative analysis of pesticide residues in various matrices in relation to environmental analysis, food safety, and biological exposure monitoring. One of the major problems in the quantitative analysis using LC-MS is that compound and matrix-dependent response suppression or enhancement may occur, the so-called matrix effect. This article reviews issues related to matrix effects, focusing on quantitative pesticide analysis, but also paying attention to expertise with respect to matrix effects acquired in other application areas of LC-MS, especially quantitative bioanalysis in the course of drug development.
A method for the simultaneous determination of several classes of aldehydes in exhaled breath condensate (EBC) was developed using liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (LC/APCI-MS/MS). EBC is a biological matrix obtained by a relatively new, simple and noninvasive technique and provides an indirect assessment of pulmonary status. The measurement of aldehydes in EBC represents a biomarker of the effect of oxidative stress caused by smoke, disease, or strong oxidants like ozone. Malondialdehyde (MDA), acrolein, α,β-unsaturated hydroxylated aldehydes [namely 4-hydroxyhexenal (4-HHE) and 4-hydroxynonenal (4-HNE)], and saturated aldehydes (n-hexanal, n-heptanal and n-nonanal) were measured in EBC after derivatization with 2,4-dinitrophenylhydrazine (DNPH). Atmospheric pressure chemical ionization of the analytes was obtained in positiveion mode for MDA, and in negativeion mode for acrolein, 4-HHE, 4-HNE, and saturated aldehydes. DNPH derivatives were separated on a C18 column using variable proportions of 20 mM aqueous acetic acid and methanol. Linearity was established over 4-5 orders of magnitude and limits of detection were in the 0.3-1.0 nM range. Intra-day and inter-day precision were in the 1.3-9.9% range for all the compounds. MDA, acrolein and n-alkanals were detectable in all EBC samples, whereas the highly reactive 4-HHE and 4-HNE were found in only a few samples. Statistically significant higher concentrations of MDA, acrolein and n-hexanal were found in EBC from smokers.Production of reactive oxygen species (ROS) contributes to oxidation of cell macromolecules, e.g. lipids, DNA and proteins, leading to a variety of products 1 including alkanes, aldehydes, oxidated nucleotides and oxidated amino acids. Among the mechanisms of free radical damage, lipid peroxidation is probably the most extensively investigated process. ROS oxidation of cell membrane phospholipids produces chain reactions whose targets are the (poly)unsaturated fatty acids (P)UFA esterified in the sn-1 and sn-2 glyceride positions, and results in the formation of unstable lipid hydroperoxides and of secondary carbonyl compounds such as aldehydic products. Oxidative stress plays an important role in pathobiology of the lung due to its large exchange surface with oxygen and with environmental pollutants contaminating Among the products of lipid peroxidation, malondial-dehyde (MDA) is commonly used as a marker of oxidative stress. 3 It has been determined in several biological matrices 3 including plasma, 4-6 serum, 7 urine, 5 bronchoalveolar lavage (BAL) fluid, 7 expired breath condensate, 8 and tissues, 9 as well as in lipid-rich foods. 10 Its colorimetric determination after reaction with 2-thiobarbituric acid (the so-called TBARS assay) has been criticized because of the nonspecifi-city of the TBARS reaction. 11,12 Therefore, several analytical methods have proposed the use of chromatographic techniques coupled with sensitive detectors. 13,14 Besides MDA, some α,β-unsaturated aldeh...
The aims of the present study were (1) to evaluate whether individual aldehydes resulting from lipid peroxidation can be measured in exhaled breath condensate, (2) to assess the influence of sampling procedures on aldehyde concentrations, and (3) to compare aldehyde levels of patients with stable, moderate to severe, chronic obstructive pulmonary disease with those of smoking and nonsmoking control subjects. Aldehydes (malondialdehyde, hexanal, heptanal, and nonanal) were measured by liquid chromatography-tandem mass spectrometry in all samples and overlapping results were obtained by different sampling procedures. Malondialdehyde (57.2 +/- 2.4 nmol/L), hexanal (63.5 +/- 4.4 nmol/L), and heptanal (26.6 +/- 3.9 nmol/L) were increased in patients as compared with nonsmoking control subjects (17.7 +/- 5.5 nmol/L, p < 0.0001; 14.2 +/- 3.5 nmol/L, p = 0.004; and 18.7 +/- 0.9 nmol/L, p = 0.002, respectively). Only malondialdehyde was increased in patients compared with smoking control subjects (35.6 +/- 4.0 nmol/L, p = 0.0007). In conclusion, different classes of aldehydes were identified in exhaled breath condensate of humans. Whereas all aldehydes but nonanal were lower in control subjects as compared with other groups, only malondialdehyde distinguished smoking control subjects from patients with chronic obstructive pulmonary disease and could be envisaged as a biomarker potentially useful to monitor the disease and its response to therapy.
Oxidative stress is implicated in the pathogenesis of asthma, and clinical studies show an imbalance in the level of oxidants to the level of antioxidants in subjects with asthma. Aldehydes and glutathione are examples of biomarkers of oxidant-induced damage and antioxidant status in asthma, respectively. In the study, we applied analytical techniques based on liquid chromatography for the assessment of aldehydes and glutathione in the exhaled breath condensate of children with asthma and in control subjects without asthma. Twelve subjects with asthma were evaluated at exacerbation and after 5 days of therapy with prednisone. At exacerbation, malondialdehyde levels were higher in patients with asthma (30.2 +/- 2.4 nM) than in control subjects (19.4 +/- 1.9 nM, p = 0.002) and were reduced after steroid therapy (18.5 +/- 1.6 nM, p = 0.001). At exacerbation, glutathione levels were lower in subjects with asthma (5.96 +/- 0.6 nM) than in control subjects (14.1 +/- 0.8 nM, p < 0.0001) and were increased after the therapy (8.44 +/- 1.2 nM, p = 0.04). Malondialdehyde and glutathione both in subjects with asthma and control subjects were negatively correlated (r = -0.5, p = 0.001). The study shows that aldehydes and glutathione are detectable in the exhaled breath condensate of children with asthma and healthy children and that their levels are modified during asthma exacerbation and after a 5-day course of therapy with oral prednisone.
A high quality eumelanin thin film featuring efficient reversibility of the water induced conductivity switch and high biocompatibility was obtained,viaammonia-induced solid state polymerization of a 5,6-dihydroxyindole thin film.
Aims: Urinary 8-oxo-7,8-dihydro-2¢-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical-and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject-and sample collection-related variables, as potential sources of variability. Results: Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs Kronos Science, Phoenix, Arizona. ANTIOXIDANTS & REDOX SIGNALINGVolume 18, Number 18, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ars.2012.4714 2377showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (r p 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). Innovation: This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. Conclusion: ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine-or SG-adjusted first morning samples are recommended.
Aberrant oxidative pathways of catecholamine neurotransmitters, i.e. dopamine and norepinephrine, are an important biochemical correlate of catecholaminergic neuron loss in some disabling neurodegenerative diseases of the elderly, notably Parkinson's disease. In an oxidative stress setting, under conditions of elevated lipid peroxidation, iron accumulation, impaired mitochondrial functioning and antioxidant depletion, catecholamines are oxidatively converted to the corresponding o-quinones, which may initiate a cascade of spontaneous reactions, including intramolecular cyclization, aminoethyl side chain fission and interaction with molecular targets. The overall outcome of the competing pathways may vary depending on contingent factors and the biochemical environment, and may include formation of nitrated derivatives, neuromelanin deposition, generation of chain fission products, conjugation with L-cysteine leading eventually to cytotoxic responses and altered cellular function. In addition, catecholamines may interact with products of lipid peroxidation and other species derived from oxidative breakdown of biomolecules, notably glyoxal and other aldehydes, leading e.g. to tetrahydroisoquinolines via Pictet-Spengler chemistry. After a brief introductory remark on oxidative stress biochemistry, the bulk of this review will deal with an overview of the basic chemical pathways of catecholamine oxidation, with special emphasis on the analogies and differences between the central neurotransmitters dopamine and norepinephrine. This chemistry will form the basis for a concise discussion of the latest advances in the mechanisms of catecholamine-associated neurotoxicity in neuronal degeneration.
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