Probing the mechanisms of electron capture dissociation mass spectrometry with nitrated peptides

Previously we have shown that the presence of 3-nitrotyrosine within a peptide sequence severely depletes the peptide backbone fragments typically observed following electron capture dissociation (ECD) mass spectrometry. Instead, ECD of nitrated peptides is characterised by abundant losses of small neutrals (hydroxyl radicals, water and ammonia). Here, we investigate the origin of ammonia loss by comparing the ECD behaviour of lysine- and arginine-containing nitrated peptides, and their N-acetylated counterparts, and nitrated peptides containing no basic amino acid residues. The results reveal that ammonia loss derives from the N-terminus of the peptides, however, the key finding of this work is the insight provided into the hierarchy of various proposed ECD mechanisms: the Utah-Washington mechanism, the electron predator mechanism and the Oslo mechanism

The 2005 World Health Organization Reevaluation of Human and Mammalian Toxic Equivalency Factors for Dioxins and Dioxin-Like Compounds

In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4′,5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3′,4,4′,5,5′-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4′-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic” TEFs for blood and adipose tissue and TEQ for body burde

Toxicological Profile of Ultrapure 2,2 ',3,4,4 ',5,5 '-Heptachlorbiphenyl (PCB 180) in Adult Rats

Peer reviewe

How aware is the public of the existence, characteristics and causes of language impairment in childhood and where have they heard about it? A European survey

Public awareness of language impairment in childhood (Developmental Language Disorder (DLD)) has been identified as an important determiner of research and clinical service delivery, yet studies directly assessing public awareness are lacking. This study surveyed awareness across 18 countries of Europe.Method: A questionnaire developed by an international team asked whether respondents had heard of language impairment affecting children, what they thought its manifestations and causes were and where they had heard of it. Respondents were also asked whether they had heard of autism, dyslexia, ADD/ADHD and speech disorder. The questionnaire was administered to members of the public in 18 European countries. A total of 1519 responses were obtained, spanning 6 age groups, 4 educational level groups and 3 income level groups.Results: Across all but one country, significantly fewer people had heard of language impairment than any of the other disorders (or 60 % compared to over 90 % for autism). Awareness tended to be lowest in Eastern Europe and greatest in North-Western Europe, and was influenced by education level, age and income level. People in countries with overall low and overall high awareness differed in their views on manifestations and causes. People had heard of language impairment and autism the same way - most frequently through the media, including Internet, and less frequently through their child’s school or a medical professional.Discussion: The study confirms that awareness of language impairment and knowledge of the breadth of its manifestations are low. It also suggests opportunities for how to increase awareness, including greater media coverage of language impairment and more efficient use of venues such as schools and healthcare. Ways in which cultural and linguistic differences may influence public awareness efforts are discussed, including the translatability of clinical labels and scientific terms. These may impact the acceptance of a common term and definition across all countries. As awareness campaigns are gaining momentum, the findings of this study can serve as a baseline against which to compare future findings.peer-reviewe

Regulatory needs and activities to address the retinoid system in the context of endocrine disruption; the European viewpoint

Endocrine disruption continues to be a matter of high concern, and a subject of intensive activities at the public, political, regulatory and academic levels. Currently, available regulatory test guidelines (TGs) relevant to the identification of endocrine disrupters are largely limited to estrogen, androgen, thyroid and steroidogenesis (EATS) pathways. Thus, there is an increasing interest and need to develop test methods, biomarkers, and Adverse Outcome Pathways (AOPs), for identification and evaluation of endocrine disrupters in addition to the EATS pathways. An activity has been initiated by the Swedish chemical authorities and the European Commission focusing on the retinoid system. The retinoid system is involved in fundamental life processes, and has been described, in previous work at the OECD, as a system susceptible to environmental endocrine disruption the disruption of which could contribute to the increasing incidence of certain disorders in humans and wildlife populations.JRC.F.3-Chemicals Safety and Alternative Method