Occupational exposure limits for manufactured nanomaterials, a systematic review

The toxicological properties of manufactured nanomaterials (MNMs) can be different from their bulk-material and uncertainty remains about the adverse health effects they may have on humans. Proposals for OELs have been put forward which can be useful for risk management and workers' protection. We performed a systematic review of proposals for OELs for MNMs to better understand the extent of such proposals, as well as their derivation methods. We searched PubMed and Embase with an extensive search string and also assessed the references in the included studies. Two authors extracted the data independently. We identified 20 studies that proposed in total 56 OEL values. Of these, two proposed a generic level for all MNMs, 14 proposed a generic OEL for a category of MNMs and 40 proposed an OEL for a specific nanomaterial. For specific fibers, four studies proposed a similar value but for carbon nanotubes (CNTs) the values differed with a factor ranging from 30 to 50 and for metals with a factor from 100 to 300. The studies did not provide explanations for this variation. We found that exposure to MNMs measured at selected workplaces may exceed even the highest proposed OEL. This indicates that the application and use of OELs may be useful for exposure reduction. OELs can provide a valuable reference point for exposure reduction measures in workplaces. There is a need for more and better supported OELs based on a more systematic approach to OEL derivation

Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death

Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM) are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins) is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1′ triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×104 M−1s−1. SERPINB4 abolished cleavage of the macromolecular GrM substrates α-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death

Connective tissue growth factor and the cicatrization of cellular crescents in ANCA-associated glomerulonephritis

BACKGROUND: Outcome in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN) is difficult to predict. Scoring of renal biopsies has significant but limited predictive value. We investigated whether analysis of plasma and urine levels, and immunostaining of biopsies for the pro-fibrotic peptide connective tissue growth factor (CTGF), might improve prediction of renal outcome. METHODS: ANCA-positive patients were included. Renal biopsies were classified according to the AGN classification. Biopsies were stained for CTGF protein. CTGF was measured by ELISA at the time of renal biopsy in plasma and urine, and during follow-up in plasma. RESULTS: Eighty-two patients were included. CTGF staining was positive in crescentic lesions. Plasma CTGF at the time of renal biopsy was 2.4 ± 1.7 pmol/mL when compared with 0.5 ± 0.0 pmol/mL in healthy controls (P < 0.01). Plasma CTGF was associated with cellular crescents, but not when corrected for renal function. Plasma CTGF at baseline was associated with fibrous crescents in the follow-up biopsy, also after correction for renal function. Plasma CTGF at baseline predicted renal survival more accurately than the AGN classification. CONCLUSION: In AGN patients, CTGF was overexpressed in crescentic glomeruli. Baseline plasma CTGF predicted the percentage of fibrous crescents in later biopsies, and renal survival, suggesting that CTGF is involved in the cicatrization, as opposed to resolution of cellular crescents in AGN

NanoLINEN: Nanotoxicology Link Between India and European Nations

Nanotoxicology link between India and European Nations (NanoLINEN) is a consortium of 7 European laboratories and Indian Institute of Toxicology Research (CSIR Laboratory) from India to strengthen the research ties in the area of Nanomaterial Toxicology. The goal of this project is to develop robust risk assessment methodologies that will be useful for the community manufacturing and using nano-products