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http://kth.diva-portal.org/smash/resultList.jsf?query=&language=en&searchType=SIMPLE&noOfRows=50&sortOrder=author_sort_asc&sortOrder2=title_sort_asc&onlyFullText=false&sf=all&aq=%5B%5B%7B%22categoryId%22%3A%2211652%22%7D%5D%5D&aqe=%5B%5D&aq2=%5B%5B%5D%5D&af=%5B%5D
Arvidsson, M.
Karolinska Inst, Dept Lab Med, Stockholm, Sweden..
Dahl, M. -L
Beck, O.
Rosenborg, S.
Nordin, K.
Karolinska Univ Hosp, Stockholm, Sweden..
Lenk, Gabriel
KTH, School of Electrical Engineering and Computer Science (EECS), Micro and Nanosystems.
Pharmacokinetics of methylphenidate in plasma, exhaled breath, oral fluid and dried blood spots after a single oral dose of ritalin 20 mg2019In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 75, p. S89-S90Article in journal (Other academic)
2. Awasthi, Saurabh
Murugan, N. Arul
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
Saraswathi, N. T.
Advanced Glycation End Products Modulate Structure and Drug Binding Properties of Albumin2015In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 12, no 9, p. 3312-3322Article in journal (Refereed)
The extraordinary ligand binding properties of albumin makes it a key player in the pharmacokinetics and pharmacodynamics of many vital drugs. Albumin is highly susceptible for nonenzymatic glycation mediated structural modifications, and there is a need to determine structural and functional impact of specific AGEs modifications. The present study was aimed toward determining the AGE mediated structure and function changes, primarily looking into the effect on binding affinity of drugs in the two major drug binding sites of albumin. The impact of the two most predominant AGEs modifications, i.e., carboxyethyllysine (CEL) and argpyrimidine (Arg-P), was studied on the basis of the combination of in vitro and in silico experiments. In vitro studies were carried out by AGEs modification of bovine serum albumin (BSA) for the formation of Arg-P and CEL followed by drug interaction studies. In silico studies involved molecular dynamics (MD) simulations and docking studies for native and AGEs modified BSAs. In particular the side chain modification was specifically carried out for the residues in the drug binding sites, i.e., Arg-194, Arg-196, Arg-198, and Arg-217, and Lys-204 (site I) and Arg-409 and Lys-413 (site II). The equilibrated structures of native BSA (n-BSA) and glycated BSA (G-BSA) as obtained from MD were used for drug binding studies using molecular docking approach. It was evident from the results of both in vitro and in silico drug interaction studies that AGEs modification results in the reduced drug binding affinity for tolbutamide (TLB) and ibuprofen (IBP) in sites I and II. Moreover, the AGEs modification mediated conformational changes resulted in the shallow binding pockets with reduced accessibility for drugs.
Badal Tejedor, Maria
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science. RISE Research Intitutes of Sweden.
Pazesh, Samaneh
Nordgren, Niklas
Schuleit, Michael
Rutland, Mark W.
Alderborn, Göran
Millqvist-Fureby, Anna
Milling induced amorphisation andrecrystallization of α-lactose monohydrate2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 537, no 1-2, p. 140-147Article in journal (Refereed)
Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the alpha-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed alpha-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between un-processed a-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spraydried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.
4. Bergmann, Troels K.
Brasch-Andersen, Charlotte
Gréen, Henrik
KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
Mirza, Mansoor R.
Skougaard, Kristin
Wihl, Jessica
Keldsen, Nina
Damkier, Per
Peterson, Curt
Vach, Werner
Brosen, Kim
Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer2012In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 110, no 2, p. 199-204Article in journal (Refereed)
The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T /A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.
5. Beronius, A.
Rudén, Christina
KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
Hanberg, A.
Improving the transparency of data evaluation in risk assessment of endocrine disrupting compounds-Implications from the bisphenol A case study2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, p. S256-S256Article in journal (Other academic)
The complex biology and toxicology of endocrine disrupting compounds (EDCs) makes toxicity testing as well as evaluation of data for risk assessment difficult. Standardized test guidelines have previously been questioned as to their applicability for evaluating EDC toxicity. However, several guidelines have been updated and enhanced in an effort to better cover EDCs. Also, EDC toxicity is a very active research field and a lot of toxicological data are generated in research studies NOT conducted according to standardized guidelines. Our previous work indicates that differences in how the reliability and relevance of toxicity studies are judged may vary greatly between risk assessments of the same compound and may result in different conclusions about the size and nature of health risks. Further, the process of data evaluation is in many cases in-transparent. The purpose of this on-going study is to contribute to making health risk assessments of EDCs more transparent, systematic, and predictable. The investigation is conducted as a literature study using the EDC bisphenol A (BPA) for a case study. We scrutinize and compare the strengths and weaknesses of both guideline and non-guideline studies evaluating developmental neurotoxicity of BPA. One goal is to further assess the applicability of standardized guidelines in this case. Another aim is to propose improvements in the process of data reporting of non-guideline studies and recommend criteria for the evaluation of data in order to facilitate risk assessment of EDCs.
Beronius, Anna
Karolinska Inst, Stockholm, Sweden.
Willighagen, Egon
Maastricht Univ, Maastricht, Netherlands .
Hanberg, Annika
Factors influencing developmental neurotoxicity study outcome in the bisphenol A case2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S128-S129Article in journal (Other academic)
7. Bosley, Jim
Borén, Christofer
Lee, Sunjae
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
Grotli, Morten
Nielsen, Jens
KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
Uhlén, Mathias
Boren, Jan
Mardinoglu, Adil
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
Improving the economics of NASH/NAFLD treatment through the use of systems biology2017In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 22, no 10, p. 1532-1538Article, review/survey (Refereed)
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH. We discuss the potential broader use of genome-scale metabolic models and integrated networks in the validation of drug targets, which could facilitate more productive and efficient drug development decisions for the treatment of NASH.
8. Chaudhry, Qasim A.
Hanke, Michael
KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Numerical Analysis, NA.
Study of intracellular reaction and diffusion mechanism of carcinogenic PAHs: Using non-standard compartment modeling approach2013In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 221, p. S182-S182Article in journal (Other academic)
Chen, Shi-Lu
Marino, Tiziana
Fang, Wei-Hai
Himo, Fahmi
Russo, Nino
Peptide hydrolysis by aminopeptidase from Aeromonas proteolytica2007In: Drugs of the future, ISSN 0377-8282, E-ISSN 2013-0368, Vol. 32, p. 71-72Article in journal (Other academic)
Cronholm, Pontus
Karlsson, Hanna L.
Hedberg, Jonas
Lowe, Troy
Elihn, Karine
Stockholm Univ, Stockholm, Sweden .
Wallinder, Inger Odnevall
Möller, Lennart
A Trojan Horse type mechanism: Cellular dose and toxicity of Ag and CuO nanoparticles2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S201-S201Article in journal (Other academic)
Di Bucchianico, Sebastiano
Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
Gliga, Anda R.
Åkerlund, Emma
Skoglund, Sara
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
Odnevall Wallinder, Inger
Fadeel, Bengt
Calcium-dependent cyto- and genotoxicity of nickel metal and nickel oxide nanoparticles in human lung cells2018In: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 15, article id 32 Article in journal (Refereed)
Background: Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. Therefore, an increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The aim of this study was to perform an in-depth investigation regarding the genotoxicity of well-characterized Ni and NiO NPs in human bronchial epithelial BEAS-2B cells and to discern possible mechanisms. Comparisons were made with NiCl2 in order to elucidate effects of ionic Ni. Methods: BEAS-2B cells were exposed to Ni and NiO NPs, as well as NiCl2, and uptake and cellular dose were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS). The NPs were characterized in terms of surface composition (X-ray photoelectron spectroscopy), agglomeration (photon cross correlation spectroscopy) and nickel release in cell medium (ICP-MS). Cell death (necrosis/apoptosis) was investigated by Annexin VFITC/PI staining and genotoxicity by cytokinesis-block micronucleus (cytome) assay (OECD 487), chromosomal aberration (OECD 473) and comet assay. The involvement of intracellular reactive oxygen species (ROS) and calcium was explored using the fluorescent probes, DCFH-DA and Fluo-4. Results: NPs were efficiently taken up by the BEAS-2B cells. In contrast, no or minor uptake was observed for ionic Ni from NiCl2. Despite differences in uptake, all exposures (NiO, Ni NPs and NiCl2) caused chromosomal damage. Furthermore, NiO NPs were most potent in causing DNA strand breaks and generating intracellular ROS. An increase in intracellular calcium was observed and modulation of intracellular calcium by using inhibitors and chelators clearly prevented the chromosomal damage. Chelation of iron also protected against induced damage, particularly for NiO and NiCl2. Conclusions: This study has revealed chromosomal damage by Ni and NiO NPs as well as Ni ionic species and provides novel evidence for a calcium-dependent mechanism of cyto- and genotoxicity.
Ding, Qian
Schenk, Linda
Malkiewicz, Katarzyna
Hansson, Sven Ove
A comparison of occupational exposure limits in Asia and Europe2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, p. S241-S241Article in journal (Other academic)
Occupational exposure limits (OELs) are used as a risk management tool aiming at protecting against negative health effects due to occupational exposure to harmful substances. The systems of OELs development have not been standardized and the divergent outcomes have been reported. However some harmonization process has been initiated, primary in Europe. This study aims at analysis of the state of harmonization in a more global context. The OELs systems of eight Asian and seventeen European organizations are analyzed with respect to: (1) the information regarding each organization's system for determining OELs; (2) similarity of substance selection in each system; (3) similarity of value levels of OEL. The analysis shows that the majority of investigated organizations declare to be influenced by the American Conference of Governmental Industrial Hygienists (ACGIH) systems, what in many cases is empirically confirmed. The EU harmonization process is also reflected in results showing the trends of convergence within the EU. However, the comparisons of Asian and European organisations indicate that there is no obvious evidence that OELs are becoming globally harmonized.
Dreij, Kristian
Karolinska Inst, Stockholm, Sweden .
Chaudhry, Qasim A.
KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA.
Zhang, Jie
Sundberg, Kathrin
Jernström, Bengt
Morgenstern, Ralf
In silico modeling of the intracellular dynamics of polycyclic aromatic hydrocarbons2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S60-S61Article in journal (Other academic)
14. El-Seedi, Hesham R.
El-Shabasy, Rehan
Sakr, Hanem
Zayed, Mervat
El-Said, Asmaa M. A.
Helmy, Khalid M. H.
Gaara, Ahmed H. M.
Turki, Zaki
Azeem, Muhammad
Ahmed, Ahmed M.
Boulos, Loutfy
Borg-Karlson, Anna-Karin
Göransson, Ulf
Anti-schistosomiasis triterpene glycoside from the Egyptian medicinal plant Asparagus stipularis2011In: REV BRAS FARMACOGN, ISSN 0102-695X, Vol. 22, no 2, p. 314-318Article in journal (Refereed)
Bioassay-guided isolation using an in vitro assay testing for anti-schistosomiasis yielded a novel triterpene saponin, asparagalin A, from the n-butanol extract of the roots of Asparagus stipularis Forssk., Asparagaceae. The structure was elucidated by spectroscopic analysis and chemical transformations. Administration of asparagalin A resulted in a retardation of worm growth and locomotion at the first day and showed a significant activity of egg-laying suppression at 200 mu g/mL concentration.
15. Fonteyne, Margot
Correia, Ana
De Plecker, Sofie
Vercruysse, Jurgen
Ilic, Ilija
Veryaet, Chris
Remon, Jean Paul
Onofre, Fernanda
De Beer, Thomas
Impact of microcrystalline cellulose material attributes: A case study on continuous twin screw granulation2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 478, no 2, p. 705-717Article in journal (Refereed)
The International Conference on Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of material attributes, manufacturing process options and process parameters. The present case study evaluates the effect of unspecified variability of raw material properties upon the quality attributes of granules; produced using a continuous from-powder-to-tablet wet granulation line (ConsiGma (TM) 25). The impact of different material attributes of six samples of microcrystalline cellulose (MCC) was investigated. During a blind study the different samples of MCC were used separately and the resulting granules were evaluated in order to identify the differences between the six samples. Variation in size distribution due to varying water binding capacity of the MCC samples was observed. The cause of this different water binding capacity was investigated and was caused by a different degree of crystallinity. Afterwards, an experimental design was conducted in order to evaluate the effect of both product and process variability upon the granule size distribution. This model was used in order to calculate the required process parameters to obtain a preset granule size distribution regardless of the type of MCC used. The difference in water binding capacity and its effect on granular properties was still present when combining the MCC grades with different binders.
Green, Henrik
Khan, Muhammad Suleman
Jakobsen-Falk, Ingrid
Avall-Lundqvist, Elisabeth
Impact of CYP3A5(*)3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer2011In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 10, p. 4205-4209Article in journal (Refereed)
The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8(*)3, CYP2C8-HapC, and CYP3A5(*)3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5(*)3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than patients with the wild-type genotype. CYP3A5(*)3/(*)1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than (*)3/(*)3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.
17. Grondin, Yohann
Cotanche, Douglas A
Manneberg, Otto
Molina, Ramon
Treviño-Villarreal, J Humberto
Sepulveda, Rosalinda
Clifford, Royce
Bortoni, Magda E
Forsberg, Scott
Labrecque, Brian
Altshul, Larisa
Brain, Joseph D
Jackson, Ronald L
Rogers, Rick A
Pulmonary delivery of d-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids.2013In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 298, p. 93-103Article in journal (Refereed)
In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as d-methionine (d-met) and acetyl-l-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [C]d-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after d-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, d-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [C]d-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of d-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment.
Gu, Chungang
AstraZeneca, R&D Boston, Waltham, MA USA.;AstraZeneca, R&D Wilmington, Wilmington, DE USA..
Lewis, Richard J.
AstraZeneca, R&D Molndal, Molndal, Sweden.;AstraZeneca, R&D Charnwood, Loughborough, Leics, England..
Wells, Andrew S.
AstraZeneca, R&D Charnwood, Loughborough, Leics, England..
Svensson, Per H.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry. AstraZeneca, R&D Sodertalje, Sodertalje, Sweden.
Hosagrahara, Vinayak P.
AstraZeneca, R&D Boston, Waltham, MA USA..
Johnsson, Eskil
AstraZeneca, R&D Molndal, Molndal, Sweden.;AstraZeneca, R&D Lund, Lund, Sweden..
Hallstrom, Gosta
AstraZeneca, R&D Lund, Lund, Sweden..
Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples2015In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 43, no 10, p. 1441-1449Article in journal (Refereed)
This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl) phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an O-18 atom from molecular O-18(2) to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or L-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.
Gupta, G. S.
Karolinska Inst, Inst Environm Med, Div Mol Toxicol, Stockholm, Sweden..
Gliga, A.
Serra, A.
Univ Tampere, Inst Biosci & Med Technol, Tampere, Finland.;Univ Helsinki, Inst Biotechnol, Helsinki, Finland..
Greco, D.
Fadeel, B.
Cobalt-impregnated tungsten nanoparticles and cobalt ions trigger toxicity in differentiating neuronal cells: potential link to parkinsonian neurodegeneration2019In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 314, p. S201-S202Article in journal (Other academic)
Philosophy and History, KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
KTH, School of Architecture and the Built Environment (ABE), Philosophy and History.
Assessment factors for extrapolation from short-time to chronic exposure-Are the REACH guidelines adequate2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 189, p. S243-S243Article in journal (Other academic)
Molander, Linda
The substitution principle2011In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 59, no 3, p. 454-460Article in journal (Refereed)
According to the substitution principle, hazardous chemicals should be replaced by less hazardous alternatives. In this paper, the major issues concerning the more precise definition of the principle are analyzed, and a general purpose definition is proposed. It is claimed that the priority between reducing hazard, functionality and economical considerations in the application of the substitution principle is a matter for adjustment in each particular case that cannot be settled beforehand. None of these objectives can have absolute priority over the others, but the substitution principle is aimed at increasing the priority given to the reduction of hazards to human health and the environment. Major methods to promote and implement the principle are summarized, current legislative approaches are discussed, and proposals for efficient implementation are made. It is emphasized that the primary responsibility for avoiding hazardous substances and processes rests with industry.
Hedberg, Yolanda
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science. Karolinska Institutet, Sweden.
Herting, Gunilla
Latvala, S.
Elihn, K.
Karlsson, H. L.
Surface passivity largely governs the bioaccessibility of nickel-based powder particles at human exposure conditions2016In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 81, p. 162-170Article in journal (Refereed)
The European chemical framework REACH requires that hazards and risks posed by chemicals, including alloys and metals, are identified and proven safe for humans and the environment. Therefore, differences in bioaccessibility in terms of released metals in synthetic biological fluids (different pH (1.5–7.4) and composition) that are relevant for different human exposure routes (inhalation, ingestion, and dermal contact) have been assessed for powder particles of an alloy containing high levels of nickel (Inconel 718, 57 wt% nickel). This powder is compared with the bioaccessibility of two nickel-containing stainless steel powders (AISI 316L, 10–12% nickel) and with powders representing their main pure alloy constituents: two nickel metal powders (100% nickel), two iron metal powders and two chromium metal powders. X-ray photoelectron spectroscopy, microscopy, light scattering, and nitrogen absorption were employed for the particle and surface oxide characterization. Atomic absorption spectroscopy was used to quantify released amounts of metals in solution. Cytotoxicity (Alamar blue assay) and DNA damage (comet assay) of the Inconel powder were assessed following exposure of the human lung cell line A549, as well as its ability to generate reactive oxygen species (DCFH-DA assay). Despite its high nickel content, the Inconel alloy powder did not release any significant amounts of metals and did not induce any toxic response. It is concluded, that this is related to the high surface passivity of the Inconel powder governed by its chromium-rich surface oxide. Read-across from the pure metal constituents is hence not recommended either for this or any other passive alloy.
Stockmann-Juvala, Helene Helene
Finnish Inst Occupat Hlth, Helsinki, Finland .
Zitting, Antti
Santonen, Tiina
Relevance of in vitro studies for in vivo inhalation toxicity of 316L powder2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S125-S125Article in journal (Other academic)
24. Henderson, Rayetta G.
Verougstraete, Violaine
Anderson, Kim
Arbildua, Jose J.
Brock, Thomas O.
Brouwers, Tony
Cappellini, Danielle
Delbeke, Katrien
Hixon, Greg
Rodriguez, Patricio H.
Van Assche, Frank
Wilrich, Peter
Oller, Adriana R.
Inter-laboratory validation of bioaccessibility testing for metals2014In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 70, no 1, p. 170-181Article in journal (Refereed)
Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intra- and inter-laboratory variability in bioaccessibility data generated by bioelution tests were evaluated in synthetic fluids relevant to oral, inhalation, and dermal exposure. Using one defined protocol, five laboratories measured metal release from cobalt oxide, cobalt powder, copper concentrate, Inconel alloy, leaded brass alloy, and nickel sulfate hexahydrate. Standard deviations of repeatability (S-r) and reproducibility (S-R) were used to evaluate the intra- and inter-laboratory variability, respectively. Examination of the s(R):s(r) ratios demonstrated that, while gastric and lysosomal fluids had reasonably good reproducibility, other fluids did not show as good concordance between laboratories. Relative standard deviation (RSD) analysis showed more favorable reproducibility outcomes for some data sets; overall results varied more between- than within-laboratories. RSD analysis of s(r) showed good within-laboratory variability for all conditions except some metals in interstitial fluid. In general, these findings indicate that absolute bioaccessibility results in some biological fluids may vary between different laboratories. However, for most applications, measures of relative bioaccessibility are needed, diminishing the requirement for high inter-laboratory reproducibility in absolute metal releases. The inter-laboratory exercise suggests that the degrees of freedom within the protocol need to be addressed.
25. Huuskonen, Sirpa
Heinala, Milla
Human health risk assessment of ferrosilicon alloys under REACH2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S178-S178Article in journal (Other academic)
26. Johansson, Mia K. V.
Johanson, Gunnar
Öberg, Mattias
Does industry take the susceptible subpopulation of asthmatic individuals into consideration when setting derived no-effect levels?2016In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 36, no 11, p. 1379-1391Article in journal (Refereed)
Asthma, a chronic respiratory disease, can be aggravated by exposure to certain chemical irritants. The objectives were first to investigate the extent to which experimental observations on asthmatic subjects are taken into consideration in connection with the registration process under the EU REACH regulation, and second, to determine whether asthmatics are provided adequate protection by the derived no-effect levels (DNELs) for acute inhalation exposure. We identified substances for which experimental data on the pulmonary functions of asthmatics exposed to chemicals under controlled conditions are available. The effect concentrations were then compared with DNELs and other guideline and limit values. As of April 2015, only 2.6% of 269 classified irritants had available experimental data on asthmatics. Fourteen of the 22 identified substances with available data were fully registered under REACH and we retrieved 114 reliable studies related to these. Sixty-three of these studies, involving nine of the 14 substances, were cited by the REACH registrants. However, only 17 of the 114 studies, involving four substances, were regarded as key studies. Furthermore, many of the DNELs for acute inhalation were higher than estimated effect levels for asthmatics, i.e., lowest observed adverse effect concentrations or no-observed adverse effect concentrations, indicating low or no safety margin. We conclude that REACH registrants tend to disregard findings on asthmatics when deriving these DNELs. In addition, we found examples of DNELs, particularly among those derived for workers, which likely do not provide adequate protection for asthmatics. Copyright (c) 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd. We investigate the extent to which experimental observations on asthmatic subjects are taken into consideration by REACH registrants and determine whether asthmatics are provided adequate protection by the acute inhalation Derived No-Effect Levels. Of 114 studies concerning 14 substances fulfilling our inclusion criteria, 63 studies, involving nine substances, were cited by the REACH registrants. However, only 17 of the 114 studies, involving four substances, were regarded as key studies. Furthermore, many of the Derived No-Effect Levels were higher than Lowest- or No-Observed Adverse Effect Concentrations values from these studies.
27. Karlsson, Hanna L.
Tornberg, Malin
De Battice, Laura
Svedhem, Sofia
Cell membrane damage and protein interaction induced by copper containing nanoparticles-Importance of the metal release process2013In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 313, no 1, p. 59-69Article in journal (Refereed)
Cu-containing nanoparticles are used in various applications in order to e.g. achieve antimicrobial activities and to increase the conductivity of fluids and polymers. Several studies have reported on toxic effects of such particles but the mechanisms are not completely clear. The aim of this study was to investigate the interactions between cell membranes and well-characterized nanoparticles of CuO, Cu metal, a binary Cu-Zn alloy and micron-sized Cu metal particles. This was conducted via in vitro investigations of the effects of the nanoparticles on (i) cell membrane damage on lung epithelial cells (A549), (ii) membrane rupture of red blood cells (hemolysis), complemented by (iii) nanoparticle interaction studies with a model lipid membrane using quartz crystal microbalance with dissipation monitoring (QCM-D). The results revealed that nanoparticles of the Cu metal and the Cu-Zn alloy were both highly membrane damaging and caused a rapid (within 1 h) increase in membrane damage at a particle mass dose of 20 mu g/mL, whereas the CuO nanoparticles and the micron-sized Cu metal particles showed no such effect. At similar nanoparticle surface area doses, the nano and micron-sized Cu particles showed more similar effects. The commonly used LDH (lactate dehydrogenase) assay for analysis of membrane damage was found impossible to use due to nanoparticle-assay interactions. None of the particles induced any hemolytic effects on red blood cells when investigated up to high particle concentrations (1 mg/mL). However, both Cu and Cu-Zn nanopartides caused hemoglobin aggregation/precipitation, a process that would conceal a possible hemolytic effect. Studies on interactions between the nanoparticles and a model membrane using QCM-D indicated a small difference between the investigated particles. Results of this study suggest that the observed membrane damage is caused by the metal release process at the cell membrane surface and highlight differences in reactivity between metallic nanoparticles of Cu and Cu-Zn and nanoparticles of CuO.
Lebedova, Jana
Karolinska Inst, Inst Environm Med, Nobels Vag 13, S-17177 Stockholm, Sweden.;Masaryk Univ, RECETOX, Kamenice 753-5,Pavilon A29, CZ-62500 Brno, Czech Republic..
Karolinska Inst, Inst Environm Med, Nobels Vag 13, S-17177 Stockholm, Sweden..
Size-dependent genotoxicity of silver, gold and platinum nanoparticles studied using the mini-gel comet assay and micronucleus scoring with flow cytometry2018In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 33, no 1, p. 77-85Article in journal (Refereed)
Metallic nanoparticles (NPs) are promising nanomaterials used in different technological solutions as well as in consumer products. Silver (Ag), gold (Au) and platinum (Pt) represent three metallic NPs with current or suggested use in different applications. Pt is also used as vehicle exhaust catalyst leading to a possible exposure via inhalation. Despite their use, there is limited data on their genotoxic potential and possible size-dependent effects, particularly for Pt NPs. The aim of this study was to explore size-dependent genotoxicity of these NPs (5 and 50 nm) following exposure of human bronchial epithelial cells. We characterised the NPs and assessed the viability (Alamar blue assay), formation of DNA strand breaks (mini-gel comet assay) and induction of micronucleus (MN) analysed using flow cytometry (in vitro microflow kit). The results confirmed the primary size (5 and 50 nm) but showed agglomeration of all NPs in the serum free medium used. Slight reduced cell viability (tested up to 50 mu g/ml) was observed following exposure to the Ag NPs of both particle sizes as well as to the smallest (5 nm) Au NPs. Similarly, at non-cytotoxic concentrations, both 5 and 50 nm-sized Ag NPs, as well as 5 nm-sized Au NPs, increased DNA strand breaks whereas for Pt NPs only the 50 nm size caused a slight increase in DNA damage. No clear induction of MN was observed in any of the doses tested (up to 20 mu g/ml). Taken together, by using the comet assay our study shows DNA strand breaks induced by Ag NPs, without any obvious differences in size, whereas effects from Au and Pt NPs were size-dependent in the sense that the 5 nm-sized Au NPs and 50 nm-sized Pt NPs particles were active. No clear induction of MN was observed for the NPs.
29. Lobmann, Korbinian
Svagan, Anna J.
Cellulose nanofibers as excipient for the delivery of poorly soluble drugs2017In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 533, no 1, p. 285-297Article in journal (Refereed)
Poor aqueous solubility of drugs is becoming an increasingly pronounced challenge in the formulation and development of drug delivery systems. To overcome the limitations associated with these problematic drugs, formulation scientists are required to use enabling strategies which often demands the use of new excipients. Cellulose nanofibers (CNFs) is such an excipient and it has only recently been described in the pharmaceutical field. In this review, the use of CNF in drug formulation with a focus on poorly soluble drugs is featured. In particular, the aim is to describe and discuss the many unique properties of CNFs, which make CNFs attractive as excipients in pharmaceutical sciences. Furthermore, the use of CNF as stabilizers for crystalline drug nanoparticles, as a matrix former to obtain a long-lasting sustained drug release over several weeks and as a film former with immediate release properties for poorly soluble drug are reported. Finally, the preparation of pharmaceutical CNF foams together with poorly soluble drugs is highlighted; foams, which offer a sustained drug delivery system with positive buoyancy.
Ma, Jianhui
Univ Calif San Diego, Ludwig Inst Canc Res, San Diego Branch, 9500 Gilman Dr, La Jolla, CA 92093 USA. i, Jie; Cavenee, Webster K.; Kolodner, Richard D.; Chen, Clark C.; Furnari, Frank B..
Benite, Jorge A.
Miki, Shunichiro
Albuquerqu, Claudio Ponte
Galatro, Thais
Orellana, Laura
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
Zanca, Ciro
Reed, Rachel
Boyer, Antonia
Koga, Tomoyuki
Varki, Nissi M.
Fenton, Tim R.
Marie, Suely Kazue Nagahashi
Lindahl, Erik
Gahman, Timothy C.
Shiau, Andrew K.
Zhou, Huilin
DeGroot, John
Sulman, Erik P.
Cavenee, Webster K.
Kolodner, Richard D.
Chen, Clark C.
Furnari, Frank B.
Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma diation Sensitivity through Attenuated DNA Repair2019In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, no 3, p. 504-518.e7Article in journal (Refereed)
Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.
Pettitt, M.
Dawson, K. A.
Lynch, I.
Lead, J.
Nanomaterials in reach2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, p. S45-S45Article in journal (Other academic)
Several critical differences between the "nano" forms of substances and their "bulk" counterparts may necessitate additional considerations in regulatory frameworks to adequately address potential risks posed by nanomaterials (NMs). The aim of this presentation is to address the problematics of assessing and managing risks of NMs by the means of EU chemicals regulation REACH (Registration, Evaluation, and Authorization of Chemicals). It is based on the results of the SKEP-ERA net project "Nanomaterials in REACH", which during year 2010 gathered international expertise on chemicals regulation, physico-chemical properties and toxicity of NMs, and environmental and technology policy. Analysis and discussion points cover following topics: definitions concerning nanomaterials, REACH provisions for registration of NMs as substances, and in articles (including "phase-in"/"non-phase-in" status, mass based tonnage thresholds, "prioritization" criteria, classification as hazardous, percentage thresholds in articles), substance identification, scope of data requirements, standardization and methodology for human and environmental hazards identification and risk characterisation. Examples of resulting recommendations include: (1) adopt a single overarching definition of NMs for regulatory purposes; (2) treat "nano" forms as different from their "bulk" counterparts and as "non-phase in" substances; (3) differentiate "nano" forms with the same core chemistry using differences in the physicochemical parameters; (4) introduce mandatory list of physicochemical properties for substance identification; (5) introduce alternatives to the tonnage triggers; (6) develop register of comprehensive information on the presence of NMs in articles; (7) extend a scope of data requirements with nano-specific data requirements; (8) develop nano-specific criteria for inclusion in the SVHC list.
32. Margeridon-Thermet, Severine
Svarovskaia, Evguenia S.
Babrzadeh, Farbod
Stanford Genome Technology Center, Stanford University, Stanford, CA, United States .
Martin, Ross
Liu, Tommy F.
Pacold, Mary
Reuman, Elizabeth C.
Holmes, Susan P.
Borroto-Esoda, Katyna
Low-Level Persistence of Drug Resistance Mutations in Hepatitis B Virus-Infected Subjects with a Past History of Lamivudine Treatment2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 1, p. 343-349Article in journal (Refereed)
We sought to determine the prevalence of hepatitis B virus (HBV) lamivudine (LAM)-resistant minority variants in subjects who once received LAM but had discontinued it prior to virus sampling. We performed direct PCR Sanger sequencing and ultradeep pyrosequencing (UDPS) of HBV reverse transcriptase (RT) of plasma viruses from 45 LAM-naive subjects and 46 LAM-experienced subjects who had discontinued LAM a median of 24 months earlier. UDPS was performed to a depth of similar to 3,000 reads per nucleotide. Minority variants were defined as differences from the Sanger sequence present in >= 0.5% of UDPS reads in a sample. Sanger sequencing identified >= 1 LAM resistance mutations (rtL80I/V, rtM204I, and rtA181T) in samples from 5 (11%) of 46 LAM-experienced and none of 45 LAM-naive subjects (0%; P = 0.06). UDPS detected >= 1 LAM resistance mutations (rtL80I/V, rtV173L, rtL180M, rtA181T, and rtM204I/V) in 10 (22%) of the 46 LAM-experienced subjects, including 5 in whom LAM resistance mutations were not identified by Sanger sequencing. Overall, LAM resistance mutations were more likely to be present in LAM-experienced (10/46, 22%) than LAM-naive subjects (0/45, 0%; P = 0.001). The median time since LAM discontinuation was 12.8 months in the 10 subjects with a LAM resistance mutation compared to 30.5 months in the 36 LAM-experienced subjects without a LAM resistance mutation (P < 0.001). The likelihood of detecting a LAM resistance mutation was significantly increased using UDPS compared to Sanger sequencing and was inversely associated with the time since LAM discontinuation.
Midander, Klara
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Corrosion Science (closed 20081231).
Bioaccessibility of nano- and micron-sized metallic particles in simulated lung systems2008Conference paper (Refereed)
Ambient airborne particles of varying size and composition, originating from anthropogenic and natural sources are today a recognized health risk in the society. The rapid development of engineered nanomaterials, including particles, is believed to become an issue of large concern. At present, few efforts have been made to investigate potential adverse health effects of nano- and micron sized metallic particles. Reliable data on surface properties and reactivity of metallic particles and its correlation to toxicity is scarce. Bioaccessibility data, in terms of metal release, is believed to reflect the toxic effects of metallic particles. The metal release process is influenced by particle size, i.e. surface area, shape and material type, e.g. passive/non-passive, pure/alloy/oxide as well as the exposure environment, e.g. within the lung. The assessment of potentially adverse health effects due to particles requires the correlation between toxic effects, bioaccessibility properties and surface characteristics. Within this context, the material aspects of metal release from Cu-particles were studied in-vitro by exposure in different synthetic biological media that simulate, to some extent, a realistic inhalation scenario. Particle toxicity in terms of DNA damage and cytotoxic effects was studied in collaboration with human toxicologists at Karolinska Institutet, and aerosol scientists at Stockholm University, using epithelial human lung cells.
Endpoints and dose-response relationships of low-dose studies of Bisphenol A2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S130-S130Article in journal (Other academic)
Breitholtz, M.
Missing links in the regulatory chain controlling life cycle emissions of hazardous chemicals from articles2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, p. S243-S243Article in journal (Other academic)
It is widely acknowledged that the management of risks associated with chemicals in articles, including consumer products, needs to be improved.
The purpose of the present study is to empirically analyze to what extent European legislations that control emissions of hazardous chemicals from articles during different life cycle phases are coherent or not. To illustrate this, the regulation of a number of case-study chemicals, used in various consumer products and in high volumes, is scrutinized. This analysis identifies missing regulatory links between the rules that are relevant for the use phase and the rules applicable to the waste phase. With the exception of the RoHS directive, a clear connection to the rules for waste is missing in the regulatory system. Clear links are also missing between the rules regulating chemical emissions during the articles' life cycle and maximum environmental concentration limits set for sludge, soil and surface water. The Waste Directive, the WEEE Directive, and the Water Framework Directive refer to EU environmental and waste policies. These policies state that environmental damage should be rectified at source. The lack of connection between the rules regulating different phases of an article's life cycle makes these objectives difficult to fulfill. These legislative gaps will encourage end-of-pipe solutions, rather than actions to manage the source of the problem. We argue that it is necessary to minimize the input of hazardous chemicals into articles, so that waste and other end-products can be recovered and used without harming human health or the environment.
Neus, Feliu Torres
Walter, Marie V.
Montanez, Maria I.
Kunzmann, Andrea
Hult, Anders
Nyström, Andreas
Malkoch, Michael
Biocompatibility of polyester dendrimers in comparison to polyamidoamine dendrimers2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S203-S204Article in journal (Other academic)
37. Rodhe, Ylva
Potacova, Zuzana
Moller, Lennart
Copper-based nanoparticles induce high toxicity in leukemic HL60 cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 7, p. 1711-1719Article in journal (Refereed)
From the increasing societal use of nanoparticles (NPs) follows the necessity to understand their potential toxic effects. This requires an in-depth understanding of the relationship between their physicochemical properties and their toxicological behavior. The aim of the present work was to study the toxicity of Cu and CuO NPs toward the leukemic cell line HL60. The toxicity was explored in terms of mitochondrial damage, DNA damage, oxidative DNA damage, cell death and reactive oxygen species (ROS) formation. Particle characteristics and copper release were specifically investigated in order to gain an improved understanding of prevailing toxic mechanisms. The Cu NPs revealed higher toxicity compared with both CuO NPs and dissolved copper (CuCl2), as well as a more rapid copper release compared with CuO NPs. Mitochondrial damage was induced by Cu NPs already after 2 h exposure. Cu NPs induced oxidation at high levels in an acellular ROS assay, and a small increase of intracellular ROS was observed. The increase of DNA damage was limited. CuO NPs did not induce any mitochondrial damage up to 6 h of exposure. No acellular ROS was induced by the CuO NPs, and the levels of intracellular ROS and DNA damage were limited after 2 h exposure. Necrosis was the main type of cell death observed after 18 h exposure to CuO NP and dissolved copper.
Principles and practices of health risk assessment under current EU regulations2006In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 44, no 1, p. 14-23Article in journal (Refereed)
Risk assessments serve as the foundation of regulatory decision-making on whether to take actions to reduce (or otherwise manage) a toxicological or ecotoxicological risk or not. To understand the complex process that leads from the generation of scientific data, via risk assessment to risk management decision-making, close studies of the scientific basis and risk assessment methods must be undertaken. This paper consists of two main parts. In the first part the principles of the European Union process for risk assessments, as defined by legislations and official guidelines, are briefly outlined. In the second part the actual workings of this system are exemplified by the results from case studies of the risk assessment processes for trichloroethylene and for acrylamide. The analysis and comparison of these two cases illustrates: (1) that generation of a large amount of data does not ensure consensus among risk assessors, (2) that controversy can regard different levels of detail, (3) that controversy can arise at different organizational and theoretical levels, (4) that risk assessments may be subject to (public) criticism even if the experts agree, and (5) that scientific controversies have a significant policy component.
Sandin, Per
The ethics of hormesis - no fuss?2008In: Human and Experimental Toxicology, ISSN 0960-3271, E-ISSN 1477-0903, Vol. 27, no 8, p. 643-646Article in journal (Refereed)
It has been argued that the phenomenon of hormesis should prompt us to revise current regulatory policy in order to take beneficial effects of small doses of various agents into account. I argue that three problems - the comparative smallness of hormetic effects, the fine-tuning problem, and the problem of aggregated actions - should lead us not to overemphasize the importance of hormesis for policy, and that they, if anything, points towards a non-consequentialist approach to the ethics of risk.
40. Sato, Kae
Sasaki, Naoki
Svahn, Helene Andersson
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
Sato, Kiichi
Microfluidics for nano-pathophysiology2014In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 74, p. 115-121Article, review/survey (Refereed)
Nanotechnology-based drug delivery systems hold promise for innovative medical treatment of cancers. While drug materials are constantly under development, there are no practical cell-based models to assess whether these materials can reach the target tissue. Recently developed microfluidic systems have revolutionized cell-based experiments. In these systems, vascular endothelial cells and interstitium are set in microchannels that mimic microvessels. Drug permeability can be assayed in these blood vessel models under fluidic conditions that mimic blood flow. In this review, we describe device fabrication, disease model development, nanoparticle permeability assays, and the potential utility of these systems in the future.
KTH, School of Architecture and the Built Environment (ABE), Philosophy.
Management of chemical risk through occupational exposure limits2009Licentiate thesis, comprehensive summary (Other academic)
Occupational Exposure Limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In paper I the OELs established by 18 different organisations or national regulatory agencies from the industrialised world were compared. The comparison concerned: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. In paper II the OELs established by 7 different national regulatory agencies of EU member states are compared to those of the European Commission (EC). In addition to the same comparisons as performed in the first study a comparison level was introduced (3) the similarity between the OELs of these EU member states and the OELs recommended by the EC.
List of OELs were collected through the web-pages of, and e-mail communication with the standard-setting agencies. The selection of agencies was determined by availability of the lists. The database of paper I contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one third of the substances are only regulated by one organisation alone. In paper II this database was narrowed down to the European perspective. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. Also within Europe there was a nearly as large difference. The average level of lists tends to decrease over time, although there are exceptions to this. The similarity index in paper II indicates that the exposure limits of EU member states are converging towards the European Commission's recommended OELs. These two studies also showed that OELs for the same substance can vary significantly between different standard-setters. The work presented in paper III identifies steps in the risk assessment that could account for these differences. Substances for which the level of OELs vary by a factor of 100 or more were identified and their documentation sought for further scrutiny. Differences in the identification of the critical effect could explain the different level of the OELs for half of the substances. The results reported in paper III also confirm the tendency of older OELs generally being higher. Furthermore, several OELs were more than 30 years old and were based on out-dated knowledge. But the age of the data review could not account for all the differences in data selection, only one fifth of the documents referred to all available key studies. Also the evaluation of the key studies varied significantly.
FULLTEXT01
Setting occupational exposure limits: Practices and outcomes2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S129-S129Article in journal (Other academic)
Setting occupational exposure limits: Practices and outcomes of toxicological risk assessment2011Doctoral thesis, comprehensive summary (Other academic)
Occupational Exposure Limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The main objective of this thesis is to study risk assessment practices in the setting of OEL in order to produce knowledge that will help improve the consistency and transparency of OELs.
For the purpose of paper I a database of OELs for a total of 1341 substances was compiled. Of these, only 25 substances have OELs from all 18 included organisations while more than one third of the substances are only regulated by one organisation alone. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland.
In paper II six EU member states' OELs are compared to the European Commission's OELs. Also within Europe there is a large difference concerning the average level of OELs (35%). The average level of lists tends to decrease over time, although there are exceptions to this. There are also indications that the exposure limits of EU member states are converging towards the European Commission's OELs.
The work presented in paper III identifies steps in the risk assessment that could account for the large differences in OELs for 14 different substances. Differences in the identification of the critical effect could explain the different level of the OELs for half of the substances. But the age of the data review could not account for all the differences in data selection, only one fifth of the documents referred to all available key studies. Also the evaluation of the key studies varied significantly.
The aim of paper IV was to investigate how the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Commission uses assessment factors when proposing health-based indicative OELs. For only one third of the investigated OELs were explicit assessment factors given. On average the safety margin of the recommendations was 2.1 higher when an explicit assessment factor had been used. It is recommended that the SCOEL develop and adhere to a more articulate framework on the use of assessment factors.
Paper V focuses on the Derived No-Effect Levels (DNELs) which are to be calculated under the new European Union REACH legislation. It is a comparison of the safety margins of 88 SCOEL recommendations with those of the corresponding worker-DNELs, derived according to the default approach as described in the REACH guidance document. Overall, the REACH safety margins were approximately six times higher than those derived from the SCOEL documentations but varied widely with REACH/SCOEL safety margin ratios ranging by two orders of magnitude, from 0.3 to 58.
SUMMARY01
Use of primary data in risk assessment for occupational exposure limitsManuscript (preprint) (Other academic)
KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy. Karolinska Inst, Sweden.
Science and policy in risk-based occupational exposure limits2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. 120-120Article in journal (Other academic)
Gilek, Michael
Are occupational exposure limits becoming more alike within the European Union?2008In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 28, no 7, p. 858-866Article in journal (Refereed)
The occupational exposure limits (OELs) established by seven different national regulatory agencies of EU member states are compared with those of the European Commission (EC). The comparison concerned: (1) what chemicals have been selected, (2) the average level of exposure limits for all chemicals, and (3) the similarity between the OELs of different EU member states and the OELs recommended by the European Commission. The average level of the exposure limits has declined during the past 10 years in four of the live countries in our study for which historical data were available to us. Poland has not changed its level noticeably and Germany has increased it. Since the first list of indicative OELs was established by the EC, a few of the EU exposure limits have been lowered. The similarity index indicates that the exposure limits of EU member states are converging towards the European Commission's recommended OELs. Still, the average level of OELs differs between organizations - the Estonian OELs are on average 35% higher than the Polish OELs.
Occupational Exposure Limits: A Comparative Study2008In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 50, no 2, p. 261-270Article in journal (Refereed)
Occupational exposure limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In this study we compared the OELs established by 18 different organisations or national regulatory agencies. The OELs were compared with respect to: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. Our database contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one-third of the substances are only regulated by one organisation. The average level of the exposure limits has declined during the past 10 years for 6 of the 8 organisations in our study for which historical data were available; it has increased for Poland and remained nearly unchanged for Sweden. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. The scientific or policy-related motivations for these differences remain to be analysed.
Johanson, G.
Comparing the safety margins in the European indicative occupational exposure limits and the derived no-effect levels under reach2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, p. S268-S268Article in journal (Other academic)
The new European Union (EU) REACH legislation requires Derived No-Effect Levels (DNEL) to be calculated for substances produced in quantities above 10 tonnes/year. Workers are one population that these DNELs are to protect. Meanwhile, the setting of occupational exposure limits (OEL) continues both at the member state and the EU level. Health-based OELs are proposed by the Commission's Scientific Committee on OELs (SCOEL) and eventually result in Indicative OEL Values (IOELV) in EU Directives. According to REACH, IOELVs may under some circumstances be used as worker-DNELs. On the other hand, worker-DNELs will be derived for several thousand substances, far more than the roughly 100 substances for which IOELVs have been established. Thus, the procedure to set health-based OELs may become influential on that of DNELs and vice versa. This study presents a comparison of the safety margins of 88 SCOEL recommendations with those of the corresponding worker-DNELs, derived according to the REACH guidance document. Overall, the REACH safety margins were approximately six times higher than those derived from the SCOEL documentation but varied widely with REACH/SCOEL ratios ranging by two orders of magnitude, from 0.3 to 58. It was also found that the REACH guidance document, although encompassing detailed advice on many issues, including default assessment factors for species and route extrapolation, gives no quantitative guidance on when and how to depart from defaults.
Institute of Environmental Medicine, Karolinska Institutet.
Use of Uncertainty Factors by the SCOEL in their derivation of health-based Occupational Exposure Limits2010In: Critical reviews in toxicology, ISSN 1040-8444, E-ISSN 1547-6898, Vol. 40, no 9, p. 791-798Article, review/survey (Refereed)
The aim of this study was to investigate how the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Commission uses uncertainty factors when proposing health-based indicative occupational exposure limit values (IOELVs). In total, 75 IOELVs in 62 summary documents published from 1991 to 2003 were analyzed. For 31 of the IOELVs, no explicit uncertainty factor (EUF) was stated. For these, we calculated an implicit safety margin (ISM) as the ratio between the point of departure (POD, derived from the NOAEL or LOAEL of the critical effect) and the proposed IOELV. We further analysed whether date of recommendation, type of critical effect, nature of POD or amount of available data influenced the magnitude of the EUFs and ISMs. The ISMs varied little (range 1-5), while the EUFs showed more variability (range 1-50). The EUFs remained unaffected over time and the ISMs decreased slightly. Significant differences in the magnitude of the EUFs, but not ISMs, were found between critical effects, however, contrary to expected the average EUFs and ISMs for irritation were similar to those for more severe systemic effects. The nature of the POD affected the ISMs and EUFs only slightly and less than expected. Both EUFs and ISMs showed a weak but significant negative correlation with the amount of available toxicological data, measured as the number of relevant publications in PubMed, whereas SCOEL statements on data sufficiency had no influence. Overall, the most striking difference was that between EUFs and ISMs, the former being on average 2.1 times higher.
Shi, Jingwen
Lundin, Maria
Karlsson, Hanna
Hemolysis of silica particles: Importance of surface properties and plasma corona2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S203-S203Article in journal (Other academic)