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  • 1. Awasthi, Saurabh
    et al.
    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, 3312-3322 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 2. Banis, George E.
    et al.
    Winkler, Thomas
    KTH, School of Electrical Engineering (EES), Micro and Nanosystems. Univ Maryland, USA.
    Barton, Patricia
    Chocron, Sheryl E.
    Kim, Eunkyoung
    Kelly, Deanna L.
    Payne, Gregory F.
    Ben-Yoav, Hadar
    Ghodssi, Reza
    The Binding Effect of Proteins on Medications and Its Impact on Electrochemical Sensing: Antipsychotic Clozapine as a Case Study2017In: Pharmaceuticals, ISSN 1424-8247, E-ISSN 1424-8247, Vol. 10, no 3, UNSP 69Article in journal (Refereed)
    Abstract [en]

    Clozapine (CLZ), a dibenzodiazepine, is demonstrated as the optimal antipsychotic for patients suffering from treatment-resistant schizophrenia. Like many other drugs, understanding the concentration of CLZ in a patient's blood is critical for managing the patients' symptoms, side effects, and overall treatment efficacy. To that end, various electrochemical techniques have been adapted due to their capabilities in concentration-dependent sensing. An open question associated with electrochemical CLZ monitoring is whether drug-protein complexes (i.e., CLZ bound to native blood proteins, such as serum albumin (SA) or alpha-1 acid-glycoprotein (AAG)) contribute to electrochemical redox signals. Here, we investigate CLZ-sensing performance using fundamental electrochemical methods with respect to the impact of protein binding. Specifically, we test the activity of bound and free fractions of a mixture of CLZ and either bovine SA or human AAG. Results suggest that bound complexes do not significantly contribute to the electrochemical signal for mixtures of CLZ with AAG or SA. Moreover, the fraction of CLZ bound to protein is relatively constant at 31% (AAG) and 73% (SA) in isolation with varying concentrations of CLZ. Thus, electrochemical sensing can enable direct monitoring of only the unbound CLZ, previously only accessible via equilibrium dialysis. The methods utilized in this work offer potential as a blueprint in developing electrochemical sensors for application to other redox-active medications with high protein binding more generally. This demonstrates that electrochemical sensing can be a new tool in accessing information not easily available previously, useful toward optimizing treatment regimens.

  • 3. Bergmann, Troels K.
    et al.
    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, 199-204 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 4. Beronius, A.
    et al.
    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, S256-S256 p.Article in journal (Other academic)
    Abstract [en]

    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.

  • 5.
    Beronius, Anna
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Willighagen, Egon
    Maastricht Univ, Maastricht, Netherlands .
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Hanberg, Annika
    Karolinska Inst, Stockholm, Sweden.
    Factors influencing developmental neurotoxicity study outcome in the bisphenol A case2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S128-S129 p.Article in journal (Other academic)
  • 6. Bosley, Jim
    et al.
    Borén, Christofer
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    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
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    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, 1532-1538 p.Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 7. Chaudhry, Qasim A.
    et al.
    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, S182-S182 p.Article in journal (Other academic)
  • 8.
    Cronholm, Pontus
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Karlsson, Hanna L.
    Karolinska Inst, Stockholm, Sweden.
    Hedberg, Jonas
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Lowe, Troy
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Elihn, Karine
    Stockholm Univ, Stockholm, Sweden .
    Wallinder, Inger Odnevall
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Möller, Lennart
    Karolinska Inst, Stockholm, Sweden.
    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, S201-S201 p.Article in journal (Other academic)
  • 9.
    Ding, Qian
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Schenk, Linda
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Malkiewicz, Katarzyna
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Hansson, Sven Ove
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    A comparison of occupational exposure limits in Asia and Europe2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, S241-S241 p.Article in journal (Other academic)
    Abstract [en]

    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.

  • 10.
    Dreij, Kristian
    et al.
    Karolinska Inst, Stockholm, Sweden .
    Chaudhry, Qasim A.
    KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA.
    Zhang, Jie
    Karolinska Inst, Stockholm, Sweden .
    Sundberg, Kathrin
    Karolinska Inst, Stockholm, Sweden .
    Jernström, Bengt
    Karolinska Inst, Stockholm, Sweden .
    Hanke, Michael
    KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA.
    Morgenstern, Ralf
    Karolinska Inst, Stockholm, Sweden .
    In silico modeling of the intracellular dynamics of polycyclic aromatic hydrocarbons2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S60-S61 p.Article in journal (Other academic)
  • 11. El-Seedi, Hesham R.
    et al.
    El-Shabasy, Rehan
    Sakr, Hanem
    Zayed, Mervat
    El-Said, Asmaa M. A.
    Helmy, Khalid M. H.
    Gaara, Ahmed H. M.
    Turki, Zaki
    Azeem, Muhammad
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Ahmed, Ahmed M.
    Boulos, Loutfy
    Borg-Karlson, Anna-Karin
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Göransson, Ulf
    Anti-schistosomiasis triterpene glycoside from the Egyptian medicinal plant Asparagus stipularis2011In: REV BRAS FARMACOGN, ISSN 0102-695X, Vol. 22, no 2, 314-318 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 12. Fonteyne, Margot
    et al.
    Correia, Ana
    De Plecker, Sofie
    Vercruysse, Jurgen
    Ilic, Ilija
    Zhou, Qi
    KTH, School of Biotechnology (BIO), Glycoscience.
    Veryaet, Chris
    Remon, Jean Paul
    Onofre, Fernanda
    Bulone, Vincent
    KTH, School of Biotechnology (BIO), Glycoscience.
    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, 705-717 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 13.
    Green, Henrik
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Khan, Muhammad Suleman
    Jakobsen-Falk, Ingrid
    Avall-Lundqvist, Elisabeth
    Peterson, Curt
    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, 4205-4209 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 14. Grondin, Yohann
    et al.
    Cotanche, Douglas A
    Manneberg, Otto
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    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, 93-103 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 15.
    Gu, Chungang
    et al.
    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, 1441-1449 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 16.
    Hansson, Sven Ove
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Molander, Linda
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    The substitution principle2011In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 59, no 3, 454-460 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 17.
    Hedberg, Yolanda
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science. Karolinska Institutet, Sweden.
    Herting, Gunilla
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Latvala, S.
    Elihn, K.
    Karlsson, H. L.
    Odnevall Wallinder, Inger
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    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, 162-170 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 18.
    Hedberg, Yolanda
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Stockmann-Juvala, Helene Helene
    Finnish Inst Occupat Hlth, Helsinki, Finland .
    Zitting, Antti
    Finnish Inst Occupat Hlth, Helsinki, Finland .
    Santonen, Tiina
    Finnish Inst Occupat Hlth, Helsinki, Finland .
    Odnevall Wallinder, Inger
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Relevance of in vitro studies for in vivo inhalation toxicity of 316L powder2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S125-S125 p.Article in journal (Other academic)
  • 19. Henderson, Rayetta G.
    et al.
    Verougstraete, Violaine
    Anderson, Kim
    Arbildua, Jose J.
    Brock, Thomas O.
    Brouwers, Tony
    Cappellini, Danielle
    Delbeke, Katrien
    Herting, Gunilla
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Hixon, Greg
    Wallinder, Inger Odnevall
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    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, 170-181 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 20. Huuskonen, Sirpa
    et al.
    Heinala, Milla
    Herting, Gunilla
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Odnevall Wallinder, Inger
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Santonen, Tiina
    Human health risk assessment of ferrosilicon alloys under REACH2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S178-S178 p.Article in journal (Other academic)
  • 21. Johansson, Mia K. V.
    et al.
    Johanson, Gunnar
    Öberg, Mattias
    Schenk, Linda
    Philosophy and History, KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    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, 1379-1391 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 22. Karlsson, Hanna L.
    et al.
    Cronholm, Pontus
    Hedberg, Yolanda
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Tornberg, Malin
    De Battice, Laura
    Svedhem, Sofia
    Odnevall Wallinder, Inger
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    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, 59-69 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 23. Lobmann, Korbinian
    et al.
    Svagan, Anna J.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    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, 285-297 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 24.
    Malkiewicz, Katarzyna
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Pettitt, M.
    Dawson, K. A.
    Hansson, Sven Ove
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Lynch, I.
    Lead, J.
    Nanomaterials in reach2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, S45-S45 p.Article in journal (Other academic)
    Abstract [en]

    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.

  • 25. Margeridon-Thermet, Severine
    et al.
    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
    Shafer, Robert W.
    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, 343-349 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 26.
    Midander, Klara
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Corrosion Science (closed 20081231).
    Odnevall Wallinder, Inger
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Corrosion Science (closed 20081231).
    Leygraf, Christofer
    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)
    Abstract [en]

    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.

  • 27.
    Molander, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Beronius, Anna
    Karolinska Inst, Stockholm, Sweden.
    Hanberg, Annika
    Karolinska Inst, Stockholm, Sweden.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Endpoints and dose-response relationships of low-dose studies of Bisphenol A2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S130-S130 p.Article in journal (Other academic)
  • 28.
    Molander, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Breitholtz, M.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    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, S243-S243 p.Article in journal (Other academic)
    Abstract [en]

    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.

  • 29.
    Neus, Feliu Torres
    et al.
    Karolinska Inst, Stockholm, Sweden .
    Walter, Marie V.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Montanez, Maria I.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Kunzmann, Andrea
    Karolinska Inst, Stockholm, Sweden .
    Hult, Anders
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Nyström, Andreas
    Karolinska Inst, Stockholm, Sweden .
    Malkoch, Michael
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Fadeel, Bengt
    Karolinska Inst, Stockholm, Sweden .
    Biocompatibility of polyester dendrimers in comparison to polyamidoamine dendrimers2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S203-S204 p.Article in journal (Other academic)
  • 30. Rodhe, Ylva
    et al.
    Skoglund, Sara
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Wallinder, Inger Odnevall
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    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, 1711-1719 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 31.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    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, 14-23 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 32.
    Sandin, Per
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    The ethics of hormesis - no fuss?2008In: Human and Experimental Toxicology, ISSN 0960-3271, E-ISSN 1477-0903, Vol. 27, no 8, 643-646 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 33. Sato, Kae
    et al.
    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, 115-121 p.Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 34.
    Schenk, Linda
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Management of chemical risk through occupational exposure limits2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    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.

  • 35.
    Schenk, Linda
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Setting occupational exposure limits: Practices and outcomes2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S129-S129 p.Article in journal (Other academic)
  • 36.
    Schenk, Linda
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Setting occupational exposure limits: Practices and outcomes of toxicological risk assessment2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    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.

  • 37.
    Schenk, Linda
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Use of primary data in risk assessment for occupational exposure limitsManuscript (preprint) (Other academic)
  • 38.
    Schenk, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy. Karolinska Inst, Sweden.
    Ding, Qian
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Hansson, Sven Ove
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    Science and policy in risk-based occupational exposure limits2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, 120-120 p.Article in journal (Other academic)
  • 39.
    Schenk, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Hansson, Sven Ove
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    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, 858-866 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 40.
    Schenk, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Hansson, Sven Ove
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Rudén, Christina
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Gilek, Michael
    Occupational Exposure Limits: A Comparative Study2008In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 50, no 2, 261-270 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 41.
    Schenk, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy and History of Technology, Philosophy.
    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, S268-S268 p.Article in journal (Other academic)
    Abstract [en]

    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.

  • 42.
    Schenk, Linda
    et al.
    KTH, School of Architecture and the Built Environment (ABE), Philosophy.
    Johanson, Gunnar
    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, 791-798 p.Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 43.
    Shi, Jingwen
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Hedberg, Yolanda
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Lundin, Maria
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Odnevall Wallinder, Inger
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Surface and Corrosion Science.
    Karlsson, Hanna
    Karolinska Inst, Stockholm, Sweden.
    Möller, Lennart
    Karolinska Inst, Stockholm, Sweden.
    Hemolysis of silica particles: Importance of surface properties and plasma corona2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S203-S203 p.Article in journal (Other academic)
  • 44.
    Stjern, Louise
    et al.
    KTH.
    Voittonen, Sandra
    KTH.
    Weldemichel, Rahel
    KTH.
    Thuresson, Sofia
    Agnes, Marco
    Benkovics, Gabor
    Fenyvesi, Eva
    Malanga, Milo
    Yannakopoulou, Konstantina
    Feiler, Adam
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Valetti, Sabrina
    Cyclodextrin-mesoporous silica particle composites for controlled antibiotic release. A proof of concept toward colon targeting2017In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 531, no 2, 595-605 p.Article in journal (Refereed)
    Abstract [en]

    Cyclodextrins (CDs) and mesoporous silica particles (MSPs) have been combined as composite carriers for controlled antibiotic release. CDs were employed as "gatekeeper" agents and grafted onto MSPs to retain drug molecules inside the MSP carrier. A variety of CDs (unfunctionalized, positively charged and carboxymethylated) and three different coupling strategies (covalent binding, electrostatic adsorption and inclusion complexation) were systematically investigated for their ability to control the release of two antibiotic drugs, metronidazole and clofazimine. The drugs had significantly different physicochemical properties (metronidazole - small hydrophilic, clofazimine-large hydrophobic). We report for the first time on the encapsulation and characterization of metronidazole-loaded-MSP. Each CD coating strategy reduced the drug release rate in phosphate buffer compared to unmodified MSP (from 20% to 100% retained drug). Covalent binding and inclusion complex approaches were significantly more effective than electrostatically adsorbed CD. In particular, the novel inclusion complex based on host/guest interaction between benzyl-modified silica surface and alpha-CD proved to be very effective (60-100% retained drug amount). Using pharmaceutical manufacturing processes, our study shows that CD-MSP composites can retain both hydrophobic and hydrophilic antibiotic compounds with potential translation to triggered release formulation targeting bacterial infections in the colon and lower intestine.

  • 45.
    Sun, Xian-qiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Chen, Lei
    Li, Yao-zong
    Li, Wei-hua
    Liu, Gui-xia
    Tu, Yao-quan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Yun
    Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors2014In: Acta Pharmacologica Sinica, ISSN 1671-4083, E-ISSN 1745-7254, Vol. 35, no 2, 301-310 p.Article in journal (Refereed)
    Abstract [en]

    Aim: To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase (EGFR TK) and its inhibitors. Methods: One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR (ensemble-QSAR) building method was developed based on the ligand conformations determined by the corresponding protein structures. Results: Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 (0.87) and Q2 (0.78) values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands. Conclusion: The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.

  • 46. Svedberg, Anna
    et al.
    Green, Henrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Linkoping Univ, Dept Med & Hlth Sci, Div Drug Res, Clin Pharmacol, SE-58185 Linkoping, Sweden.
    Vikström, Anders
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Vikingsson, Svante
    A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma2015In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 107, 186-195 p.Article in journal (Refereed)
    Abstract [en]

    A liquid chromatography tandem mass spectrometry method was developed and validated for quantification of erlotinib and its metabolites in human plasma. The method is suitable for therapeutic drug monitoring and pharmacokinetic studies. The substances were extracted using protein precipitation, separated on a BEH XBridge C18 column (100 x 2.1 mm, 1.7 mu m) by gradient elution at 0.7 mL/min of acetonitrile and 5 mM ammonium acetate. The concentration was determined using a Waters Xevo triple quadrupole mass spectrometer in a multi reaction monitoring mode. The total run time was 7 min. Deuterated erlotinib and OSI-597 were used as internal standard for erlotinib and its metabolites, respectively. Erlotinib, OSI-420 and didesmethyl erlotinib were quantified in the concentration range 25-5000 ng/mL, 0.5-500 ng/mL and 0.15-10 ng/mL, respectively. Precision and accuracy was <14% except for OSI-420 at LLOQ (17%). Extraction recovery was above 89%, 99% and 89% for erlotinib, OSI-420 and didesmethyl erlotinib, respectively. The human liver microsomes generated 14 metabolites, three of them not previously reported. Twelve metabolites were measured semi-quantitatively and validated with respect to selectivity, precision and stability.

  • 47.
    Svärd, Michael
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
    Valavi, Masood
    Khamar, Dikshitkumar
    Kuhs, Manuel
    Rasmuson, Åke C.
    KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
    Thermodynamic Stability Analysis of Tolbutamide Polymorphs and Solubility in Organic Solvents2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 6, 1901-1906 p.Article in journal (Refereed)
    Abstract [en]

    Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for 2 polymorphs of the drug tolbutamide: FIH and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FIL, FIH, FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FIH through a thermodynamic cycle. Calorimetric data have been used to derive a quantitative polymorphic stability relationship between these 4 polymorphs, showing that FII is the stable polymorph below approximately 333 K, above which temperature FIH is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FIL and FIH has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in 5 pure organic solvents ( methanol, 1-propanol, ethyl acetate, acetonitrile, and toluene) over the temperature range 278 to 323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the 5 solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are nonlinear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data have been correlated and extrapolated to the melting point using a semiempirical regression model.

  • 48.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova.
    Exploring the Human Protein Atlas in the field of toxicology2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, S2-S2 p.Article in journal (Other academic)
  • 49. Velkov, Zhivko A.
    et al.
    Velkov, Yasen Zh.
    Galunska, Bistra T.
    Paskalev, Dobrin N.
    Tadjer, Alia V.
    Melatonin: Quantum-chemical and biochemical investigation of antioxidant activity2009In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 44, no 7, 2834-2839 p.Article in journal (Refereed)
    Abstract [en]

    Experimental and theoretical investigation of the antioxidant activity of melatonin is carried out. The theoretical approach comprises the evaluation of several appropriate descriptors of scavenging activity with the help of quantum-chemistry methods. The values obtained are compared with available data for substances with established antioxidant properties. One of the most widely used markers for in vivo free radical oxidation processes is malondialdehyde (MDA) as an end product of membrane lipid peroxidation. Experimental support of the computed scavenging parameters is provided by estimation of the effect of supplementary melatonin therapy on the plasma levels of MDA in CRF patients on maintenance HD therapy. Different reaction paths have been considered and related to the obtained data, allowing speculations about the reaction mechanism and the antioxidant potential of melatonin for practical purposes.

  • 50.
    Yan, Ming
    et al.
    Department of Life Science and Biomedical Engineering, Zhejiang.
    Zhang, Yun
    Department of Life Science and Biomedical Engineering, Zhejiang.
    Xu, Kedi
    Department of Life Science and Biomedical Engineering, Zhejiang.
    Fu, Tao
    Centre for Optical and Electromagnetic Research, Zhejiang University.
    Qin, Haiyan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Zheng, Xiaoxiang
    Department of Life Science and Biomedical Engineering, Zhejiang.
    An in vitro study of vascular endothelial toxicity of CdTe quantum dots2011In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 282, no 3, 94-103 p.Article in journal (Refereed)
    Abstract [en]

    Quantum dots (QDs), as novel bioimaging and drug delivery agents, are generally introduced into vascular system by injection, and thus directly exposed to vascular endothelial cells (ECs). However, the adverse effects of QDs on ECs are poorly understood. In this study, employing human umbilical vein ECs (HUVECs), we investigated the potential vascular endothelial toxicity of mercaptosuccinic acid (MSA)-capped CdTe QDs in vitro. In the experiment, water-soluble and pH stable CdTe QDs were synthesized; and the cell viability assays showed that CdTe QDs (0.1-100 mu g/mL) dose-dependently decreased the cell viability of HUVECs, indicating CdTe QDs induced significant endothelial toxicity. The flow cytometric and immunofluorescence results revealed that 10 mu g/mL CdTe QDs elicited significant oxidative stress, mitochondrial network fragmentation as well as disruption of mitochondrial membrane potential (Delta psi(m)); whereas ROS scavenger could protect HUVECs from QDs-induced mitochondrial dysfunction. Moreover, upon 24h exposure to 10 mu g/mL CdTe QDs, the apoptotic HUVECs dramatically increased by 402.01%, accompanied with alternative expression of apoptosis proteins, which were upregulation of Bax, down-regulation of Bcl-2, release of mitochondrial cytochrome c and cleavage of caspase-9/caspase-3. These results suggested that CdTe QDs could not only impair mitochondria but also exert endothelial toxicity through activation of mitochondrial death pathway and induction of endothelial apoptosis. Our results provide strong evidences of the direct toxic effects of QDs on human vascular ECs, and reveal that exposure to QDs is a significant risk for the development of cardiovascular diseases. These results also provide helpful guidance on the future safe use and manipulation of QDs to make them more suitable tools in nanomedicine.

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