Norsk Selskap for Farmakologi og Toksikologi Norwegian Society of Pharmacology and Toxicology. Vintermøtet på Beitostølen

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1 Norsk Selskap for Farmakologi og Toksikologi Norwegian Society of Pharmacology and Toxicology Member of EPHAR, IUPHAR, EUROTOX and IUTOX Vintermøtet på Beitostølen 2018

2 [2]

3 Sponsor av NSFTs vintermøte 2018 [3]

4 [4]

5 Norsk Selskap for Farmakologi og Toksikologi Program Torsdag 25. januar 13:00-14:30 14:30 Lunsj Velkommen v/ NSFTs leder Mohammad Nouri Sharikabad BEITOHALLEN Alzheimer causes and new targets Fellessymposium Møteleder: Mohammad Nouri Sharikabad (Drammen kommune) BEITOHALLEN 14:40-15:10 15:10-15:40 15:40-16:10 Pathogenic mechanisms and potential drug targets Lars Nilsson(UiO) Early Alzheimer s disease diagnostics, experimental and clinical trials Tormod Fladby (UiO) Traffic-related exhaust and other environmental pollutants mixtures as risk factors for dementia and neurodevelopmental disorders Oddvar Myhre (FHI) 10 min pause Priser for årets beste artikler Fellessymposium Møteledere: Hubert Dirven/Ida Robertsen BEITOHALLEN 16:20-16:40 16:40-17:00 Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice Jérôme Ruzzin (UiB) (Årets artikkel i farmakologi) Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model Susann Wolf-Grosse (NTNU) (Årets artikkel i toksikologi) Kaffe [5]

6 Toksikologi: Perfluorerte forbindelser Møteleder: Erik Ropstad (NMBU) Besseggen 1 Farmakologi: Antidepressiva og barn Møteleder: Sigrid Narum (Diakonhjemmet) Besseggen 2 17:30-17:50 17:50-18:10 Does fluor in your ski wax give an anti-climax for your health or the environment Line Småstuen Haug (FHI) Perfluorocarbons in aquatic environments - presence and effects Eirik Fjeld (NIVA) Økende bruk av antidepressiva hos unge, bekymring eller ikke? Ingeborg Hartz (Sykehuset Innlandet) 17:30-18:00 18:10-18:30 Effects of perfluorocarbons on human health Birgitte Lindeman (FHI) Studie om bivirkninger/ sikkerhet ved bruk av antidepressiva til barn Tone Westergren(RELIS) 18:00-18:30 19:30 Samling i baren 20:00 Middag [6]

7 Fredag 26. januar 12:30-14:00 Lunsj Real-World Evidence Fellessymposium Møteleder: Hubert Dirven (FHI) BEITOHALLEN 14:00-14:30 POPS in breastmilk. Is there a reason for concern? Merete Eggesbø (FHI) 14:30-15:00 Use and effects of prescription drugs and drugs of abuse - Real world evidence Svetlana Skurtveit (UiO/FHI) 15:00-15:10 Vitenskapskomiteen for mat og miljø (VKM) søker medlemmer for perioden Kirsten E. Rakkestad (VKM) Kaffe [7]

8 Toksikologi Møteleder: Merete Grung (NIVA) Besseggen 1 15:30 15:40 15:50 16:00 16:10 16:20 16:30 16:40 16:50 17:00 A systematic review of approaches for grouping of manufactured nanomaterials to facilitate hazard and risk assessment of human health and the environment Shan Zienolddiny (STAMI) PFOS exposure induces excitotoxicity in rat cerebellar granule neurons in vitro Hanne Friis Berntsen (NMBU/STAMI) Real-life exposure to mixtures of chemicals in the EuroMix human biomonitoring study results from repeated 24-hour diaries reporting the use of personal care products Monica Andreassen (FHI) Di-n-butyl phthalate enhances PMAinduced macrophage differentiation of THP-1 monocytes via PPARγ Vegard Sæter Grytting (FHI) Diesel exhaust particles induced [Ca 2+ ] i in human endothelial cells through organic chemicals in the lipophilic fraction via an AhRdependent mechanism Bendik Brinchmann (FHI) Effects of hydrosilicate nanofibers on inflammatory responses and cytotoxicity in macrophages and lung epitehlial cells Tonje Skuland (FHI) Effects of HEMA on protein S- glutathionylation in BEAS-2B cells Solveig Uvsløkk (NIOM) Nrf2 signaling and cytoprotection in HEMA exposed human epithelial airway cells Bergitte P. Olderbø (NIOM) Hepatocyte-specific deletion of the mono-adp-ribosyltransferase, TIPARP, increases sensitivity to dioxin-induced toxicities Jason Matthews (UOT/UiO) Risk assessment of brominated flame retardants in Norwegian seafood Ole Jakob Nøstbakken (NIFES) Frie foredrag [8] Farmakologi Møteleder: Kristine Hole (Diakonhjemmet) Besseggen 2 High tacrolimus clearance a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney Erlend J. Egeland (UiO) Characterization of small molecular enhancers of the natriuretic peptide system a potential treatment of resistant hypertension Henriette Andresen (UiO) Betydning av SLC6A4-genotype (5- HTTLPR) for terapisvikt av escitalopram Dilan Baker (Diakonhjemmet/UiO) Development of biosensors with nanomolar affinity for cgmp using structure-based design Gaia Calamera (UiO/OUS) Characterization of acute cardiac dysfunction caused by calcineurin inhibitors and potential therapeutic approach Bernadin Ndongson-Dongmo (UiO) Extracellular cyclophilin A inhibitor MM284 attenuates intrinsic myocardial contractile dysfunction in endotoxemic mice Bernadin Ndongson-Dongmo (UiO) Pharmacokinetics of lidocaine infusion in cancer patients during and after surgery Rolf A. Klaasen (OUS) Interacting proteins of natriuretic peptide receptors Lise Román Moltzau (UiO/OUS) Significantly higher impact of CYP2D6*41 than *9 and *10 on in vivo metabolizer phenotype in a study of more than 1000 Norwegian patients Tore Haslemo (Diakonhjemmet) Hospitalization of children after prenatal exposure to Methadone and Buprenorphine in pregnancy: National Registry Studies from Czech Republic Marte Handal (FHI) 15:30 15:40 15:50 16:00 16:10 16:20 16:30 16:40 16:50 17:00

9 Pause 17:30 Characterization of the aryl hydrocarbon receptors Ahr1a and Ahr2a in Atlantic cod (Gadus morhua) Libe Aranguren-Abadía (UiB) 17:40 Ecotoxicologial responses in caged Atlantic cod (Gadus morhua) at a capped waste disposal site in Kollevåg, Western Norway Karina Dale (UiB) 17:50 Adverse health effects related to chemical exposure in Atlantic cod (Gadus morhua) from Norwegian fjords Mette Bjørge Müller (NMBU) 18:00 18:10 RNA-seq analysis of transcriptome responses in Atlantic cod (Gadus morhua) precision cut liver slices exposed to benzo[a]pyrene and 17α-ethynylestradiol Fékadu Yadetie (UiB) Agonistic and antagonistic effects of perfluorinated compounds on Atlantic cod (Gadus morhua) PPARαa and PPARαb nuclear receptors Sofie Söderström (UiB) 18:20 Establishing A Cell-Free Method for Xenobiotic Detection Using Ligand Activated Receptors from The Atlantic Cod (Gadus morhua) Siri Øfsthus Goksøyr (UiB) 18:30 Crude oil disrupts retinoid metabolism and signaling in Atlantic haddock (Melanogrammus aeglefinus) embryo and larvae Kai K. Lie (NIFES) 18:40 Er det en sammenheng mellom miljøgift-eksponering og DNA-skade i spretthaler, hoppekreps, blåskjell, fisk, fugl og isbjørn? Ketil Hylland (UiO) [9]

10 Toksikologi Besseggen 1 (kl. 19:00) Biological effects of environmental contaminants from road runoff on tadpoles of common European frog (Rana temporaria) Amalie Sofie Liane (UiO) Occurrence of selected organic contaminants and urban markers in sedimentation ponds Merete Grung (NIVA) Persistent Organic Pollutants in Fish from the Mureş River Vidar Berg (NMBU) Human in vitro liver 3D model in nanotoxicology Elisabeth Elje (NILU) Preventive measures to reduce the adverse health impact of traffic-related air pollution (PrevenTAP): An in vitro assessment of the effects of particulate matter on lung cells Vegard Sæter Grytting (FHI) Effect of silica nanoparticles and diesel exhaust particles in a 3D-triculture lung system involving macrophages, epithelial and endothelial cells Tonje Skuland (FHI) Impact of POPs on intestinal homeostasis June Helen Gudmestad (UiB) Postervisning Farmakologi Møteleder: Ida Robertsen (UiO) Besseggen 2 (kl. 17:30) Betydningen av CYP2D6-genotype for terapisvikt av antipsykotika Karianne Hodt (Diakonhjemmet/UiT) Utvikling av analysemetode for fri fraksjon av midazolam for å studere effekt av hemodialyse pa CYP3A-aktvitet i pasienter med nyresvikt Karoline Hansen (UiO) Effekt av inflammasjon på regulering av cysteinproteasene legumain og cathepsin B under differensiering av humane mesenkymale stamceller til osteoblaster Nora Gjonbalaj (UiO) Effekt av gastrisk bypass-operasjon på CYP3A-aktivitet i pasienter med sykelig overvekt Ingeborg Karbø (UiO) Diacylglycerol acyltransferase 1 og 2 sin rolle i lipidmetabolismen i humane skjelettmuskelceller Nhi T. H. Le (UiO) Energy metabolism and myokine production in skeletal muscle cells Nora Albakaa (HiOA) Regulation of beta-adrenoceptor-evoked inotropic responses by inhibitory G protein, adenylyl cyclase isoforms 5 and 6 and phosphodiesterases Marie-Victoire Cosson (UiO/OUS) Are nanoparticles used in dental materials neurotoxic? Alexandra I. S Treimo (UiO/NIOM) Hypothermia-induced diastolic dysfunction in ventricular trabeculae from human failing explanted hearts is caused by elongated contraction-relaxation cycle time and is worsened by increased heart rate Marie-Victoire Cosson (UiO/OUS) Sikkerhet ved bruk av SGLT2-hemmeren empagliflozin hos nyretransplanterte pasienter med posttransplantasjonsdiabetes mellitus Laavanyaah Rajakumar (OUS/UiO) Effekt av Maresin1 (MaR1) på immortaliserte musemakrofager Asma Shouket (UiO) [10]

11 Impact of UGT1A4 *3 (142 T>G) genotype on serum concentration of lamotrigine in relation to age, gender and valproic acid comedication a large-scale observational study Robert Løvsletten Smith (Diakonhjemmet) Physiologically based pharmacokinetic modeling of atorvastatin - calcineurin inhibitor drug-drug interactions Ana Todosijevic (UiO/Vitusapotek) A quantitative LC-MSMS method for measuring 13 antihypertensive drugs in serum Mimi Stokke Opdal (OUS/UiO) 20:00 Middag 22:00-22:30 Kveldsnytt Besseggen 1 og 2 [11]

12 Lørdag 27. januar Generalforsamling og årsmøter 09:00-09:30 Årsmøte Seksjon for toksikologi Besseggen 1 Årsmøte Seksjon for farmakologi Besseggen 2 09:30-10:30 Generalforsamling Norsk Selskap for Farmakologi og Toksikologi Besseggen 2 12:30-14:00 14:00-14:50 Lunsj Beitoforelesningen 2017 (BCPT-sponsored) Møteleder: Hubert Dirven (FHI) BEITOHALLEN Developmental neurotoxic effects of environmental toxicants and pharmaceutical drugs and the contribution of in vitro systems Anna Price (EU Joint Research Centre) Nordic symposium (BCPT-sponsored) Toxicology and pharmacology without animal experiments: will it be possible in the next 10 years? Fellessymposium Møteleder: Mohammad Nouri Sharikabad (Drammen kommune) BEITOHALLEN 14:50-15:20 Animal free toxicology - exemplified by human placenta studies in the studies of transport of environmental contaminants and pharmaceutical drugs Lisbeth Knutsen (Københavns Universitet) Kaffe 15:50-16:20 16:20 16:50 Toxicity testing in the 21st Century; special focus on sensitization Henrik Appelgren (Senzagen) Pharmacology and drug discovery pipelines at the dawn of synthetic tissues and artificial intelligence: what may we expect? Andy Edwards (Simula) Pause [12]

13 Toksikologi Hot topics in risk assessment Møteleder: Nina Landvik (STAMI) Besseggen 1 Farmakologi Dagens behandling - for mye, for lenge? Møteleder: Lise Roman Moltzau (UiO) Besseggen 2 17:10-17:40 17:40-18:10 Titandioxide and other chemicals for hazard assessment and risk assessment in ECHAs Risk Assessment Committee Christine Bjørge (Miljødirektoratet) Setting health-based occupational exposure limits Gunnar Johanson (Karolinska Institutet) 20:00 Festmiddag Overbehandling av eldre Henning Økland (RELIS Sør-Øst) Overbehandling av osteoporose Trine Finnes (Sykehuset Innlandet) 17:10-17:40 17:40-18:10 Søndag 28. januar 08:00-12:00 Brunsj [13]

14 Innholdsfortegnelse Program... 5 NSFTs vintermøte nr Oversikt over styremedlemmer i NSFT...15 Velkommen til NSFTs vintermøte Praktisk informasjon...18 Årsberetning Innkalling til generalforsamling i NSFT...23 Årsberetning seksjon for farmakologi...24 Innkalling til årsmøte i seksjon for farmakologi...27 Årsberetning 2017 seksjon for toksikologi...28 Innkalling til årsmøte i seksjon for toksikologi...32 Inviterte foredrag...33 Frie foredrag...53 Frie foredrag i toksikologi...54 Frie foredrag farmakologi...72 Postere...82 Postere i toksikologi...83 Postere i farmakologi...91 Deltakerliste vintermøtet Stipendmottakere [14]

15 NSFTs vintermøte nr. 46 Norsk Selskap for Farmakologi og Toksikologi (NSFT) har arrangert vintermøter hvert år siden 1973, det vil si at årets møte er nummer 46 i rekken. Selskapets styre gikk i 1972 sterkt inn for å få i gang nasjonale møter, som både kunne bli et kontaktforum og en faglig arena for selskapets voksende antall medlemmer fra de ulike deler av landet. I det programmet leveres til trykking er det påmeldt 105 deltakere til årets møte (ledsagere og barn ikke inkludert), og det er 20 inviterte foredragsholdere fordelt på 9 symposier. Til sammen er det meldt inn 28 frie foredrag og 21 postere fordelt på farmakologi og toksikologi. I år har NSFT mottatt økonomisk støtte fra Basic & Clinical Pharmacology & Toxicology (BCPT) for å invitere flere utenlandske foredragsholdere og holde et nordisk symposium. Støtten har også gjort det mulig å opprettholde stipendtildelingen for studenter som presenterer poster eller frie fordrag. Styret i NSFT takker for året som har gått og håper at deltakerne får både faglig og sosialt påfyll på årets vintermøte. Vennlig hilsen Styret Oversikt over styremedlemmer i NSFT NSFTs hovedstyre Leder: Mohammad Nouri Sharikabad Sekretær: Jan Tore Samuelsen Kasserer: Kristine Hole Styremedlem: David Eidsvoll Representant for bedriftsmedlemmer: Lars Erik Eng Eibak Representanter fra seksjonsstyrene: Ida Robertsen og Hubert Dirven Varamedlemmer: Sara Bremer, Birgitte Lyrån og Aina Westrheim Ravna Seksjon for farmakologi Leder: Ida Robertsen Styremedlemmer: Sigrid Narum, Lise Román Moltzau, Kristin Nordal og Ingvild Holdø Kontaktpersoner for seksjon for farmakologi Bergen: Jon Andsnes Berg Trondheim: Ola Dale Tromsø: Aina Westrheim Ravna Seksjon for toksikologi Leder: Hubert Dirven Styremedlemmer: Merete Grung, Dag Marcus Eide, Marit Nøst Hegseth, Yke Arnoldussen, Gunnar Sundstøl Eriksen og Odd Andre Karlsen. Varastyremedlem: Nina Landvik. Kontaktpersoner for seksjon for toksikologi Trondheim: Åse Krøkje Tromsø: Sandra Huber Kristiansand: Hege Stubberud [15]

16 Velkommen til NSFTs vintermøte 2018 Norsk Farmakologisk Selskap ble stiftet i 1936 og etter hvert innlemmet fagområde toksikologi og skiftet navn til Norsk Selskap for Farmakologi og Toksikologi (NSFT) i Vintermøte har vært organisert og holdt siden 1973 og med dette ønsker jeg dere velkommen til vintermøte nummer 46. Medlemmer i NSFT og deltagere på våre arrangementer dekker mange fagfelt, og arbeider fra eksperimentell forskning til klinisk arbeid. Vi har medlemmer og deltagere fra offentlige institusjoner, sykehus, akademia og farmasøytisk industri. NSFT sitt vintermøte er dermed en meget god arena for å oppdatere seg innen basal og klinisk farmakologi og toksikologi og ikke minst danne nye kontakter på tvers av kompetanser og fagfelt. Jeg ble valgt som ny leder i NSFT i år. Min erfaring er at NSFT og spesielt vintermøtene er et høydepunkt for folk som arbeider innen farmakologi og toksikologi i Norge. Jeg har selv deltatt på vintermøte siden 1994 og opplevd vintermøtene som student, stipendiat og etter hvert som ansatt i forskjellige stillinger. Uansett alder og rolle har det vært veldig hyggelig og lærerikt. Jeg vil gjerne utfordre alle ʺerfarneʺ deltagere til å passe på studenter og yngre deltagere og få dem til å trives og føle seg inkludert. Vi trenger nyrekruttering av trofaste medlemmer i NSFT og deltagere på våre arrangementer i fremtiden. Fjoråret passerte kanskje uten de største hendelsene for farmakologiens- og toksikologiens del i Norge. Jeg har likevel lyst til å trekke fram bekymringen rundt toksikologiutdanningen som ble meldt av NSFT i januar Et bekymringsbrev ble sent til en rekke departementer og utdanningsinstitusjoner, der det advares om at utdanningen av toksikologer er i fare grunnet lite forskningsmidler (Dagens Medisin ). Både farmakologi og toksikologi er fag i skjæringspunktet mellom medisin, biologi og kjemi. De må markeres som viktige fagfelt og innen helse- og miljø- fag. Vi håper at NSFT og våre samlinger kan være en arena for samarbeid og nytenkning på tvers av begge fagfeltene både eksperimentelt og klinisk og stimulere til gode søknader om forskningsmidler På vegne av NSFT vil jeg gi en stor takk til alle våre foredragsholdere og medforfattere av postere og muntlige presentasjoner fra Norge og særlig våre kolleger fra utlandet. Vi har et variert og spennende program i år. Vi begynner med en fellessesjon om Alzheimer. Det er godt kjent at befolkningssammensetningen i Norge forandres og vi får mye større andel eldre mennesker fra ca Vi gleder oss deretter til foredrag og priser for beste artikkel innen farmakologi og toksikologi. To spennende sesjoner om perfluorerte forbindelser og antidepressiva behandling hos barn avslutter torsdagen. På fredag har vi en høyaktuell sesjon med bruk av registerdata som fortiden omtales som en gullgruve. Deretter fortsetter vi med noe av det viktigste, nemlig frie foredrag og postere innen begge fagfeltene. Ikke glem kveldsnytt som er vintermøtes overraskelses innslag på fredagskveld etter middagen. Jeg oppfordrer alle medlemmene til å delta på årsmøter og generalforsamling på lørdag morgen. Fagsesjonene på lørdag begynner først etter lunsj med årets Beitoforelesning (BCPT sponset). Vi fortsetter med Nordic symposium (BCPT sponset) som inneholder tre flotte foredrag innen temaet farmakologi og toksikologi i fremtiden og mulighet for reduksjon/bortfall av bruk av forsøksdyr. Siste faglige del vil bli to foredrag i høyaktuelle tema innen toksikologisk risikovurdering og to foredrag innen overbehandling av eldre. Etter tre dager med fag håper jeg at alle har mulighet til å delta på festmiddagen og ha det riktig hyggelig. [16]

17 Jeg håper at alle deltagere og ledsagere koser seg i dette nydelige stedet og får mulighet til noen turer i naturen enten på bena eller på ski. Gi oss gjerne tilbakemelding på hva du syns om arrangementet og forbedringsforslag enten direkte eller i evaluering av arrangementet som dere får elektronisk etter vintermøte Med vennlig hilsen Mohammad Nouri Sharikabad Leder, NSFT [17]

18 Praktisk informasjon Hotelloversikt Første gang en er på Beitostølen høyfjellshotell (Radisson Blu Resort Beitostølen) kan det være vanskelig å vite i hvilken retning en skal gå for å få med seg de første foredragene. Dersom det ikke er en folkemengde å følge etter foreslås følgende: Beitohallen: Andre etasje, ta til venstre. Beitohallen er i enden av korridoren. Konferanseavdelingen: Andre etasje, gå rett fram gjennom glasshallen. Her finner du rommene Besseggen 1 og Besseggen 2. Vintermøtet er godkjent som etter- og videreutdanningskurs Farmasøyters etter- og videreutdanning (FEVU) er et poengsystem for registrering av deltakelse i faglige etterutdanningsaktiviteter. Norges Farmaceutiske Forening (NFF) har tildelt NSFTs vintermøte 2018 totalt 11 FEVU-poeng. Farmasøyter som er medlemmer av NFF kan selv registrere deltakelse på vintermøtet ved å logge inn på «Min side» på i etterkant av arrangementet. For mer informasjon om FEVU-poeng, se: Vintermøtet er også godkjent av Den norske legeforening som valgfritt kurs (17 timer) innen klinisk farmakologi. [18]

19 Norsk Selskap for Farmakologi og Toksikologi Årsberetning Styrets sammensetning Generalforsamlingen i NSFT ble holdt 28. januar 2017 på Radisson BLU Resort Beitostølen. Styrets sammensetning etter valget på generalforsamlingen har vært som følger: - Leder: Mohammad Nouri Sharikabad ( ) - Sekretær: Jan Tore Samuelsen ( ) - Kasserer: Kristine Hole ( ) - Styremedlem: David Eidsvoll ( ) Vararepresentanter: - Sara Bremer ( ) - Birgitte Lyrån ( ) - Aina Westrheim Ravna ( , og ) Seksjonene har utpekt følgende representanter til styret: - Toksikologi: Hubert Dirven - Farmakologi: Ida Robertsen Representant for industrien: - Lars Erik Eng Eibak ( ) Valgkomité for 2018: - Jørn A. Holme ( ) - Vigdis Aas ( ) - Eili Tranheim Kase ( ) - Norith Eckbo ( ) Revisor: - Lise Timm Haug ( ) 2. Styrets arbeid Det har vært avholdt 8 møter i hovedstyret. Deler av styrets arbeid har vært utført via e-post. Styret har i perioden jobbet med: - Organisering av NSFTs faglige virksomhet (vår-, høst- og vintermøter) - Planlegging og organisering av utdeling av Poulssonprisen og pris for beste publikasjon - Organisering av styrets arbeid og møter - Rekruttering av nye medlemmer - Formidling av informasjon på NSFTs nettsider, i nyhetsbrev og via Facebook - Europeisk registrert toksikolog (ERT)-registreringer - Etablering av ny ordning for Europeisk sertifisert farmakolog (EuCP) - Finansiering av Selskapets aktiviteter [19]

20 3. Økonomi Økonomien til NSFT vurderes som tilfredsstillende. Medlemskontingenten er kr 400,- for vanlige medlemmer og kr 150,- for studenter. Medlemskontingenten for bedriftsmedlemmer er fortsatt kr 3500,-. NSFT har i 2017 mottatt økonomiske støtte fra Basic & Clinical Pharmacology & Toxicology (BCPT) og The Federation of European Pharmacological Societies (EPHAR) til NSFTs vintermøtet 2017 som gikk til forelesere, da spesielt Beitoforelesningen, Nordisk symposium og støtte til studenter. For Vintermøtet 2018 er det satt av ,- til stipend for studenter som presenterer poster eller fritt foredrag. Stipend, Beitoforelesningen, årets artikkel og Nordisk symposium støttes i år av BCPT. 4. Faglig virksomhet Vintermøtet Vintermøtet 2017 ble holdt på Radisson Blu Resort Beitostølen 26. januar 29. januar. Det var påmeldt 104 deltakere (ledsagere og barn ikke inkludert) og det var invitert 25 foredragsholdere fordelt på 9 symposier. Symposiene hadde følgende hovedtema: - Effects of drugs and environmental toxicants on CNS (felles) - Årets artikkel (Farmakologi & toksikologi, felles) - Kvikksølvforurensing (toksikologi) - Behandlingsprinsipper (farmakologi) - Obesity causes and pharmacological consequences (felles) - Preventing opioid overdose deaths with take-home naloxone (Beitoforelesningen, felles) - The next generation of alternative methods for drug development and toxicity testing (Nordic symposium, felles) - Luftforurensing (toksikologi) - Opioid overdoses: Heroin replacement and naloxone continued (farmakologi) Kveldsnytt, «Hjerteinfarkt i ødemarken i Peru», ble holdt av Ola Dale, NTNU/St. Olavs Hospital. Til sammen var det meldt inn 17 frie foredrag og 34 postere fordelt på farmakologi og toksikologi. Vårmøte Practical implications of mechanistic studies in toxicology (BCPT Award seminar). Tid og sted: 30. mars 2017, Folkehelseinstituttet. Arrangør: NSFT/BCPT Høstmøte Microplastics in the environment Tid og sted: 19. oktober 2017, STAMI. Arrangør: NSFT Poulssonforelesning og seminar: Poulssonmedaljen 2017 innen klinisk farmakologi ble tildelt professor Sonia Hernandez-Diaz ved Harvard T.H. Chan School of Public Health. Boston, USA., Medaljeoverrekkelsen og Poulssonseminar ble holdt 12. desember i Auditorium 1, Georg Sverdrups Hus, UIO. Seminaret ble filmet og er tilgjengelig på nett (lenke frå NSFTs nettside) Arrangør: NSFT [20]

21 NSFTs publikasjonspris NSFT opprettet i 2014 en ny pris for beste publikasjon fra norske fagmiljøer innen hhv. farmakologi og toksikologi. De første prisene ble delt ut på vintermøtet Vinner av årets publikasjonspris innen farmakologi er Bérengère Benoit (UiB) og medarbeidere for artikkelen «Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice», Nature Medicine, Styret mottok til sammen 8 nominasjoner innen farmakologi og komiteen for vurderingen av publikasjonene har bestått av Hege S. Christensen (UiO), Hege Thoresen (UiO) og Sigrid Narum (Diakonhjemmet sykehus). Vinner av publikasjonsprisen innen toksikologi er Susann Wolf-Grosse (NTNU) for artikkelen «Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model», International journal of nanomedicine, Komiteen for vurderingen har bestått av Merete Grung (NIVA/UiO), Odd Andre Karlsen (UiB) og Håkon Wallin (STAMI). 5. Medlemmer Selskapet har 412 medlemmer (per ). Av disse har 107 medlemmer oppgitt tilhørighet til farmakologiseksjonen, 166 til toksikologiseksjonen og 50 medlemmer har tilhørighet til begge seksjonene. De resterende medlemmene har ikke valgt seksjonstilhørighet. Det er fortsatt mange medlemmer som ikke har betalt medlemskontingent. Ved utgangen av 2017 hadde 38 % av medlemmene betalt medlemskontingenten for Medlemmer uten funksjonell e-postadresse og manglende medlemskontingent vil etter hvert fjernes automatisk fra databasen. Fra 2017 kan medlemskontingenten også betales med «Vipps». 6. Formidling av faglig informasjon i nyhetsbrev og på nettsider NSFT har i løpet av 2016 sendt ut 10 elektroniske nyhetsbrev til samtlige medlemmer. Nyhetsbrevene inneholder bl.a. informasjon om kommende kurs og arrangementer innen farmakologi og toksikologi. Faglig informasjon har også blitt publisert på NSFTs nettsider og på NSFTs Facebook-side. 7. Toksikologen Elektronisk versjon av medlemsbladet «Toksikologen» har blitt lagt ut på NSFTs nettsider i mars (nr. 1), juni (nr. 2) og oktober (nr. 3). Lenker til bladet har også blitt publisert i nyhetsbrev og på NSFTs Facebook-side. 8. Registreringsordningen for Europeisk-registrerte toksikologer (ERT) Registreringsordningen er underlagt NSFT og er administrert gjennom en nasjonal godkjenningskomité. Komitéen har bestått av: Birgitte Lindeman (leder), FHI - Folkehelseinstituttet, Oslo (valgt til 2019); Christine Bjørge, Miljødirektoratet, Oslo (valgt til 2019); Espen Mariussen, NILU-Norsk institutt for luftforskning, Kjeller (valgt til 2019); Hege Stubberud, Glencore Nikkelverk AS, Kristiansand (valgt til 2017); Åse Krøkje, Norges teknisknaturvitenskapelige universitet, Trondheim (valgt til 2018); Ketil Hylland, Universitetet i Oslo, Oslo (valgt til 2018); Marie Bjørgan, Yara International ASA, Oslo (valgt til 2018); Elise Rundén- Pran, NILU-Norsk institutt for luftforskning, Kjeller (valgt til 2019), Shan Zienolddiny, Statens Arbeidsmiljøinstitutt (Stami), (valgt til 2019). Mer informasjon om ordningen finnes på NSFTs nettsider: [21]

22 9. Ny registreringsordning for Europeisk sertifisert farmakolog (EuCP) NSFT har satt sammen en komité for å etablere Europeisk sertifisert farmakolog (EuCP) i Norge. Komiteen består av Hege Thoresen (UiO), Harald Thidemann Johansen (UiO), Aina Westrheim Ravna (UiT), Laila Sortvik Nilssen (SLV), Janne K. Sund (NTNU), Siri Amundsen (UNN) og Tone Otterhaug (PCI Biotech). Komiteen har utarbeidet et forslag til nasjonale retningslinjer for EuCP som tilfredsstiller de internasjonale retningslinjene fra The Federation of European Pharmacological Societies (EPHAR). Søknad om å opprette ordningen er sendt til EPHAR Mer informasjon om ordningen finnes på: Styret for 2017 takker for seg og ønsker det nye styret lykke til i det videre arbeidet. Oslo, januar 2018 Mohammad Nouri Sharikabad (leder) Jan Tore Samuelsen (sekretær) Kristine Hole (kasserer) David Eidsvoll (styremedlem) Ida Robertsen (leder, Seksjon for farmakologi) Hubert Dirven (leder, Seksjon for toksikologi) Lars Erik Eng Eibak (industrirepresentant) Sara Bremer (vara) Birgitte Lyrån (vara) Aina Westrheim Ravna (vara) [22]

23 Norsk Selskap for Farmakologi og Toksikologi Innkalling til generalforsamling i NSFT Beitostølen, 27. januar 2018, kl. 09:30 DAGSORDEN: 1. Konstituering av generalforsamlingen ved sekretær Jan Tore Samuelsen a. Godkjenning av møteinnkalling og dagsorden b. Valg av ordstyrer og referent 2. Årsberetning for gjennomgang ved Jan Tore Samuelsen 3. Økonomi - gjennomgang ved kasserer Kristine Hole a. NSFTs regnskap for 2017 og budsjett for Valg ved valgkomiteen a. Nytt styre b. Ny revisor c. Ny valgkomité 5. Innmeldte saker: a. Forslag om å etablere æresmedlemskap i NSFT. Det er foreslått at medlemmer som har gjort en ekstraordinær innsats i styrearbeid over lengre tid kan belønnes med æresmedlemskap i NSFT. Det foreslås at styret hvert tredje år vurderer om det er aktuelle kandidater for utnevnelse til æresmedlem og at disse ikke trenger å betale årskontingent til NSFT. 6. Eventuelt Oslo, 5. januar 2018 Hovedstyret i NSFT [23]

24 Norsk Selskap for Farmakologi og Toksikologi Årsberetning seksjon for farmakologi Dette er styrets beretning om aktiviteter i perioden fra 1. februar 2017 til 27. januar Årsberetningen legges fram for godkjenning på årsmøtet i Seksjon for farmakologi på Beitostølen 27. januar Styret har hatt følgende sammensetning: Leder: Ida Robertsen ( ) Sekretær: Ingvild Holdø ( ) Styremedlem: Sigrid Narum ( ) Styremedlem: Lise Román Moltzau ( ) Styremedlem: Kristin Nordal ( ) Kontaktpersoner utenfor Oslo har vært: Bergen: Jon Andsnes Berg Trondheim: Ola Dale Tromsø: Aina Ravna Representant for seksjonen i NSFTs hovedstyre har vært Ida Robertsen. Valgkomiteen har bestått av Kjetil Wessel Andressen, Gunhild Heide og Maria Ulvestad. Styret har i perioden avholdt 4 styremøter, og har ellers hatt fortløpende kontakt via e-post og telefon om aktuelle saker. Seksjonen har pr medlemmer. Av disse er 50 i tillegg medlem av Seksjon for toksikologi. Totalt registrerte medlemmer i NSFT er 412. EPHAR (www.ephar.org) Neste EACPT-møte: The 14 th congress of the European Association for Clinical Pharmacology and Therapeutics Stockholm, Sweden, June 29- July IUPHAR (www.iuphar.org) Neste IUPHAR-møte: XVIIIth World Congress of Basic and Clinical Pharmacology 2018 Kyoto, Japan, July 1-5, 2018 NSFT kan ha en representant på generalforsamlingen. NSFTs publikasjonspris innen farmakologi 2017 Vinner av årets publikasjonspris innen farmakologi er Bérengère Benoit og medarbeidere for artikkelen «Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice», Nature Medicine, Styret mottok til sammen 8 nominasjoner innen farmakologi og komiteen for vurderingen av publikasjonene har bestått av Hege Christensen (UiO), Hege Thoresen (UiO), Sigrid Narum (Diakonhjemmet sykehus) og Ida Robertsen (UiO). [24]

25 Begrunnelse: Prisen for beste publikasjon innenfor fagfeltet farmakologi går til: Bérengère Benoit og medarbeidere for artikkelen «Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice». Artikkelen er publisert i det meget anerkjente tidsskriftet Nature Medicine. Dette er et samarbeidsprosjekt mellom Avdeling for biologi ved Universitetet i Bergen og Universitetet i Lyon, CarMeN Laboratoriet i Frankrike. Bérengère Benoit og medarbeidere har avdekket en ny funksjon av fibroblast vekstfaktor 19 (FGF 19), som innbefatter at denne er involvert i regulering av størrelsen på muskelfibre, et funn som kan ha betydning for behandling av og beskyttelse mot sykdommer som gir muskelatrofi. Det er anvendt en rekke avanserte cellebiologiske metoder i dette arbeidet, og i tillegg til in vitro metodikk, er det gjort in vivo studier i mus. Arbeidet har en klar farmakologisk problemstilling, er godt skrevet og har en klinisk relevans. Utdeling av Poulssonmedaljen 2017 Poulssonmedaljen 2017 innen klinisk farmakologi ble tildelt professor Sonia Hernandez-Diaz, Harvard T.H Chan School of Public Health tirsdag 12. desember 2017 i auditorium 1, Georg Sverdrups hus, Universitetet i Oslo. PROGRAM 13:00-13:15 Welcome and short introduction of Poulsson Award Recipient: Prof Sonia Hernandes-Diaz Mohammad Nouri Sharikabad, Leader of NSFT 14:15-14:15 The Poulsson Award Lecture Professor Sonia Hernandez-Diaz, Harvard T.H Chan School of Public Health Application of causal inference approaches in medication safety in pregnancy studies 14:30-15:10 The unique Nordic data sources examples of real world opportunities and challenges: I. Opioid Maintenance treatment of opioid addicted pregnant women benefits the pregnant women, but what about the fetus? Senior Reseacher Marte Handal, FHI II. Is it safe to use paracetamol and antidepressants in pregnancy? And, how do we communicate risk to the public? Professor Hedvig Nordeng, UiO 15:10-15:30 Pharmacokinetic changes of psychotropic drugs in pregnancy - implications for dosing regimens? Professor Olav Spigset, NTNU, St. Olavs hospital Vintermøtet 2018 Seksjonen har deltatt i utformingen av programmet for NSFTs vintermøte. Regnskap Regnskapet for seksjonen har i 2017 vært håndtert sammen med regnskapet for NSFT som helhet. For en formell økonomisk oversikt henvises det derfor til NSFTs regnskap. [25]

26 Avslutning Seksjonsstyret for 2017 takker for seg og ønsker det nye styret lykke til med det videre arbeidet. Ingvild Holdø Sigrid Narum Lise Román Moltzau Kristin Nordal (Sekretær) (Styremedlem) (Styremedlem) (Styremedlem) Ida Robertsen (Leder) [26]

27 Norsk Selskap for Farmakologi og Toksikologi Innkalling til årsmøte i seksjon for farmakologi NSFT Beitostølen, 27. januar 2018, kl. 09:00-09:30 DAGSORDEN 1. Konstituering av årsmøtet a. Godkjenning av møteinnkalling og dagsorden b. Valg av ordstyrer og referent 2. Årsberetning for farmakologiseksjonen Godkjenning av budsjett for seksjon for farmakologi 4. Valg a. Nytt styre i farmakologiseksjonen b. Ny valgkomité 5. Orienterings- og diskusjonssaker a. Vår/høstmøte 2018 b. Innspill til vintermøte Eventuelt Oslo, januar 2018 Styret i farmakologiseksjonen NSFT [27]

28 Norsk Selskap for Farmakologi og Toksikologi Årsberetning 2017 seksjon for toksikologi 1. Styrets sammensetning Årsmøtet for toksikologiseksjonen ble avholdt på Vintermøtet 27. januar 2017 på Radisson BLU Resort Beitostølen. Styrets sammensetning for toksikologiseksjonen i året 2017 har vært som følgende: Leder - Hubert Dirven ( ) FHI, Oslo Merete Grung ( ) NIVA/UiO, Oslo Dag Marcus Eide ( ) FHI, Oslo Yke Arnoldussen ( ) STAMI, Oslo Gunnar Sundstøl Eriksen ( ) - VI, Oslo Odd Andre Karlsen ( ) UiB, Bergen Marit Nøst Hegseth ( )- UiT, Tromsø Vara-medlemmer: Nina Landvik ( ) STAMI Vidar Berg ( ) - NMBU Valgkomiteen for : Shan Zienolddiny og Marianne van der Hagen 2. Styrets arbeid Styret har i perioden avholdt 4 møter og har hatt omfattende kommunikasjon via e-post. Styret har i perioden jobbet med: - Organisering av seksjonens faglige virksomhet (vår-, høst- og vintermøter) - Organisering av pris for beste publikasjon - Bekymringsbrev rund utdanning fra toksikologien til flere departementer - Rekruttering og utdanning av toksikologer (inkludert støtte til Fagrådet for humantoksikologi) - Utgivelse av seksjonens tidsskrift "Toksikologen" - Formidling av informasjon på NSFTs nettsider og i nyhetsbrev - Europeisk registrert toksikolog (ERT)-registreringer - Hubert Dirven deltok i Eurotox business council meeting i Bratislava (september 2017) 3. Faglig virksomhet Vintermøtet 2017 Pris for beste poster gikk til Solveig Uvsløkk (NIOM): Effects of HEMA on the cytoskeleton in BEAS-2B cells Pris for beste frie foredrag gikk til Ole Jakob Nøstbakken (NIFES): Mice strain and administration route impact the toxicity of methylmercury [28]

29 Vårmøtet 2017 Tema: Practical implications of mechanistic studies in toxicology. Symposium to mark that Prof Jan Alexander received the BCPT award for his major scientific contributions to toxicology. Agenda Welcome Hubert Dirven (NSFT) BCPT Award ceremony Jan Alexander Kim Brøsen, Basic & Clinical Pharmacology & Toxicology Practical implications of mechanistic studies in toxicology Jan Alexander (NIPH) Break Experimental models to study mechanisms of neurotoxicity Ragnhild Paulsen Farmasøytisk institutt - UIO Mechanistic studies of immune effects by xenobiotics Unni Cecilie Nygaard Folkehelseinstituttet Adverse outcome pathways a system to organize mechanistic information and identify research needs Knut Erik Tollefsen (NIVA / NMBU) Chemicals and obesity/ metabolic syndrome can experimental models help us to understand? Inger-Lise Steffensen Folkehelseinstituttet Identifying initial triggering mechanisms an important challenge in mechanistic toxicology Johan Øvrevik Folkehelseinstituttet Rundt 60 deltakere deltok på dette vårmøtet. Høstmøtet 2017 Tema: Microplastics in the environment Agenda 13:00 Welcome Hubert Dirven (NSFT) Introduction by the chair of the meeting (Merete Grung, NIVA/UiO) 13:10 Plastic in the ocean Geir Wing Gabrielsen (Norsk Polarinstitutt) 13:50 Ecotoxicity related to microplastics Amy Lusher (NIVA) 14:40 Is microplastics a big issue? Elisabeth Magnus (Svanemerket) 15:10 Vertical Transport to, and quantification of, microplastic in sediment Hans Peter Arp (NGI) 15:40 Microplastics in terrestrial environments Rachel Hurley (NIVA) Rund 70 deltakere deltok på dette høstmøtet. [29]

30 Nominasjon av NSFT s publikasjonspris innen toksikologi for 2017 Siden 2014 har NSFT tildelt pris for årets beste publikasjon fra norske fagmiljøer innen hhv. farmakologi og toksikologi (akseptert for publikasjon i perioden fra 1. november året før til 31. oktober inneværende år). I 2017 har komiteen for vurderingen bestått av Merete Grung (NIVA/UiO), Odd Andre Karlsen (UiB) og Håkon Wallin (STAMI. Toksikologiseksjonen fikk inn 3 nominasjoner til denne prisen. Vinner av publikasjonsprisen innen toksikologi er Susan Wolf-Grosse, for artikkelen Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model publisert i International Journal of Nanomedicine Toxicol In Vitro Sep;35: Artikkelen ble nominert med følgende begrunnelse: I studien benyttes et nytt ex vivo system med hel-blod for å studere effekter av nanopartikler (Fe- NP) på det medfødte immunsystemet, henholdsvis komplement-aktivering og cytokin sekresjon. Mye er ukjent angående toksisiteten til NP. Dette gjør det svært viktig å kartlegge toksisiteten med tanke på videre bruk av NP i f.eks. biomedisinsk anvendelse. Dette er den første studien av inflammatoriske effekter av Fe-NP i hel-blod, og det første studiet som viser at Fe-NP induserer cytokin sekresjon på en komplement-avhengig måte. Metodemessig fremstår den som omfattende, og resultatene gir en mekanistisk forståelse av toksisiteten til Fe-NP. Konklusjonene virker troverdige basert på dataene presentert i artikkelen Europeiskregistrerte toksikologer (ERT)-komiteen Registreringsordning for toksikologer: Den norske komiteen for godkjenning av Europeiskregistrerte toksikologer (ERT) har etter Vintermøtet 2017 bestått av: Birgitte Lindeman (leder), FHI - Folkehelseinstituttet, Oslo (valgt til 2019); Christine Bjørge, Miljødirektoratet, Oslo (valgt til 2019); Espen Mariussen, NILU-Norsk institutt for luftforskning, Kjeller (valgt til 2019); Hege Stubberud, Glencore Nikkelverk AS, Kristiansand (valgt til 2017); Åse Krøkje, Norges teknisk-naturvitenskapelige universitet, Trondheim (valgt til 2018); Ketil Hylland, Universitetet i Oslo, Oslo (valgt til 2018); Marie Bjørgan, Yara International ASA, Oslo (valgt til 2018); Elise Rundén-Pran, NILU-Norsk institutt for luftforskning, Kjeller (valgt til 2019), Shan Zienolddiny, Statens Arbeidsmiljøinstitutt (Stami), (valgt til 2019). Informasjon om ERT-ordningen finnes på NSFTs nettsider: Oppsummering av ERT-komitéens arbeid i 2017 Komiteen mottok høsten 2017 én søknad om førstegangs-registrering og 11 søknader om reregistrering. Søknadene blir behandlet i ERT-komitéen i januar Vi har deltatt på EUROTOX sitt ERT-møte i september Både i Europa/Eurotox og nasjonalt jobbes det med å fremme toksikologiens stilling i samfunnet, og å styrke og harmonisere ERTsertifiseringen. Dette arbeidet fortsetter. Det var i 2016 i underkant av 1500 Eurotox-registrerte ERTer og per i dag noe over 80 ERTer på den norske listen. Den norske ERT-komiteen ser på alternativer for å forenkle søknadsprosedyrene for ny-registrering og re-registrering og med bedre spredning av informasjon om relevante kurs som tilbys på ved ulike Universiteter og institusjoner i Norge og Norden. [30]

31 Vintermøtet 2018 Styret har foreslått en del temaer til symposia (Perfluorerte forbindinger, Hot topics in risk assessment, Alzheimer causes and new targets, Real-world evidence (Registerforskning) og Toxicology and pharamacology without animal experiments: will it be possible in the 10 years) og har vært aktiv til å få program og foredragsholdere på plass. Toksikologiseksjonen fikk inn 18 abstrakter for orale presentasjoner og 8 abstrakter for postervisninger for Vintermøtet For å lage mer plass til frie foredrag har vi i 2018 byttet ut et toks-symposium med en frie foredragseksjon. 4. Utgivelse av "TOKSIKOLOGEN"- Toksikologiseksjonens fagtidskrift Fagbladet «Toksikologen» har blitt sendt ut (elektronisk versjon) til samtlige medlemmer i mars (nr. 1), juni (nr. 2), september (nr. 3). Lenker til bladet har også blitt publisert på NSFTs nettsider og i nyhetsbrev. Redaksjonen i Toksikologen i 2017 besto av: Thomas Aga Legøy (redaktør), Gunhild Rogne Halland, Pernille Kvernland, Marie Dahlberg Persson. 5. Andre aktiviteter I januar 2017 sendte NSFT et brev til universiteter og departementer med bekymringer om utdanningssituasjonen innen toksikologi. Brevet var signert Jørn Holme og Hubert Dirven. Brevet ble sendt til Helse- og omsorgsdepartementet, Klima- og miljødepartementet, Landbruks- og matdepartementet, Nærings- og fiskeridepartementet, Kunnskapsdepartementet, Arbeids- og sosialdepartementet, Forsvarsdepartementet, Norges forskningsråd, Universitetet i Oslo, Universitetet i Bergen, Norges teknisk-naturvitenskapelige universitet, Norges miljø- og biovitenskapelige universitet, Norges arktiske universitet og Universitetet i Tromsø. Kopi av brevet ble sendt til Helse- og omsorgsgruppen på Stortinget De siste årene er utdanningen innen humantoksikologi blitt svekket. Dette er bekymringsfullt, da både forskning og forvaltning har et stort behov for humantoksikologer. Miljøgifter, kjemikalier og forurensning truer helsa vår, og det kreves både gode forskningsmiljøer og solid faglig kompetanse for å dekke forvaltningens behov innenfor regulering av kjemikalier. Humantoksikologer med god kompetanse er nødvendig for å utføre risikovurderinger i et sykdomsforebyggende perspektiv for en rekke departementer som er ansvarlige for regulering og forvaltning av blant annet matvarer, kjemikalier, lokal luftkvalitet, arbeidsmiljø, landbruk og havbruk. Et svekket utdanningstilbud innen toksikologi vil få store konsekvenser for rekruttering av humantoksikologer til forvaltningen, næringslivet og internasjonale organisasjoner som EFSA, ECHA og WHO, og vil på sikt også kunne true etablerte humantoksikologiske forskningsmiljøer i instituttsektoren og ved enkelte universiteter. Norsk selskap for farmakologi og toksikologi (NSFT) og det humantoksikologiske miljøet i Norge er derfor sterkt bekymret for situasjonen rundt utdanning og forskning innenfor fagområdet humantoksikologi. Brevet fikk en del medieomtale (Dagens medisin, Universitas) og innenfor Forskningsrådet, men trenger oppfølging. [31]

32 Fagrådet for humantoksikologi Mange miljøer er bekymret for utdanningstilbudet på MSc, PhD og post-doc nivå innen humantoksikologi. FHI har opprettet et fagråd for humantoksikologi som Hubert Dirven leder. Toks-styret i NSFT støtter aktivt arbeidet til fagrådet. 5. Medlemmer 166 NSFT-medlemmer har oppgitt tilhørighet til toksikologiseksjonen og 50 medlemmer har tilhørighet til begge seksjonene. Oslo, januar 2018 Styret for Toksikologiseksjonen [32]

33 Norsk Selskap for Farmakologi og Toksikologi Innkalling til årsmøte i Seksjon for toksikologi, NSFT Beitostølen, 27. januar 2018, kl. 09:00-09:30 DAGSORDEN: 1. Konstituering av årsmøtet a. Godkjenning av møteinnkalling og dagsorden b. Valg av ordstyrer og referent 2. Årsberetning for toksikologiseksjonen Godkjenning av budsjett for seksjon for toksikologi 4. Valg a. Nytt styre i toksikologiseksjonen b. Ny valgkomité 5. Møter 2018 nye forslag og videreføring av idéer a. Vår- og høstmøte 2018 b. Innspill til vintermøte Eventuelt a. Fagrådet for humantoksikologi / utdanning av toksikologer b. Behov for toksikologer i de neste 5 år Oslo, januar 2018 Styret i toksikologiseksjonen NSFT [33]

34 Inviterte foredrag (IF) IF1 Pathogenic mechanisms and potential drug targets Lars Nilsson(UiO) IF2 Early Alzheimer s disease diagnostics, experimental and clinical trials Tormod Fladby (UiO) [34]

35 IF3 Traffic-related exhaust and other environmental pollutants mixtures as risk factors for dementia and neurodevelopmental disorders Oddvar Myhre 1, Johan Øvrevik 1, Marit Låg 1, Gro Villanger 1, Heidi Aase 1, Bente Oftedal 1, Erik Ropstad 2, Erik Le Ferrec 3, Joanna Gromadzka-Ostrowska 4, Jørn A. Holme 1. Norwegian Institute of Public Health 1, Norwegian University of Life Sciences 2, University of Rennes 3, Warsaw University of Life Sciences 4, In recent years the prevalence of neurodevelopmental disorders (NDDs) like Attention- Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorders (ASD) have increased. In addition sub-clinical cognitive and learning disabilities have been observed (1). Also, neurodegenerative diseases resulting in dementia have increased. Genetic factors seems to be important, but exposure to toxicants has been proposed as a contributing risk factor. Research has identified critical windows of vulnerability during embryonic and foetal development, early childhood and adolescence, where environmental toxicant exposures in particular may cause neurodevelopmental disabilities. Exposure to urban air may result in premature death as well as long term chronic diseases. The increased death rate is related to cardiovascular and pulmonary effects of particular matter (PM), however, in recent years the brain has been considered a potential target organ for air pollution exposure. Epidemiological studies indicate neurodevelopmental toxicity resulting from exposure to traffic-related air pollution, lead, mercury, organophosphate pesticides, PBDEs, phthalates and PCBs. Also, associations between traffic-related air pollution and dementia have been reported. However, as most of these studies are crosssectional, longitudinal studies are needed to imply causality. Furthermore, mechanistic studies are needed to explain and substantiate a causal association. Based on experimental studies, some mechanisms have been proposed as key events linking pollution exposure and NDDs. These include disturbed dopamine and noradrenaline signaling, dysregulation of thyroid hormones and neurotrophic factors, as well as oxidative stress, and inflammation. Our experiments presented here show that inhalation of biodiesel exhaust in rats and in utero feeding exposure of a POP mixture in mice resulted in cognitive deficits and disturbed intracellular signaling related to oxidative stress, inflammation, disturbance of endocrine signaling and cognitive pathways. Most interestingly, members of our consortium have seen that air pollution components like PAHs bind to beta adrenergic receptors (2,3), receptors that have been suggested as causative factors for NDDs (4). Toxicological studies and regulatory evaluation seldom address combined effects of chemical mixtures, despite evidence that all people are exposed to dozens of chemicals at any given time. The closure of the knowledge gaps between exposure and associated CNS effects in epidemiological studies requires the combined use of modern epidemiological studies, new high through-put screening techniques, and sophisticated experimental animal studies combined with recent developments in mechanistic in vitro studies. References. 1. Boyle et al Trends in the prevalence of developmental disabilities in U.S. children, Pediatrics 127, Mayati et al Calcium signaling and beta2-adrenergic receptors regulate 1-nitropyrene induced CXCL8 responses in BEAS-2B cells. Toxicology in vitro 28, Mayati et al Benzo(a)pyrene triggers desensitization of beta2-adrenergic pathway. Sci Rep 7, Bonvicini et al Common and specific genes and peripheral biomarkers in children and adults with Attention-Deficit/Hyperactivity Disorder. Biological Psychiatry, [35]

36 IF4 Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice Jérôme Ruzzin (UiB) The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellularsignal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mtor-dependent master regulator of muscle cell growth. Moreover, mice with a skeletalmuscle-specific genetic deficiency of β-klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting. [36]

37 IF5 Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model Susann Wolf-Grosse 1, Anne Mari Rokstad 1-3, Syed Ali 4, John D Lambris 5, Tom E Mollnes 2,6-9, Asbjørn M Nilsen 1, Jørgen Stenvik 1,2 1 Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim 2 Centre of Molecular Inflammation Research (CEMIR), Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim 3 Central Norway Regional Health Authority, Stjørdal, Norway 4 Division of Neurotoxicology, US FDA/National Center for Toxicological Research, Jefferson, AR, USA 5 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA 6 Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway 7 Research Laboratory, Nordland Hospital, Bodø, Norway 8 K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway 9 Faculty of Health Sciences, K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway Background Iron oxide nanoparticles (IONPs) are promising nanomaterials for various biomedical applications, including contrast agents for magnetic resonance imaging, in targeted drug delivery systems and for induced hyperthermia cancer treatment. However, their inflammatory potential has not been fully established. Methods We used a lepirudin anti-coagulated human whole blood model to evaluate the inflammatory potential of 10 nm IONPs with a focus on complement activation, production of cytokines and reactive oxygen species, and cell death. Results The 10 nm IONPs activated complement, as measured by C3a, C5a and sc5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 μg/ml IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (Soliris (eculizumab); Alexion Pharmaceuticals, Zürich, Switzerland) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs. Additionally, blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated. The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines. Conclusion These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood. [37]

38 IF6 Does fluor in your ski wax give an anti-climax for your health or the environment? Line Småstuen Haug 1, Ragna Bogen Hetland 1, Kristine Bjerve Gützkow 1, Birgitte Lindeman 1, Rune Becher 1 1 Division of Infection Control and Environmental Health, Norwegian Institute of Public Health Aim Previously, the National Institute of Occupational Health (STAMI) in Norway has investigated the exposure to particles and per- and polyfluoroalkyl substances (PFASs) from indoor air in professional ski waxers waxing booths. The professional ski waxers had small reductions in lung function tests, and there were indications that particles generated during ski preparation could induce inflammatory reactions in their lungs. The same individuals had also indications of more general inflammatory conditions expressed as elevated blood levels of C-reactive protein. However, to what extent amateurs are exposed to particles and PFASs from air during ski preparation is not known. The Norwegian Institute of Public Health (NIPH) was asked by the Norwegian Environment Agency to perform a pilot study in order to determine the concentrations of particulate matter and PFASs in the air from ski waxing booths in a selection of Cross Country and biathlon competitions at non-professional level during the season Method Particles in indoor air were collected during four different competitions in February and March Inhalable particles (<100μm) in air from waxing booths were collected using a GSP inhalable aerosol sampler. Two samplers, with a distance of approx. 50 cm, were mounted on a stand approx. 150 cm from the floor to reflect the air inhaled by the ski waxers. The PFAS content in the collected particles was determined using on-line column switching LC-MS/MS. Results Analysis of the collected samples demonstrated that the concentrations of particles in air from the waxing booths varied widely, both during one competition and between the different competitions. Nevertheless, the results were highly comparable to the results reported by STAMI for professional ski waxers. A range of PFASs was determined in the particles collected in air from the waxing booths, and again the concentrations were in the same range as previously reported by STAMI. As an example, the median concentration of perfluorooctanoate (PFOA) in the present study was 12 µg/g particulate matter while in the STAMI report it was 15 µg/g. These PFOA concentrations are around three orders of magnitude higher than the concentrations found in house dust from Norwegian households. Conclusion The concentrations of particles and PFASs in air from ski waxing booths used by amateurs were comparable to that shown to represent a possible health hazard to professional ski waxers. The results confirmed the basis for maintaining previous advice and recommendations on ventilation and protection measures given by the NIPH. [38]

39 IF7 Perfluorocarbons in aquatic environments - presence and effects Eirik Fjeld, Norwegian Institute for Water Research Abstract Per- and polyfluoroalkyl substances (PFASs) are a large group of different man-made chemicals, not found naturally in the environment. They are extremely persistent and resistant to typical environmental degradation processes, may accumulate in organisms and have adverse biological effects. In this presentation, I will first give a short introduction to the different families of PFAFs and the most extensively produced and studied of these substances (PFOS and PFOA). Then I will present some studies treating pollution of PFASs in the aquatic environment: i) The "C8" case of DuPont where the company's Washington Works plant in West Virginia polluted the aquatic environment and drinking water reservoirs in the neighbourhood and downstream the waterways with PFOA. Based on an epidemiological survey, a scientific panel concluded that there was a probable link to PFOA exposure for six disease categories: diagnosed high cholesterol, ulcerative colitis, thyroid disease, testicular cancer, kidney cancer, and pregnancy-induced hypertension. In 2017, DuPont and its spinoff company, Chemours, agreed to pay more than $670m to settle thousands of lawsuits brought by residents of Ohio and West Virginia that claimed the companies poisoned their water with PFOA. ii) PFAS pollution at Norwegian airports. Surveys of soils and the aquatic environment at more than 50 Norwegian airports (both civilian and military) have shown that most of these have polluted their environment with PFAS. Actions for remediation and cleaning of polluted soils and ground water have been initiated. iii) The Norwegian Environment Agency has initiated surveys on the occurrence of PFAS in the environment, including coastal waters and lakes. While PFOS is the dominating PFAS in marine organisms, do the more long-chained perfluorocarboxylic acids dominate in freshwater organisms from lakes without local discharges. This may indicate that precursors of perfluorocarboxylic acids, such the more volatile fluorotelomer alcohols, are subject to atmospheric transport / depositions and are primary sources for the long-chained perfluorocarboxylic acids found in pristine freshwaters. [39]

40 IF8 Effects of perfluoroalkyl substances on metabolic health Birgitte Lindeman 1, Kristine Bjerve Gützkow 1, Inger-Lise Steffensen 1 1 Division of Infection Control and Environmental Health, Norwegian Institute of Public Health Evidence indicating that perfluoroalkyl substances (PFAS) may increase the susceptibility to metabolic dysfunction is building up. The focus of this talk is on evidence for metabolic disruption caused by exposure to perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), as these two PFAS are found in human blood and are by far the most studied with regard to toxicity. Main health concerns identified for PFAS exposure were diagnosed high cholesterol, ulcerative colitis, thyroid disease, testicular cancer, kidney cancer, and pregnancy-induced hypertension. Among the most consistent findings from human epidemiological studies is the association of PFOA with increased blood cholesterol. More recently, associations between PFAS and blood glucose concentration have been reported, but the data concerning glucose regulation and risk of type 2 diabetes appear conflicting. Rodent models show liver toxicity, including liver steatosis (fatty liver), in response to PFOA and PFOS exposure. Developmental exposure of rodents to human relevant PFAS doses has been reported to cause persistent structural and functional disturbances in liver of adult animals. PFAS are known to activate peroxisome proliferator-activated receptor alpha (PPARα) that induce liver peroxisome proliferation and controls lipid and glucose metabolism. There are important species differences in PPARα mediated peroxisome proliferation that influence the sensitivity to PFAS toxicity. However, several of the hepatic effects observed following developmental exposures appear to be peroxisome proliferation independent, indicating a concern also for human liver effects. The mechanisms underpinning PPARα-independent toxicity are far from clear. However, PFAS have been shown to interfere with metabolic signalling through other receptors, like PPARγ, oestrogen receptor (ERα) and hepatic nuclear factor 4 alpha (HNF4α). In conclusion, data suggest that human relevant exposures levels of PFAS may induce metabolic disturbances and possibly increase the susceptibility of humans to metabolic disease. Increased cholesterol levels and increased liver lipids are two endpoints of potential concern for humans. Elucidating these associations and causal mechanisms will aid the regulatory decisions regarding safety of other PFAS. References C8 Science Panel: Filgo AJ, Quist EM, Hoenerhoff MJ, Brix AE, Kissling GE, Fenton SE (2015) Perfluorooctanoic Acid (PFOA)-induced Liver Lesions in Two Strains of Mice Following Developmental Exposures: PPARα Is Not Required. Toxicol Pathol.43(4): Ngo HT, Hetland RB, Sabaredzovic A, Haug LS and Steffensen I-L (2014) In utero exposure to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) did not increase body weight or intestinal tumorigenesis in multiple intestinal neoplasia (Min/+) mice. Environ. Res. 132, [40]

41 IF9 Increasing use of antidepressants in young people worrisome or not? Ingeborg Hartz Sykehuset Innlandet, Nasjonalt Folkehelseinstitutt, Høgskolen i Innlandet Recent studies have shown an increasing use of antidepressants (ADs) among adolescents in European countries and in the USA. In Norway, we have also seen a pronounced increase in the use of ADs between 2009 and 2016, particularly among adolescent girls. According to the Norwegian child and adolescent psychiatry guidelines SSRIs may be used to treat moderate to severe depression and obsessive-compulsive disorders. On this background, are the trend of increasing AD use in young people worrisome? To explore this further results from Norwegian epidemiological studies including data from nationwide individual-level health registries, such as Primary health care database (KUHR), the Norwegian Patient Registry (NPR) and the Norwegian Prescription Database (NorPD) will be presented. [41]

42 IF10 Studie om bivirkninger/sikkerhet ved bruk av antidepressiva til barn Tone Westergren 1, Sigrid Narum 2, Marianne Klemp 3 1 RELIS Sør-Øst, Avdeling for farmakologi, Oslo universitetssykehus Rikshospitalet 2 Senter for psykofarmakologi, Diakonhjemmet sykehus 3 Avdeling for farmakologi, Universitetet i Oslo Problemstilling Det er kjent at bivirkningsrapporteringen i mange tilfeller er mangelfull ved publisering av kliniske studier. Dette kan skyldes metodene som er brukt for å avdekke bivirkninger, hvilke bivirkninger som vil kunne oppdages og på hvilken måte funnene er gjengitt i publikasjonen. Det er en økende bruk av antidepressiva til barn og unge. Flere artikler diskuterer nytte-/ risikoforholdet ved antidepressivabehandling, der det stort sett har vært fokusert på risiko for selvmordsrelaterte bivirkninger. Vi ønsket å analysere forekomst og rapportering av alle typer bivirkninger i en sentral studie av fluoksetin og/eller kognitiv terapi gitt til barn med depresjon (The Treatment for Adolescents With Depression Study (TADS-studien)(1)). Metode Litteratursøk for å identifisere alle publikasjoner fra TADS-studien. Gjennomgang av publikasjonene for å finne rapporterte bivirkningsdata, og vurdere rapportering av bivirkninger i forhold til studiens protokoll, utfallsmål, behandlingsvarighet og det som er kjent om bivirkningsprofilen til fluoksetin. Resultater Vi identifiserte 48 publikasjoner som omhandlet planlegging, gjennomføring og resultater fra TADS-studien. Flertallet av studiene omhandlet andre typer data enn effekt og bivirkninger. Eksempelvis gjaldt 25 publikasjoner metodespørsmål, demografiske data eller utfallsmål som ikke var primære eller sekundære i følge studieprotokollen. 12 av 48 publikasjoner beskrev primære og/eller sekundære endepunkter. Enkelte publikasjoner presenterte utelukkende data for effektparametre og nevnte ikke bivirkninger. Publikasjonene som i størst grad ga informasjon om bivirkningsforekomst beskrev selvmordstanker og selvmordshandlinger. Andre mulige bivirkninger, som forverring av depresjon, irritabilitet, agitasjon og angst/panikk var kun nevnt i få artikler og var ikke utfyllende eller konsistent beskrevet. De var ikke omtalt i publikasjonen som ga resultater fra langtidsbehandling (52 uker). Konklusjon TADS-studien har gitt opphav til mange publikasjoner, men få av disse presenterer utfyllende bivirkningsdata i henhold til studieprotokollen. Bivirkningsrisiko er i flere artikler begrenset til å omfatte selvmordsrelatert adferd, mens andre typer bivirkninger er mangelfullt beskrevet. Det reiser spørsmålet om på hvilken måte bivirkningsdata fra studien er gjengitt eller referert til i behandlingsanbefalinger og retningslinjer, og om risiko/nyttevurderinger for antidepressivabehandling av barn kan være gjort på mangelfullt grunnlag. Referanse 1. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004;292(7): [42]

43 IF11 POPs in breastmilk; is there a reason for concern Merete Å Eggesbø 1 1 Norwegian Institute of Public Health POPs biomagnify and bioaccumulate and these properties results in the human fetus and breastfed baby being the most exposed of all species and ages. The history of exposure to industrial chemicals is short and only until recently are studies emerging that are sufficiently powered, take mixtures into account, and uses appropriate exposure assessment in the perinatal period where concentrations fluctuate widely over time. Especially the initiative to pool data from multiple birth cohorts has been very successful as it increases power, eliminate report bias and controls unmeasured confounding better. I will focus mainly on pooled studies and studies including data from Norway, when giving highlights from research. Several studies have investigated the obesogenic effect of chemicals. Taken together the data support the conclusion that exposure to polychlorinated biphenyl 153 (PCB-153) results in reduced fetal growth resulting in lower birth weight (1). Moreover, if the baby was breastfed and thus further exposed to PCB during the postnatal period, this was associated with a further reduction in growth(2). In contrast prenatal exposure to p,p -dichlorodiphenyldichloroethylene (p,p -DDE) increases birth weight (3). It was uncertain whether any added exposure to DDE through breastfeeding had a further effect. Dioxin and dioxin-like compounds were also associated with increased infant growth and BMI, with a significant 54% increased risk of over weight at 7 years, but only in girls. The disadvantage of pooled studies is that data are usually only available on a couple of toxicants at a time. In a mixture study on 789 babies, Hexachlorobenzene, β-hexachlorocyclohexane (β-hch), and PCB-74 were identified to effect growth, only β-hch statistically significantly decreasing postnatal growth (4). With regard to neurodevelopment, preliminary data from a pooled study with 7 European birth cohorts, did not indicate any association between PCB-153, HCB or p,p - DDE and ADHD. In contrast studies including a large mixture of toxicants in concentrations Norwegian infants are exposed to, show neurodevelopmental effects of DDT (5), and also of β-hch and arsenic (6), but the latter two are based on preliminary data. Interestingly, preliminary data indicates that one of the potential mechanisms through which POPs exert their adverse effects, may be through disruption of the microbiota. In conclusion, multiple studies report adverse effects of POPs at the current level of exposure in Norway. The studies support a recent WHO-UN report, which concluded that environmental toxicants are a threat to human health. The largest exposure takes place in the postnatal period, although the prenatal period seems the most sensitive at least for some, but not all, chemicals. References 1.Govarts E et al Environ Health Perspect 2012 ;Volum 120.(2) s Iszatt N et al. Environ Health Perspect Jul;123(7): Iszatt N et al. Environ Int Sep;94: Criswell R et al. Ann Nutr Metab Mar Forns J et al. Env Research Nov;151: Stiboller M et al. Environ. Sci. Technol. Lett., 2017, 4 (7), pp [43]

44 IF12 Use and effects of prescription drugs and drugs of abuse. Real world evidence? Svetlana Skurtveit Department of mental disorders, Norwegian Institute of Public Health, Oslo Senter for rus- og avhengighetsforskning (SERAF), University of Oslo Norway and other Nordic countries are in a special position with their detailed and thorough records of information about the country's populations. Headlines like Health data is the new oil" is presented by the authorities, journalists and researchers. The health registries together with the demographic and socio-economic records, population health surveys and other health data and biobanks make the data in Norway especially attractive. Existence of personal identification number gives us the possibility to link registries and other data sources together. National registries of health data from birth to death, overview of family relationships and the ability to use registry information along with data from health surveys or other cohort studies and associated biobanks, provide unique research opportunities. Such links provide the opportunity to study risk factors not registered in national registries, such as genetics, environmental and lifestyle factors, and symptoms and conditions that are not treated or registered in health services. The purpose of the presentation will be give an overview of which kind of health data we have in Norway. Different central health registries, medical quality registries, health surveys and biobanks will be presented. Further, the possibility of linkage between different data sources and the prescription database or other data sources with information on prescription drugs and drugs of abuse will be described. The possibilities of how real world data from registry linkages can contribute to new knowledge in current public health challenges with some examples will be presented. [44]

45 IF13 Developmental neurotoxic effects of environmental toxicants and pharmaceutical drugs and the contribution of in vitro systems. Anna Price European Commission Joint Research Centre (JRC), Directorate F Health, Consumers and Reference Materials, Unit F3: Chemicals Safety and Alternative Methods, Ispra (Italy) Recent societal concerns have been raised linking the rise in children s developmental learning disabilities such as attention deficit/hyperactivity disorder, autism spectrum disorders and learning disabilities to chemical exposures. In addition to genetic factors, such exposure might be causally linked to an increased prevalence of the neurodevelopmental disorders. Moreover, there is a profound lack of understanding of the mechanisms of chemical- or drug-induced developmental neurotoxicity (DNT). Current performance of the DNT in vivo guideline study involves the use of large numbers of animals and is therefore cost- and time-intensive. These facts contribute to the reason why only a few environmental chemicals (12) are classified as human developmental neurotoxicants. Therefore, there are on-going initiatives that promote novel approaches in DNT testing, including mechanistic in vitro studies. During this talk, an overview of the most advanced in vitro neuronal/glial models (including those derived from human induced pluripotent stem cells) and assays such as gene and mirna expression and electrical activity measurements will be presented. New DNT testing approaches, based on a battery of in vitro DNT assays anchored to common key events identified in the existing DNT Adverse Outcome Pathways (AOPs) will be proposed, followed by an attempt to build an AOP-informed Integrated Approach to Testing and Assessment (IATA) for an initial chemicals and pharmaceutical drugs screening and prioritization. Such IATA would facilitate an application of mechanistic in vitro data into DNT evaluation, increasing scientific confidence in decision making processes, delivering mechanistic knowledge that could contribute to hazard identification and characterization and possibly safety assessment of chemicals, speeding up evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential. [45]

46 IF14 Animal free toxicology exemplified by human placenta studies in the studies of transport of enviromental contaminants and pharmaceutical drugs Lisbeth E. Knudsen, professor, PhD, in the board of the Danish 3R Centre Department of Public Health, University iof Copenhagen Problem Toxicology and pharmacology information from human cells and tissues provides information readily applicable in human safety and efficacy assessment. The 3Rs principle in animal studies includes the use of human material in the replacement R. The reduction and refinement Rs are related to animal use. Knowledge about the 3Rs and successfull examples is a prerequiste for less animal experiments in the future. And more collaboration between animal and animal free researchers is necessary with mutual respect. Methods The Danish 3R centre performed a survey amongst researchers involed in animal experiments. The study comprises a quantitative study with a questionnaire issued to animal researchers. A total of 293 animal researchers participated in the online survey, of which 234 responded to all 54 questions. Studies with human placental tissue is an example in animal free toxicology (Knudsen 2013) replacing transport studies and. Results The majority of the informants participating in the survey report that no factor would allow them to continue to achieve their research objectives without using animals since their work demands that they look at the whole animal system. Scientific factors such as greater availability of human tissues, more relevant cell cultures and more predictive computer models were the most important requirements in terms of being able to replace animals in experiments (Nøhr et al 2016) Studies with human placental tissue provides useful human data related to transport across the term placenta (Poulsen et al 2015, Mose et al 2012) and establishment of an international network will promote utilization (Brownbill et al 2016) Conclusion A decline in expermental animal use the next 10 years is realistic if continued focused on. References Brownbill P, Chernyavsky I, Bottalico B, Desoye G, Hansson S, Kenna G, Knudsen LE, Markert UR, Powles Glover N, Schneider H, Leach L (2016) An international network (PlaNet) to evaluate a human placental testing platform for chemicals safety testing in pregnancy. Reprod Toxicol. 64: Knudsen LE (2013) Animal-free toxicology: the use of human tissue to replace the use of animals - examples from human biomonitoring and human placental transport studies. Altern Lab Anim. 41(6): Mose T, Mathiesen L, Karttunen V, Nielsen JK, Sieppi E, Kummu M, Mørck TA, Myöhänen K, Partanen H, Vähäkangas K, Knudsen LE, Myllynen P. (2012) Meta-analysis of data from human ex vivo placental perfusion studies on genotoxic and immunotoxic agents within the integrated European project NewGeneris. Placenta. 33(5): Nøhr R, Lund TB, Lassen J (2016). The Danish 3R survey: knowledge, attitudes and experiences with the 3Rs among researchers involved in animal experiments in Denmark. Department of Food and Resource Economics, University of Copenhagen. IFRO Report, No Poulsen MS, MoseT, Maroun LL, Mathiesen L, Knudsen LE, Rytting E. (2015) Kinetics of silica nanoparticles in the human placenta. Nanotoxicology 9:79- [46]

47 IF15 Toxicity testing in the 21st Century; special focus on sensitisation Henrik Appelgren, SenzaGen. The field of toxicology is under change, moving from traditional animal-based assays towards modern, more relevant, faster, often cheaper testing strategies that at the same time use substantially less animals. Several large research programs and global initiatives like EUToxRisk and US Tox21 are leading the paradigm shift. Fundamental in the new testing strategies is mechanistic understanding of normal biology and toxicity. Adverse Outcome Pathways (AOPs) and Key Events outlined herein are central and of great aid for the development of new assays. The OECD develops guidance for the development and reporting of AOPs and secures harmonisation and standardisation for the use of AOPs and new test methods. New test methods are often, or the aim is, to combine them in Integrated Approches to Testing and Assessment (IATA) or more precisely in Defined Approaches (DA) in order to be able to draw firm conclusions regarding a certain toxicity endpoint. However, some assays may also be used as stand-alone assays. One of the most advanced AOPs is that for skin sensitisation (OECD, 2012). Several in vitro assays have been developed and addresses the various Key Events in the skin sensitisation AOP. The Genomic Allergen Rapid Detection (GARD) assay is based on human cells and genomic profiling of about 200 marker genes that are involved in sensitisation. GARD enables a robust and accurate way of predicting the ability of chemicals to induce sensitisation including the potency in the sensitisation reaction, without the use of animal experimentation in compliance with the 3R principle. This lecture will describe the contents of EUToxRisk and, in the second part, outline how sensitisation testing in the 21st century can be perfomed, not using animals, but instead genomics-based GARD as a stand alone assay but also in OECD/ECVAM defined approaches. References EUToxRisk, GARD, SenzaGen, Johansson H., Gradin R., Skin Sensitization: Challenging the Conventional Thinking A Case Against 2 Out of 3 as Integrated Testing Strategy. Toxicological Sciences, kfx115, https://doi.org/ /toxsci/kfx115. Published: 27 June, 2017 Zeller K. S., Forreryd A., Lindberg T., Gradin R., Chawade A., and Lindstedt M., The GARD platform for potency assessment of skin sensitizing chemicals. ALTEX Online first published April 12, 2017, version 2 https://doi.org/ /altex Johansson H., Gradin R., Forreryd A., Agemark M., Zeller K., Johansson A., Larne O., van Vliet E., Borrebaeck C., Lindstedt M., Evaluation of the GARD assay in a blind Cosmetics Europe study. ALTEX Online first February 17, 2017 Forreryd A., Zeller K., Lindberg T., Johansson H., Lindstedt M. From genome-wide arrays to tailormade biomarker readout Progress towards routine analysis of skin sensitizing chemicals with GARD. Toxicolgy In Vitro Sep 13. Johansson H., Rydnert F., Kuehnl J., Schepky A., Borrebaeck C.A.K., Lindstedt M. GARD in-house validation A proof of concept. Tox Sci, Johansson H., Albrekt A.S., Borrebaeck C.A.K., Lindstedt M. The GARD assay for assessment of chemical skin sensitizers. Toxicol In Vitro, [47]

48 IF16 Title: Pharmacology and drug discovery pipelines at the dawn of synthetic tissues and artificial intelligence: what may we expect? Andy Edwards (Simula) Abstract: Today s prototypical drug discovery and screening pipeline involves a progressive whittling down of candidate molecules from enormous compound libraries. This sequence increasingly begins with an expanding range of in silico methods, and moves on through laborious in vitro pharmacology, animal-based in vivo preclinical studies, and finally the clinical trial pathway. A number of technological advancements have altered the speed with which these procedures can be performed, and thus the range of compounds that can be tested, yet the cost of bringing the average drug to market has increased tremendously over the last 20 years, without an accompanying acceleration of drug development. With this talk I will provide a brief overview of existing computational methods used in drug development, and present a view of how future drug discovery may be capable of leveraging rapid advancements in data science, machine learning, and human tissue engineering. These technologies have the potential to supplant many existing steps currently supported by animal work, and I will discuss the prospect of a future of pharmacology that does not involve animal testing. [48]

49 IF17 Titanium dioxide and other chemicals for hazard assessment and risk assessment in ECHAs Risk Assessment Committee Christine Bjørge Norwegian Environment Agency The Committee for Risk Assessment (RAC) prepares the opinions of the European Chemical Agency (ECHA) related to the hazard assessment and to the risk assessment of substances for human health and the environment in the following legislations; REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) and CLP (Classification, Labelling and Packaging of substances and mixtures) processes. The final decisions on the risk- and hazard assessments made by RAC are taken by the European Commission. The members of RAC are appointed by ECHA's Management Board based on candidates nominated by the Members States for a renewable term of three years (https://echa.europa.eu/about-us/who-we-are/committee-for-risk-assessment ). As regards the harmonised classification and labelling of chemicals RAC examines the proposals made by Member States or Industry and gives an opinion on the proposed harmonised classification of substances as carcinogenic, mutagenic, toxic for reproduction or as a respiratory sensitiser, as well as other effects on a case-by-case basis. One of the recent opinions on harmonised classification from RAC was the hazard classification on titanium dioxide (TiO2) as suspected of causing cancer through the inhalation route (carcinogenic in category 2) based on experimental animal data and epidemiological data. This classification has received much attention due to the potential dowstream concequences of this classification. No final decission on the classification for carcinogenicity has been taken by the European Commission yet. When it comes to the restrictions of chemicals, RAC evaluates whether proposed restrictions on manufacture, placing on the market or use of a substance is appropriate in reducing the risk to human health and/or the environment. Examples of opinions on such restrictions are; use of bisphenol A in thermal paper and the use of lead and its compound in jewellery and consumer articles. The RAC opinions of these restrictions are agreed upon in the European Commission. [49]

50 IF18 Setting health-based occupational exposure limits Gunnar Johanson Work Environment Toxicology, Institute of Environmental Medciine, Karolinska Institutet This lecture will describe the procedures and some of the difficulties in setting occupational exposure limits (OEL) with focus on the European Union (EU). Some recent problem areas will be described, relating to formaldehyde, N-methyl pyrrolidone, diesel engine exhaust and the new EU chemicals legislation REACH. OELs aim to protect workers from exposure to airborne pollutants at levels that might compromise their health. The OELs have been gradually developed over the last century by various institutions (e.g. national/governmental institutions, the American Conference of Governmental Industrial Hygienists (ACGIH), EU) and the legal status and policy claims as well as the terminology and acronyms, sometimes even the numerical values, vary widely. A common feature is that the OELs are maximum allowable concentrations expressed as time-weighted average concentrations (TWA) in air. OELs are generally health-based (e.g. EU indicative values, IOELV), although in some cases economic and technical feasibility is also considered (e.g. EU binding values, BOELV). The term OEL usually refers to the 8-h TWA, corresponding to a normal working day. However, there are also other types of OELs such as short-term excursion limits (STEL), ceiling limits (CL) and biological limit values (BLV). In addition to these numerical OELs, qualitative notations are commonly used to warn eg for uptake via skin, sensitizers and substances that in combination with noise may cause hearing impairment. The basic premise for OELs is that life-long exposure below or at the 8-h OEL should not cause adverse health effects. However, as people differ in susceptibility it cannot be excluded that a few individuals may experience health effects even below the OEL. Life-long exposure is usually considered as 8 hours/day, 5 days/week for 40 or 45 years. Therefore, one may need to adjust the OEL for other work patterns, such as longer workdays or work weeks. The setting of OELs is a step-wise procedure, typically involving: (1) request, (2) expert committee work: collection, review and discussion of scientific data, resulting in draft proposal, (3) external circulation, (4) adoption and publication of proposal, (5) decision at institutional level, and finally (6) implementation in the legislation. Many aspects are considered when setting an OEL, including strength and consistency of the data, nature and severity of the critical effect, methods for scaling and extrapolations (eg animal to man, oral to inhalation), sensitive groups, choice of assessment factors etc. The critical effects is the first adverse effect that appears as dose increases. The critical effect level may be the no-observed (NOAEC) or lowest observed (LOAEC) adverse effect concentration, but may also be based on benchmark dose calculations (eg BMDL). The critical effect level determines the point of departure to set the OEL. Background papers Deveau M, Chen CP, Johanson G, et al, 2015, J Occup Environ Hyg 12, S Johanson G (ed), 2003, Arbete och Hälsa 17, 1-109, https://gupea.ub.gu.se/bitstream/2077/4293/1/ah2003_17.pdf [50]

51 Some useful links ACGIH TLV/BEI values - https://www.acgih.org/tlv-bei-guidelines/policies-procedurespresentations/overview EU OELs - https://osha.europa.eu/en/legislation/directive/directive eu-indicative-occupationalexposure-limit-values EU REACH, DNELs - https://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf https://echa.europa.eu/documents/10162/13632/r8_dnel_hd_draft_rev2-1_final_clean_en.pdf German MAK values - groups/derivation_mak/index.html Nordic Expert Group - Swedish OELs - https://www.av.se/halsa-och-sakerhet/luftfororeningar-och-kemiskarisker/gransvarden/?hl=gränsvärden [51]

52 IF19 Overbehandling av eldre Henning Økland (RELIS Sør-Øst) IF20 Overbehandling av osteoporose Trine Finnes (UiO) [52]

53 Frie foredrag De frie foredragene er på 10 minutter hver, hvorav 8 minutter er til foredraget og 2 minutter er til spørsmål og diskusjon. NSFTs pris for beste frie foredrag 2018 En priskomité vil vurdere alle bidrag og finne en vinner innen henholdsvis farmakologi og toksikologi. Hver vinner får tildelt diplom og en vandreplakett under festmiddagen lørdag 27. januar. Priskomiteen for frie foredrag i toksikologi 2018 består av Erik Ropstad (NMBU) og Ketil Hylland (UiO). Priskomiteen for frie foredrag innen farmakologi 2018 består av: Kristine Hole (Diakonhjemmet sykehus), Anders Åsberg (OUS/UiO) og Eili Tranheim Kase (UiO). Vinnere av pris for beste frie foredrag 2017 var: Farmakologi: Veronica Krogstad (UiO) Toksikologi: Ole Jacob Nøstbakken (NIFES) [53]

54 Frie foredrag i toksikologi (TF) TF1 A systematic review of approaches for grouping of manufactured nanomaterials to facilitate hazard and risk assessment of human health and the environment Shan Zienolddiny *, Nina Landvik, Vidar Skaug 1 National Institute of Occupational Health, Oslo, Norway Department of Chemical and Biological Work Environment, 1 National Institute of Occupational Health, Oslo, Norway. *Presenting author Background: With the emergence of nanotechnology the number of manufactured nanomaterials (MNM) in production and use is constantly increasing. Exposure to MNM is of concern, especially in workers, because still much is unknown about how MNM may affect health. With the rapid increase in new MNM with different properties, testing of each material is time consuming and costly. There are a number of approaches to group or categorize MNM depending on the toxicological properties. Grouping is assumed to facilitate hazard and risk assessment of human health effects of current and also new MNM. Methods: We performed a systematic review and a literature search from 2000 to 2015 to identify views on how to group MNM for regulatory purposes. Results: We found more than 800 published articles but only 22 articles fulfilled our inclusion criteria. These 22 reviews reported 17 proposals with three proposals for groups and 14 proposals for criteria for grouping. Five proposals suggested one or more of the following groups of concern: fibrous, biopersistent, high solubility, with high toxicity, chemically active. Criteria proposed in multiple studies were mode of action, physicochemical properties predicting toxicity. Conclusion: The grouping approaches are valuable to facilitate risk assessment of the MNM for human health and the environment. However, the number of approaches that are proposed are limited and further research should be conducted to underpin the proposed grouping approaches. [54]

55 TF 2 PFOS exposure induces excitotoxicity in rat cerebellar granule neurons in vitro Hanne Friis Berntsen 1,2, Cesilie Granum Bjørklund 1, Rønnaug Strandabø 3, Angel Moldes- Anaya 4, Trude Haug 5, Steven Verhaegen 1, Ragnhild Paulsen 6, Erik Ropstad 1 1 Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science 2 Department of Administration, Lab Animal Unit, National Institute of Occupational Health, Oslo 3 Department of Biosciences, University of Oslo 4 Department of Clinical Medicine, University of Tromsø 5 Department of Oral Biology, University of Oslo 6 Department of Pharmaceutical Biosciences, University of Oslo Introduction Perfluoroalkyl acids (PFAAs) are persistent compounds that for many years have been used in consumer products, as well as by the industry. Despite restriction in the use of some of these compounds, they may be found at measurable concentrations in human samples. Exposure to bromine- or chlorine-substituted hydrocarbons has previously been reported to induce excitotoxicity in nerve cell cultures. The aim of the present study was to screen whether effects on viability in cultures of cerebellar granule neurons (CGN) induced by exposure to six different PFAAs, could be associated with activation of the NMDA receptor (NMDA-R). Materials and Methods Effects on viability, after exposure of rat or chicken CGNs as well as PC12 cells to one or several PFAA, were assessed using the MTT or Trypan Blue assays. Protective effects induced by co-application of NMDA-R antagonists, and extracellular or intracellular calcium chelators was also studied. Levels of cytosolic calcium [Ca 2+ ] i was measured by single cell imaging using Fura-2. Amino acid release to the extracellular medium was further measured by HPLC-PDA. Results PFOS induced cytotoxic effects in both rat and chicken CGNs within the same concentration range. In PC12 cells a higher concentration of PFOS was required to induce similar levels of toxicity. Both the uncompetitive NMDA-R antagonists dizocilpine (MK-801) and memantine, as well as the competitive antagonist CPP, significantly protected against PFOSinduced effects on viability in rat CGNs at 8 and 14 days in vitro (DIV). PFOS-induced toxicity in PC12 cells, lacking the functional expression of NMDA-R, was not blocked by CPP. Incubation of rat CGNs with PFOS alone or together with EGTA, BAPTA-AM or CPP, showed that PFOS rapidly reduced viability within 60 minutes. EGTA and CPP protected against these effects, but no protection was afforded by BAPTA-AM. [Ca 2+ ] i was observed to significantly increase after 30 and 60 min exposure to PFOS, an increase which was completely blocked by 5 min pre-incubation with MK-801. A small increase in levels of extracellular glutamate, although not statistically significant, was observed during the first three hours of PFOS exposure. Finally, non-toxic concentrations of PFOS caused a significant shift of the glutamate concentration-response curve in rat CGNs at DIV 8 and 14. Conclusion In conclusion, PFOS at the tested concentrations, induces rapid excitotoxicity in rat CGNs, which likely involves influx of extracellular calcium via the NMDA-R. This effect can be blocked by specific NMDA-R antagonists. [55]

56 TF 3 Real-life exposure to mixtures of chemicals in the EuroMix human biomonitoring study results from repeated 24-hour diaries reporting the use of personal care products Andreassen, M., Hjertholm, H., Dirven, H. & Husøy, T. Norwegian Institute of Public Health, Oslo, Norway The Horizon 2020 EuroMix project aim to provide validated test strategies for the toxicity of chemicals in mixtures, including exposure assessments via oral and dermal exposure routes. A human biomonitoring study was performed to collect exposure data on chemicals from foods and the use of personal care products (PCPs) in 140 participants in Norway. The participants weighed and gave detailed information (diaries) on all foods consumed (type/brand, packaging-material, and type of cookware) and the PCPs used (type/brand of product, time and number of applications, number of showers and hand washes) during two 24-hour study periods separated by 2-3 weeks. In parallel, 24 hours urine was collected, enabling the investigation of the variation of exposure within and between days for chemicals with short half-lives. Skin wipes and blood samples were taken at the end of each study period. Preliminary result on the PCP use in 68 women and 26 men, aged 23-70, show that the number of products used during the first 24-hour study period ranged from one to 36 (mean 11.68, SD 7.35). Women used significantly more PCP s than men (mean versus 5.92, p < 0.001). The total number of products applied was not significantly correlated to the age of the participant (Pearson s r , p = 0.336) regardless of gender. Frequently used products were toothpaste (used by 93.2% of the participants) > deodorant (80.5%) > facial moisturizing cream (56.8%) > lipstick/lip-gloss (23.7%). Among the participants, 86.6% had a shower, 68.0% reported the use of shower gel, while 42.3% and 27.8% reported the use of shampoo and conditioner, respectively. The number of hand washes ranged from one to 28 (mean 9.94, SD 5.03) during the first 24-hour period. Detailed data on PCP use together with consumption of foods in a repeated 24-hour study is essential for properly assessing the aggregated exposure of mixtures of chemicals from several routes. The next step will be to study the association of chemicals from PCPs and foods with concentrations of metabolites in urine or blood for several groups of chemicals, such as pesticides, phthalates, parabens and bisphenols. [56]

57 TF 4 Di-n-butyl phthalate enhances PMA-induced macrophage differentiation of THP-1 monocytes via PPARγ Vegard Sæter Grytting 1, Bergitte Pearl Olderbø 2, Jørn Andreas Holme 1, Jan Tore Samuelsen 2, Anita Solhaug 3, Rune Becher 1, Anette Kocbach Bølling 1 1 Norwegian Institute of Public Health, Domain of Infection Control and Environmental Health, PO Box 4404 Nydalen, N-0403 Oslo, Norway 2 Nordic Institute of Dental Materials, Sognsveien 70A, N-0855 Oslo, Norway, 3 Norwegian Veterinary Institute, Toxicology Research Group, P.O. Box 750 Sentrum, N Oslo, Norway Di-n-butyl phthalate (DBP) has been linked to the prevalence of asthma and airway symptoms in epidemiological studies. Moreover, DBP affects immunological properties of macrophages, cells that are central to the pulmonary innate immunity and implicated in the pathogenesis of asthma. The present study examined effects of DBP on phorbol myristate acetate (PMA)-induced macrophage differentiation of THP-1 monocytes, determined by morphological classification and flow cytometry analysis. Focusing on the expression of the surface marker CD36, the role of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) was assessed using a combined exposure of DBP, the PPARγ antagonist GW9662 and the agonists rosiglitazone and 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ). DBP accelerated the PMA-induced differentiation and increased the expression of CD36, although not to the same extent as the agonists rosiglitazone and 15d-PGJ 2, indicating weak agonistic properties. During combined exposure, DBP attenuated the effect of rosiglitazone on CD36 expression, but increased the effects of 15d-PGJ 2. Pre-incubation with GW9662 failed to supress the effect of DBP on CD36, while the same doses effectively blocked the effect of rosiglitazone. PPARγ has multiple ligand-binding sites. Thus, the reduction in the effect of rosiglitazone indicates that DBP may displace a reversibly bound agonist in the canonical ligand-binding site, while the DBP-induced increase in CD36 in the presence of the covalently bound ligands 15d-PGJ 2 and GW9662 indicates affinity for the alternative ligandbinding site. Overall, the results suggest that DBP may enhance macrophage differentiation via PPARγ binding that may occur at both the canonical and alternative ligand-binding site. [57]

58 TF 5 DIESEL EXHAUST PARTICLES INDUCED [Ca 2+ ] i IN HUMAN ENDOTHELIAL CELLS THROUGH ORGANIC CHEMICALS IN THE LIPOPHILIC FRACTION VIA AN AHR- DEPENDENT MECHANISM. BC. Brinchmann 1, E. Le Ferrec 2, T. Skuland 1, E. Moschini 3, K. Kukowski 4, A. Kubátová 4, AC. Gutleb 3, M. Låg 1, M. Refsnes 1, D. Lagadic-Gossman 2, JA. Holme 1 and J Øvrevik 1. 1 Norwegian Institute of Public Health, Oslo, Norway; 2 UMR Inserm 1085/Université de Rennes 1, France; 3 University of North Dakota, USA; 4 Luxembourg Institute of Science and Technology, Grand Duchy of Luxembourg. Financially supported by: The Norwegian Research Council grant no , Rennes Métropole and the In vitro models for the prediction of respiratory irritation and sensitization - IMPERIS project. Particulate matter (PM) is a leading environmental cause of cardiovascular disease (CVD). Diesel exhaust particles (DEP), a major contributor to PM, consist of elemental carbon and a complex mixture of organic chemicals (OC) adhered to the surface. It is still debated how inhaled PM can cause CVD; pulmonary effects may have systemic consequences, but PM- OC could also affect endothelial cells more directly. Endothelial calcium homeostasis is important for regulation of blood pressure and flow, both through myoendothelial microdomains and via enos. Thus, dysregulation of the intracellular calcium [Ca 2+ ] i in endothelial cells, could potentially contribute to the development of CVD. In the present study we found that exposure relevant doses of DEP (0.12 μg/cm 2 ) on the epithelial side of a 3D tri-culture mimicking alveoli, rapidly induced inflammation-associated and metabolic genes in the basolateral endothelial cells illustrating the importance of OC. The DEP we used has a high content of OC, but the chemicals are relevant to what is characteristic for ambient combustion PM. DEP-OC were extracted (DEP-OE), fractionated and characterized, and the effects on Ca 2+ -signaling in human microvascular endothelial (HMEC-1) cells were examined. PAH and alkanes were extracted with n-hexane (n-hex) and DCM, with the non-polar n-hex containing the highest levels. The two OE containing the most lipophilic OC, n-hex and DCM, triggered marked and rapid increase in [[Ca 2+ ] i, while the two OE containing polar OC had negligible effects. Both n-hex and DCM triggered [Ca 2+ ] i increases were inhibited by the aryl hydrocarbon receptor (AhR) inhibitor CH The importance of AhR was further confirmed by knock-down with SiRNA. In conclusion, the results support the hypothesis that DEP-OC may contribute to CVD by disrupting endothelial calcium homeostasis, through an AhR-dependent mechanism, possibly leading to endothelial dysfunction and thus hypertension. [58]

59 TF 6 Effects of hydrosilicate nanofibers on inflammatory responses and cytotoxicity in macrophages and lung epitehlial cells Skuland T 1, Maslennikova T 2, Låg M 1, Kruchinina I 2, Schwarze PE 1, and Refsnes M 1 1 Norwegian Institute of Public Health; Oslo, Norway 2 Institute of Silicate Chemistry, Russian Academy of Sciences, St.Petersburg, Russia e.mail: Introduction: Use of nanoparticles/nanofibers represent great opportunities in syntheses of different materials/consumer products. However, when making new nanomaterials with advantageous properties it is critical to avoid that the materials pose an increased health risk to the workers that are producing them, and to the consumers/the public, that potentially may be exposed. Exposure to asbestos (chrysotile) is known to induce toxicity, inflammation and lung carcinogenesis. The potency of the chrysotile is dependent on the aspect ratio of the fibre, the relationship between length and width. However, metal contaminants may potentially contribute in inducing adverse health effects. Magnesium (Mg)-nanofibers, with similar basal chemical structure, but shorter length than chrysotile, are made and are planned to be used in different products due to their advantageous material properties. They can be used as sorbents for cleaning aqueous media from organic impurities and heavy metals. Furthermore, the Mg-nanofibers may be effectively used as inorganic nanotubes for specific technological applications, such as manufacturing of nanowires. This project is part of a Russian-Norwegian collaboration where the Silica Institute in St-Petersburg is developing and producing the Mg-hydrosilicate nanofibers. Aim: Examine the toxicity of synthetized Mg-hydrosilicates of different length in macrophages and bronchial epithelial lung cells. The endpoints examined are cytotoxicity and pro-inflammatory responses (cytokines). Methods: The potential health risks of the hydrosilicated nanofibers were assessed by measuring cytotoxicity and release of inflammatory mediators in HBEC3-KT and PMAdifferentiated THP-1 cells. The cells were exposed to five different Mg-hydrosilicated nanofibers of different length (table 1), and compared to chrysotile and to a silica nanoparticle of 10 nm size (Si10) for 20 h. The cytokine release was measured by ELISA, and cytotoxicity by Alamar blue (measures mitochondria activity) Results: The five different Mg-hydrosilicate nanofibers gave no cytotoxicity in any of the cell models, in contrast to chrysotile and Si10 that induced cytotoxicity in both cell types. Exposing the HBEC3-KT cells to the nanofibers (NT-1 to NT-5) induced no or only small changes in cytokine responses, whereas chrysotile and Si10 induced marked effects. In the PMA-differentiated THP-1 cells the two longest fibres (NT-4 and NT-5, with lengths of and µm), but not the shorter ones, induced cytokine increase after 20 h of exposure. However, compared to chrysotile (>10 µm) the increase was rather small. Conclusion and discussion: The main findings was that the length of the hydrosilicate fibers seems critical for the pro-inflammatory effects in the TPA-differentiated THP-1 macrophages, but not in the epithelial HBEC3-KT cells. Notably, the shortest synthetized nanofibers showed no activity in neither of the cell models, potentially making them more safe. In contrast to the THP-1 macrophages, the difference between chrysotile and the hydrosilicate fibers in the HBEC3-KT cells seems attributed to other factors than length, possibly metal content. Table 1: NT nm NT nm NT nm NT nm NT nm [59]

60 TF 7 Effects of HEMA on protein S-glutathionylation in BEAS-2B cells Solveig Uvsløkk, Ida S. R. Stenhagen, Jan T. Samuelsen Nordisk institutt for odontologiske materialer, Oslo Introduction Resin-based dental materials are a common first choice when restoring dental function. These materials never cure completely and both dental personnel and patients are exposed to methacrylate monomers, one main component in these materials. A concern regarding possible side effects these materials may induce has been the motivation of several in vitro studies. A cytotoxic potential have been described in vitro, but detailed knowledge regarding the underlying molecular interactions of monomers remain scarce. A suggested mechanism, however, involves thiol-reactivity and increased levels of oxidative stress. 2- Hydroxyethylmethacrylate (HEMA) is known to spontaneous form adduct with cysteine in glutathione (GSH), and it is suggested if similar reactions towards nucleophilic amino acids in proteins occurs. The aim of this study was to investigate if the commonly used methacrylate HEMA affects protein cysteines. Methods For this in vitro study, a bronchial epithelial cell line (BEAS-2B) was used as a model. Cells were grown in Lechner and La Veck (LHC-9) medium and exposed to HEMA. GSH-levels in HEMA-exposed cells were measured by flow cytometry after staining with monobromobimane (mbrb). Specific antibodies were used to detect β-actin and changes in protein S-glutathionylation in cells after HEMA-exposure. Data was quantified using western blot and Odyssey CLx Infrared System. LC-MS was used to detect bindings between HEMA and synthetic peptides containing lysine and/or cysteine. Four different peptides with similar amino acid chain sequence were ordered from GenScript and analysed on UHPLC-MS. Results Results showed that exposure to HEMA reduced the levels of GSH and S-glutathionylation of at least one protein (MW approx. 42 kda) in cells exposed to HEMA. The results further imply that the observed protein is β-actin. LC-MS analysis implies binding between synthetic peptides and HEMA where there was cysteine present in the amino acid chain. Conclusion This study has shown that HEMA lowers the level of S glutathionylation in BEAS-2B cells, and it is suggested that the main protein affected is β-actin. Both altered GSH-levels and competitive binding of HEMA to the S-glutathionylation site of β-actin may explain this effect. [60]

61 TF 8 Nrf2 signaling and cytoprotection in HEMA exposed human epithelial airway cells Bergitte P Olderbø 1, Else Morisbak 1, Solveig Uvsløkk 1, Jan Tore Samuelsen 1, Rune Becher 1,2 1 Nordic Institute of Dental Materials, Oslo, Norway 2 Norwegian Institute of Public Health, Oslo, Norway Introduction Resin-based biomaterials are widely used in dentistry, and consist of methacrylate monomers that are polymerized in situ. The conversion to polymer is never complete and cause leakage and patient exposure to electrophile monomers such as 2-hydroxyethyl methacrylate (HEMA). In addition, dental personnel that handle these materials are daily exposed. Methacrylates are shown to be cytotoxic in a dose-dependent manner and increased oxidative stress is a suggested key event in the onset of the toxic response. The mechanisms involved in the cytotoxic effects of HEMA have not been fully elucidated; however activation of nuclear factor erythroid 2-related factor 2 (Nrf2) appears to play a central role. Nrf2 is a master regulator of cellular resistance to oxidants. In this study we aim to determine if the in vitro toxicity to HEMA depend on Nrf2 activity. Methods The effects of 24 hours of HEMA exposure (0-8 mm) on two human epithelial airway cell lines were compared; the human bronchial epithelial cell line BEAS-2B and the human alveolar epithelial cancer cell line A549. The first cell line holds a normal regulation of Nrf2 activity, whereas the latter contain a mutation in the Keap1 gene, an important regulator of Nrf2 level and activity. The viability was measured using MTT assay and western blot was used to explore altered levels of Nrf2-regulated gene products known to be affected by HEMA exposure. Results Both BEAS-2B and A549 cells exposed to 0-8 mm HEMA for 24 hours resulted in dosedependent decrease in viability; however the two different cell lines exhibited different protein expression profiles of the investigated gene products. BEAS-2B cells exposed to HEMA significantly increased Nrf2-regulated proteins, while no change was observed in A549 cells. Interestingly, the basal levels of these proteins in A549 cells were relatively high and comparable to HEMA exposed BEAS-2B cells. Conclusion These results indicate that HEMA induce the Nrf2 activity in BEAS-2B, while the Nrf2 pathway is constantly activated in A549 cells as if the cells are under stressed conditions. Furthermore, the viability decreased in both cell lines after HEMA exposure. Consequently it appears that increased Nrf2 activation does not protect against HEMA induced toxicity. [61]

62 TF 9 Hepatocyte-specific deletion of the mono-adp-ribosyltransferase, TIPARP, increases sensitivity to dioxin-induced toxicities David Hutin 1, Giulia Grimaldi 2, Helen Södling 2, Alvin Gomez 1, Shaimaa Ahmed 1, Christin Lucas 2, Hilde Nebb 2, Denis M. Grant 1,3, and Jason Matthews 1,2* 1 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. 2 Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 3 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada. Background: The aryl hydrocarbon receptor (AHR) mediates diverse cellular responses to numerous phytochemicals, metabolites and environmental pollutants, such as dioxin (2,3,7,8,-tetrachlorodibenzo-p-dioxin; TCDD). Dioxin causes a range of toxic responses in laboratory rodents, including thymic atrophy, hepatosteatosis and a lethal wasting syndrome. Although the mechanisms of dioxin-toxicity remain unknown, AHR signaling in hepatocytes is necessary for dioxin-induced liver toxicity. We have previously reported that loss of TCDD-inducible poly(adp-ribose) polymerase (TIPARP/PARP7/ARTD14), an AHR target gene and mono-adp-ribosyltransferase, increases the sensitivity of mice to dioxin-induced toxicities. To test the hypothesis that Tiparp is a negative regulator of AHR signaling in hepatocytes, we generated Tiparp fl/fl mice where exon 3 of Tiparp was flanked by loxp sites. Methods: Using Cre-lox technology, we created hepatocyte-specific Tiparp (Tiparp fl/fl Cre Alb ) and full knockout mice (Tiparp fl/fl Cre CMV ; referred to as Tiparp Ex3-/- ) by crossing with mice expressing Albumin Cre or CMV Cre, respectively. Results: Tiparp fl/fl Alb Cre or Tiparp Ex3-/- mice given a single injection of 10 µg/kg dioxin did not survive beyond day 7 and 9, respectively, whereas Tiparp null mice treated with 100 µg/kg did not survive beyond day 3. All Tiparp +/+ mice survived the 30-day treatment. Tiparp fl/fl Alb Cre or Tiparp Ex3-/- mice treated with 10 µg/kg dioxin displayed increased hepatosteatosis and hepatotoxicity as indicated by increased alanine aminotransferase activity compared with similarly treated wildtype mice. Tiparp fl/fl Alb Cre or Tiparp Ex3-/- mice exhibited increased Ahr signalling denoted by increase expression of dioxin-induced gene expression. The ability of Tiparp to mono-adp-ribosylate and repress AHR activity was also found to be conserved among dioxin-sensitive and insensitive species. Conclusion: Taken together, these data illustrate that TIPARP is a key negative regulator or repressor of AHR activity and its specific loss in hepatocytes is sufficient to increase the sensitivity to dioxin-induced hepatosteatosis and lethality. The data also reveal that the AHR- Tiparp axis is conserved among species. * presenting author [62]

63 TF 10 Risk assessment of brominated flame retardants in Norwegian seafood Ole Jakob Nøstbakken,1, Arne Duinker 1, Josef D. Rasinger 1, Bente M. Nilsen 1, Monica Sanden 1, Sylvia Frantzen 1, Helge T. Hove 1, Anne-Katrine Lundebye 1, Marc H.G. Berntssen 1, Rita Hannisdal 1, Lise Madsen 1,2, & Amund Maage 1,3 1 NIFES (Nasjonalt Institutt For Ernæring og Sjømatforsking) 2 Department of Biology, University of Copenhagen, Denmark 3 Present address, University of Bergen, Norway Problemstilling Brominated flame-retardants (BFRs) such as polybrominated diphenyl ethers (PBDE), hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) accumulate in aquatic biota due to their persistence, and are considered hazardous to human health. Metode Data from more than 9700 samples of wild fish caught in the North Atlantic, farmed fish from the Norwegian coast and fish feed and fish feed ingredients sampled at Norwegian feed factories between 2006 and 2016 were used to assess risks related to human exposure to BFRs through seafood, and subsequently scrutinize factors complicating such risk assessments. Risk assessment was done using the margin of exposure (MOE) approach, based on Benchmark doses (BMDs) for BDE 47, 99, 153 and HBCD established by the European Food Safety Authority (EFSA). Resultater Mean PBDE in fillet samples ranged from below limit of quantification (LOQ) in Atlantic cod fillet to 2.0 µg kg -1 wet weight (w.w.) in Atlantic halibut, and our risk assessment showed low risk at the current dietary intake. However, the dietary intake of BDE 99 is of concern, particularly for toddlers, when including other sources of exposure. The mean levels of HBCD in fillets ranged from concentrations below the LOQ in several species to 1.4 µg kg -1 w.w. in European eel, and our risk assessment showed low risk at current dietary intake. The levels of TBBPA were below the LOQ in most samples rendering calculation of risk unfeasible. Many factors affected the levels of BFRs in seafood, with the most important being age, fat content, and geographical origin. The choice of dietary studies, choice of statistics, as well as exposure from other sources than seafood, were all factors that influenced the risk assessment of BFRs. Konklusjon Our risk assessment indicates that there is low risk related to exposure to BDE 47, BDE 99, BDE 153 and HBCD from consumption of seafood from the North Atlantic. However, when including other sources of exposure, the dietary intake of BDE 99 is of concern, particularly for toddlers. A number of aspects, particularly regarding exposure sources, congener composition of food, use of statistics and dietary surveys, complicate risk assessments of BFRs. An updated evaluation of the risk associated with exposure to BFRs from diet, air and dust is warranted. [63]

64 TF 11 Characterization of the aryl hydrocarbon receptors Ahr1a and Ahr2a in Atlantic cod (Gadus morhua) Libe Aranguren-Abadía 1, Roger Lille-Langøy 1, Sibel I. Karchner 2, Diana G Franks 2, Mark E. Hahn 2, Alexander K. Madsen 1, Fekadu Yadetie 1, Anders Goksøyr 1, and Odd André Karlsen 1 1 Department of Biological Sciences, University of Bergen, Bergen, Norway 2 Department of Biology, Woods Hole Oceanographic Institution, Woods Hole, MA, USA Background The aryl hydrocarbon receptor (AHR) is a transcription factor that regulates the expression of important enzymes involved in the biotransformation of xenobiotics. The main groups of pollutants involved in AHR activation are polycyclic aromatic hydrocarbons (PAHs), dioxins, and co-planar polychlorinated biphenyls (PCBs). Atlantic cod (Gadus morhua) is important to North Atlantic fisheries industry and is commonly used as a marine indicator species. Recently, the cod genome was sequenced and phylogenetical analyses revealed two Ahr-encoding genes, ahr1a and ahr2a. In order to expand our understanding on how Atlantic cod cope with environmental stressors, increased knowledge of Ahr-mediated xenobiotic responses is important. Method The cod ahr1a and ahr2a were therefore cloned and used in in vitro luciferase reporter gene assays, together with the aryl hydrocarbon receptor nuclear translocator (Arnt). To compare the transcriptional activity of the cod Ahrs, four model AHR agonists, including 6-formylindolo [3,2-b] carbazole (FICZ), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3,4,4,5-polychlorinated biphenyl (PCB 126), and benzo[a]pyrene (B[a]P) were used as agonists in luciferase reporter gene assays. Furthermore, velocity sedimentation assays were performed to assess the ligand binding affinity of either 3 H[TCDD] or 3 H[BNF] to Ahr1a and Ahr2a. Conclusions The aim of this study is to continue the characterization of the two cod Ahrs and their role in the response to environmental pollutants in the Atlantic cod. This work has been funded by the Ocean Outlook fellowship 2017 and the Research Council of Norway projects icod2.0 (244564) and dcod1.0 (248840). [64]

65 TF 12 [65]

66 TF 13 Adverse health effects related to chemical exposure in Atlantic cod (Gadus morhua) from Norwegian fjords Zhanna Tairova 1*, Mette HB Müller 2*, Jan L Lyche 2, Ian Mayer 2, Vidar Berg 2, Nello Blaser 3, Morten Brun 3, Merete Grung 1,5, Anders Goksøyr 4, Marta Eide 4, Karina Dale 4, Siri Goksøyr 4, Libe Aranguren 4, Ketil Hylland 1 1 Department of Biosciences, University of Oslo, Norway. 2 Department of Food Safety and Infection Biology, Norwegian University of Life Sciences, Oslo, Norway. 3 Department of Mathematics, University of Bergen, Norway. 4 Department of Biology, University of Bergen, Norway. 5 Norwegian Institute for Water Research, Oslo, Norway.* - equal contribution Introduction and aims: Environmental pollutants and climate change may have an impact on cod health along the Norwegian coastline. The present study is a part of the dcod project on the systems toxicology of Atlantic cod, which aims to create tools for environmental monitoring and risk assessment by combining environmental toxicology, biology, bioinformatics and mathematics. This study assessed potential adverse health effects related to chemical exposure in Atlantic cod from known polluted Norwegian fjords by linking exposure levels, pathological and physiological phenotypes, biomarkers and topological data analysis. Materials and methods: Atlantic cod was caught by trawling from the inner (polluted) and outer (reference) Oslofjord (OF) in November 2016, and from Frierfjord (FF) (polluted) and outer OF in March Blood and organs were sampled for chemical analysis and assessment of biological effects, including biliary polycyclic aromatic hydrocarbons (PAH) metabolites (HPLC/F), heavy metals and persistent organic pollutants (POPs) (GC/MS) and perfluorinated compounds (LC/MS-MS) in liver, DNA-damage in white blood cells (Comet assay), histopathology and plasma levels of steroid hormones, enzymes, proteins and lipids. Results: In general, the levels of PAH metabolites, POPs and heavy metals were higher in the inner OF compared to the outer OF. The median liver lipid contents in inner OF, outer OF and FF were 57%, 48% and 15%, respectively. Cod from outer OF had significantly higher plasma levels of proteins (albumin, total protein) and lipids (triglycerides, free fatty acids) than the inner OF, suggesting alterations in liver physiology, such as lipid metabolism. Furthermore, histopathological findings were more prevalent in the outer OF compared to inner OF, with inflammation, granulomas and/or steatosis in 60% of the cod livers from outer OF compared to 20% in the inner OF. Analyses of cod from FF are ongoing and will be included at the conference. Conclusion: This study suggests that despite the higher levels of chemical exposure in the inner OF and FF, unknown environmental factors may affect cod health in the outer OF. Genomics and proteomics analyses will be performed to relate the phenotypic findings to genotype. dcod 1.0 (Project no ) is associated with the Center for Digital Life Norway (DLN), a national resource for biotechnology research and innovation, funded by the Research Council of Norway (NFR). [66]

67 TF 14 RNA-seq analysis of transcriptome responses in Atlantic cod (Gadus morhua) precision cut liver slices exposed to benzo[a]pyrene and 17α-ethynylestradiol Fekadu Yadetie 1, Xiaokang Zhang 2, Eileen Marie Hanna 2, Libe Aranguren 1, Marta Eide 1, Nello Blaser 3, Inge Jonassen 2, Anders Goksøyr 1, Odd André Karlsen 1 1 Department of Biological Sciences, University of Bergen 2 Computational Biology Unit, Department of Informatics, University of Bergen 3 Department of Mathematics, University of Bergen Background Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP), that activate the aryl hydrocarbon receptor (AHR) pathway, and endocrine disruptors acting through the estrogen receptor (ER) pathway are among environmental pollutants of major concern. The aim of this study is to comprehensively map gene expression responses to AHR and ER ligands in Atlantic cod (Gadus morhua) precision cut liver slices (PCLS). Method We exposed liver slice ex vivo cultures to BaP and ethynylestradiol (EE2), alone and as binary mixtures for 48 hours and performed in-depth RNA-seq based transcriptome mapping followed by systematic bioinformatics analyses. Liver slices from a total of 8 fish (n = 8 biological replicates) were used in a paired-sample design in seven treatment groups consisting of DMSO (control), BaP (10 nm and 1 um), EE2 (10 nm and 1 um), equimolar mixtures of BaP and EE2 (10 nm and 1 um). In total, 47 RNA samples were sequenced at a depth of approximately 50 million 75 bp paired-end reads per sample using Illumina HiSeq Sequence read counts were generated from alignments to Atlantic cod genome and differential expression analysis was performed using the Bioconductor edger software package in R. Results Exposure of liver slices in culture to BaP and EE2 resulted in significant differential expression (FDR < 0.05) of several genes. Strong up-regulation of genes coding for the cytochrome P450 1a (CYP1A) enzyme and the AHR repressor (ahrrb) was observed in BaP treated liver slices. EE2 treatment of liver slices up-regulated larger number genes including genes coding for precursors of vitellogenin (VTG) and eggshell zona pellucida (ZP) proteins. Some genes previously unknown to be induced by estrogens were also up-regulated by EE2. Pathway enrichment and network analysis of the differentially expressed genes showed that the AHR and ER pathways are among the top affected by BaP and EE2 treatments, respectively. The signature expression profiles of top differentially expressed genes in response to the single compound (BaP or EE2) treatments were largely maintained in the expression responses to the equimolar binary mixtures. Quantitative real-time PCR for selected genes confirmed the RNA-seq results. qpcr for selected genes confirmed the RNAseq results. Conclusion The transcriptome analysis showed similar responses to BaP and EE2 in the ex vivo slice culture compared to in vivo previous experiments in other fish species demonstrating the usefulness of PCLS for omics studies. The study was supported by the dcod 1.0 (248840) and the icod 2.0 (244564) grants from the Research Council of Norway. [67]

68 TF 15 Agonistic and antagonistic effects of perfluorinated compounds on Atlantic cod (Gadus morhua) PPARαa and PPARαb nuclear receptors Sofie Söderström, Anders Goksøyr, Odd André Karlsen Dept. of Biological Sciences, University of Bergen, Norway Background: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the superfamily of nuclear receptors, with four subtypes expressed in Atlantic cod (Gadus morhua): PPARαa, PPARαb, PPARβ/δ, and PPARγ. PPARs control the expression of genes involved in the lipid- and glucose metabolism, as well as in inflammatory response. We have previously tested the ability of a structurally diverse set of legacy- and emerging environmental pollutants to agonistically activate the Atlantic cod PPARs. We found that some perfluorinated compounds (PFCs) were able to activate one of the PPARα subtypes. We therefore aim to assess a larger set of PFCs for agonistic, as well as antagonistic effects, focusing on characterizing the activation/inhibition profiles of PPARαa and PPARαb. Methods: Ligand-activation analyses will be performed using an in vitro luciferase reporter gene assay (LRA) in COS-7 cells. In addition, we also intend to study ligand-receptor interactions in silico by protein structure modeling based on crystallized PPARs from other species, followed by ligand-docking analyze with PFCs. Aim: In a previous study we found that the perfluoroalkyl carboxylic acids (PFCAs) PFOA and PFNA were able to activate PPARαb, but not PPARαa. In contrast, the perfluoroalkyl sulfonic acids (PFSAs) PFOS and PFHxS did not activate any of the PPARα subtypes. Thus, by including a larger test set of PFCs (including several PFCAs and PFSAs) we will test for antagonism, in addition to agonism, in order to obtain a better understanding of how PFCs can potentially affect the energy homeostasis in Atlantic cod by interfering with the PPARα subtypes. PPARαa and PPARαb share a rather high degree of sequence similarity though still they exhibit quite different ligand-activation profiles. By further characterizing the ligandactivation/inhibition profiles of the PPARα subtypes we hope to elucidate how these two receptors differ in response to PFCs and, further to denote which amino acids are of importance in regard to ligand binding. The project is funded by the Research Council of Norway grant icod 2.0 (project no ) and dcod 1.0 (project no ). [68]

69 TF 16 Establishing A Cell-Free Method for Xenobiotic Detection Using Ligand Activated Receptors from The Atlantic Cod (Gadus morhua) Siri Øfsthus Goksøyr 1, Sofie Söderström 1, Bjørn Einar Grøsvik 2, Daniela M. Pampanin 3, Anders Goksøyr 1 & Odd André Karlsen 1 1 Department of Biological Sciences, University of Bergen, Norway 2 Institute of Marine Research (IMR), Bergen, Norway 3 International Research Institute of Stavanger (IRIS), Stavanger, Norway The aim of this project is to develop receptor-ligand based xenosensors for use in detector systems for contaminant monitoring. The Atlantic cod has become an attractive model species for environmental monitoring because of its distribution along the coast of the North Atlantic Ocean. The coastline is affected by pollution from both land and sea; fertilizers, sewage disposal, oil, pharmaceuticals, and other chemicals will all eventually end up in the ocean. The chemical defensome is a collection of genes that participates in responses to environmental stressors, and includes protein families such as the cytochrome P450s (CYPs). The CYPs are a large superfamily of proteins where some subfamilies (CYP1, CYP2, CYP3 and CYP4) are essential for metabolizing xenobiotic compounds. The expression of CYPs is regulated by certain ligand-activated receptors, or xenosensors. Xenosensors contain a ligand-binding domain (LBD) and a DNA-binding domain (DBD). Vitamin D receptor (VDR) is part of the NR1I-subgroup of the nuclear receptors, which also includes the xenobiotic sensor, pregnane X receptor (PXR). VDR is naturally activated by vitamin D and controls the transcription of genes that have important roles in regulating the calcium and phosphate homeostasis in vertebrates. Two isoforms of VDR are present in Atlantic cod; VDRα and VDRβ. Interestingly, Atlantic cod lack a PXR-encoding gene, and it is tempting to hypothesize if one, or both, of the VDR isoforms have adapted a broader functional role in sensing and responding to xenobiotic compounds. VDR in Atlantic cod seems to be expressed in most tissues, which is in contrast to the PXR that normally is highly expressed in tissues that accumulates and degrades chemical compounds, such as the liver and intestine. Vitamin D 3 or calcitriol were found to activate both VDRα and β in Atlantic cod using a luciferase gene-reporter assay. Ligand activation assays were also performed with bile acid derivatives, and various exogenous compounds, including environmental contaminants. So far none of the ligands tested seemed to activate VDR, except for calcitriol. We are establishing a new, cell-free method to study the interaction between ligands and receptors based on a modified version of the AlphaLISA protocol. It is a bead-based technique, that use stable receptor proteins conjugated to the bead surface. To obtain this, a fusion protein containing cod VDR is cloned into a plate11 vector for expression in E. coli followed by purification of the recombinant protein. Preliminary results from the development of this method will be presented. This is part of the dcod 1.0 project (dcod 1.0: decoding the systems toxicology of Atlantic cod (Gadus morhua)), funded by the Research Council of Norway (248840), linked to Center for Digital Life Norway. [69]

70 TF 17 Crude oil disrupts retinoid metabolism and signaling in Atlantic haddock (Melanogrammus aeglefinus) embryo and larvae Kai K Lie 1, Sonnich Meier 2, Elin Sørhus 2, Rolf Edvardsen 2, Ørjan Karlsen 2, Pål A. Olsvik 1,3, 1 National Institute of Nutrition and Seafood Research, Bergen, Norway 2 Institute of Marine Research, Bergen, Norway 3 Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway Retinoids are involved in a range of biological processes during embryo development and growth. Retinoids, and especially the active metabolite retinoic acid, have been shown to control limb patterning and its teratogenic potential is well known. Disruption of this tightly controlled system has previously been shown to affect craniofacial and heart development. The aim of this study was to examine the impact of dispersed crude oil on disruption of vitamin A metabolism and signaling in developing Atlantic haddock (Melanogrammus aeglefinus) larvae. Atlantic haddock were exposed to crude oil during two important periods of organogenesis and growth. The first group (embryo group) were exposed to crude oil during the embryonic period from 2 10 days post fertilization (dpf). The second group (larvae group) was exposed to crude oil from hatching until 19 days post hatch (dph). gene expression was analyzed in whole-larvae samples throughout the experiment and retinoids were measured at the end of exposure for both embryo and larvae group. The present study indicates that crude oil exposure disrupts retinoid signaling by affecting known feedback mechanisms. Increased retinol levels were observed for both embryo and larvae groups contrary to what we originally expected. We also observed differences in response between the larval group and the embryo group. While retinal was decreased in the larvae group following crude oil exposure no difference was observed for the embryo group. We also observed different retinoid-related gene expression patterns in the haddock exposed during the embryonic period compared to fish exposed at the larval stage. The increase in retinoic acid, in addition to a decreased expression of the main retinoic acid metabolizing gene, cyp26a, following embryonic exposure to crude oil, indicates a more severe disruption of the retinoid signaling in the embryos compared to the larvae. The results on retinoid metabolism could be seen in connection with the increased incidence of craniofacial deformities and heart defects observed in the embryo and larvae group. [70]

71 TF 18 Er det en sammenheng mellom miljøgift-eksponering og DNAskade i spretthaler, hoppekreps, blåskjell, fisk, fugl og isbjørn? Ketil Hylland, Bjørn Skei*, Erik Gilmore, Lene Frediksen#, Ellen Keilen, Silje Kristiansen, Andrea Sahlmann, Torben Lode, Ane Haarr, Tor Fredrik Holth^, Hans Petter Leinaas, Katrine Borgå Institutt for Biovitenskap, Universitetet i Oslo Det er avgjørende for alt liv at genmaterialet beholdes intakt og uforandret fra celledeling til celledeling. Det indre av celler er veldig dynamisk med tusenvis av kjemiske reaksjoner hvert minutt, og det dannes kontinuerlig reaktive molekyler som fører til skade på cellekomponenter. Alle celler har derfor både et forsvar mot slike reaktive molekyler og effektiv reparasjon. Grunnen til at man er så opptatt av slik skade er at det kan føre til endringer i celler som kan føre til kreft og celledød, samt påvirke funksjonen til celler, for eksempel i immunsystemet. Eksponering for toksiske stoffer kan føre til økt DNAskade. Målet med denne presentasjonen er å gi en oversikt over tildels overraskende resultater fra studier med ulike marine og terrestriske organismer. Hemocytter fra virvelløse dyr som blåskjell, sjøstjerne og strandkrabbe er svært følsomme for oksidativ stress og får lettere DNA-skade enn lymfocytter fra torsk. For torsk i indre Oslofjord ser det ut som miljøgifteksponering fører til mer skade hos immunceller i blodet, men også større evne til å motstå slik skade sammenlignet med torsk fra rene områder. Resultater for isbjørn er mindre åpenbare for denne arten ser det ut som om individer med høy miljøgift-belastning har mindre DNA-trådbrudd i lymfocytter enn i individer med mindre miljøgifter i kroppen. Dette kan være relatert til kondisjon og fødeinntak. Resultater for DNA-skader i lymfocytter hos ulike arter av sjøfugl i relasjon til miljøgift-belastning var også overraskende og lignet på de vi har funnet for isbjørn. Nåværende adresser: * VI, Trondheim; # NIVA, Oslo; ^Fylkesmannens miljøvernavdeling i Vestfold, Tønsberg [71]

72 Frie foredrag farmakologi (FF) FF1 High tacrolimus clearance a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney Erlend J. Egeland 1 *, Anna V. Reisæter 2, Ida Robertsen 1, Karsten Midtvedt 2, Erik H. Strøm 3, Hallvard Holdaas 2, Anders Hartmann 2, Anders Åsberg 1,2 1 School of Pharmacy, University of Oslo, 2 Department of Transplantation Medicine and 3 Department of Pathology, Oslo University Hospital, Rikshospitalet Background Patients showing high tacrolimus clearance eliminate the drug more rapidly, and in order to reach the same trough concentration they need higher daily doses compared to those with low clearance. The high clearance makes them more exposed to transient underimmunosuppression in case of a missed/delayed dose but the higher daily tacrolimus doses cause higher maximum concentrations (C max ). Both are hypothesized to induce development of interstitial fibrosis and tubular atrophy (IFTA) in the transplanted graft. We wanted to investigate the association between estimated tacrolimus clearance and development of IFTA in the renal transplant during the first year post-engraftment. Methods Data from all patients transplanted between 2009 and 2013 at Oslo University Hospital, Rikshospitalet were included in the analysis. Association between estimated tacrolimus clearance (daily tacrolimus dose [mg] / trough concentration [µg/l]) and development of IFTA, (defined as i+t 1 and ci+ct 2) in renal protocol biopsies from 6 weeks to 12 months post-transplantation was investigated. Results In total, 510 patients were treated with tacrolimus and had paired protocol biopsies (6 weeks + 12 months) after transplantation, were included in the analysis. Patients were divided in four groups according to their estimated tacrolimus clearance. There were no differences in biopsy scores between the groups at 6 weeks. The high clearance group developed significantly more IFTA from 6 weeks to 12 months compared to the low clearance group (50% vs 22%, P<0.007). Of the 233 patients without IFTA in the 6-week biopsies a 1-unit increase in tacrolimus clearance was associated with an odds ratio of 1.88 (95% CI; ) for development of IFTA after adjusting for donor age and deceased donor. Conclusion High tacrolimus clearance was significantly associated with development of IFTA within the first year following renal transplantation. The effect may be explained by higher peak concentrations and/or more severe transient under-immunosuppressive episodes in these patients. [72]

73 FF2 Characterization of small molecular enhancers of the natriuretic peptide system a potential treatment of resistant hypertension Henriette Andresen 1,2, Lise Román Moltzau 2, Adrian Hobbs 3, Cristina Pérez-Ternero 3, Alessandro Cataliotti 1, Finn Olav Levy 2 1 Institute for experimental medical research, University of Oslo 2 Department of Pharmacology, University of Oslo and Oslo University Hospital 3 William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London Introduction Treatment resistant hypertension is associated with increased risk of cardiovascular and renal disease and is a condition with currently no good treatment options available. Natriuretic peptides play an important role in the regulation of blood pressure. Hypertension is associated with an impaired natriuretic peptide system and a reduced natriuretic peptide receptor-a (NPR-A) activation. Atrial (ANP) and brain natriuretic peptide (BNP) activate NPR-A, causing production of cyclic GMP (cgmp). Administration of recombinant BNP has shown effective blood pressure reduction in uncontrolled hypertension, suggesting BNP as a potential treatment of uncontrolled hypertension. However, as a potential antihypertensive drug, small molecular compounds could offer better pharmaceutical properties, such as oral administration and longer half-life than peptides. Method About 30,000 small molecular compounds were screened for activity towards NPR-A expressing cells using a cgmp assay based on AlphaScreen technology. Compounds were optimized using in silico methods and tested for efficacy and potency. Selectivity was assessed using NPR-B expressing cells and affinity for the NPR-A was investigated using radiolabeled binding assay. Effects on vessel relaxation were tested ex vivo in rat aortic vessels. Results and conclusion We found one compound from the high throughput screening with activity and selectivity towards NPR-A. After optimization, compounds with over 10-fold higher potency were identified. These compounds were characterized as selective allosteric enhancers of NPR-A which modulated the efficacy, but not the affinity of ANP and BNP while having no effect on their own. In rat aortic vessels, compounds were able to increase the potency of ANP on relaxation. Although further optimization and characterization of these compounds are needed, allosteric enhancers of NPR-A can provide a novel mechanism of action in the treatment of uncontrolled and resistant hypertension. [73]

74 FF3 Betydning av SLC6A4-genotype (5-HTTLPR) for terapisvikt av escitalopram Baker D. 1,2, Molden E. 1,2, Smith R. 1, Haslemo T. 1 1 Senter for Psykofarmakologi, Diakonhjemmet sykehus 2 Farmasøytisk institutt, Seksjon for farmasøytisk biovitenskap, Universitetet i Oslo Problemstilling En nylig studie fra Diakonhjemmet Sykehus viste at CYP2C19-genotype var signifikant knyttet til terapisvikt av escitalopram, som er det mest brukte legemiddelet i gruppen av selektive serotoninreopptakshemmere (SSRI). SSRI medierer effekt ved å blokkere serotonintransportøren, som regulerer synaptisk serotoninnivå. Genet som koder for serotonintransportøren (SLC6A4) er polymorft, og uttrykk av transportproteinet er knyttet en mutasjon i promotordelen av SLC6A4, som betegnes serotonin (5-HT) transporter genelinked polymorphic region (5-HTTLPR). Denne finnes i en kort (s) og en lang (l) variant, hvorav s-varianten medfører lavere serotonintransportør-uttrykk enn l-varianten. Lavt uttrykk av serotonintransportøren har vært assosiert med nedsatt effekt av SSRI-preparater, og hensikten med denne studien er å undersøke om SLC6A4-genotype (5-HTTLPR) er av betydning for terapisvikt av escitalopram. Metode Studien benyttet retrospektive data fra rutineanalyser utført ved Senter for Psykofarmakologi, Diakonhjemmet Sykehus. Basert på søk i laboratoriedatabasen (Swisslab II, Roche) ble det inkludert pasienter med tilgjengelig genotype av 5-HTTLPR og CYP2C19, samt historikk over utførte serumkonsentrasjonsanalyser av escitalopram og tilhørende informasjon om dosering og tid mellom siste dose og prøvetaking. Søket inkluderte også uthenting av informasjon om alder, kjønn og analysehistorikk av andre antidepressiva. Terapisvikt (primært endepunkt) ble definert som analyse av ett eller flere antidepressive legemidler enn escitalopram innen 1 år etter siste serumkonsentrasjonsanalyse av escitalopram. Byttefrekvens blant pasienter med 5-HTTLPR s/s-genotype ble sammenlignet med bærere av s/l- eller l/l-genotype. Sekundært ble også daglig dosering av escitalopram og totalt antall målte antidepressiva sammenlignet mellom genotype-subgruppene. Statistiske analyser ble utført ved bruk av IBM SPSS Statistics 22.0 Resultater Det ble identifisert totalt 1119 unike pasienter som har utført minst 1 serumkonsentrasjonsmåling av escitalopram i perioden , samt farmakogenetisk analyse av 5-HTTLPR og CYP2C19. Av disse var 199 pasienter bærer av s/s-genotype (17,8 %), mens henholdsvis 571 (51.0 %) og 349 pasienter (31,2 %) hadde s/l- eller l/l-genotype. Kjønns- og alderfordelingen mellom gruppene var ikke signifikant forskjellig (p>0,5), og det var heller ingen signifikante forskjeller mellom oppgitt dosering og målt serumkonsentrasjon av escitalopram mellom gruppene (p>0,5). Resultater for sammenligninger av byttefrekvens og totalt antall antidepressiva mellom subgruppene blir presentert på møtet. Konklusjon Demografiske variable og behandlingsintensitet av escitalopram er ikke knyttet til genotype av SLC6A4 (5-HTTLPR), men det gjenstår å få svar på om terapisvikt av escitalopram er assosiert med uttrykk av serotonintransportøren. [74]

75 FF4 Development of biosensors with nanomolar affinity for cgmp using structure-based design Gaia Calamera 1,2, Andrea Hembre Ulsund 1,2, Marianne Bjørnerem 1,2, Jeong Joo Kim 3, Choel Kim 3,4, Finn Olav Levy 1,2, Kjetil Wessel Andressen 1,2 1 Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway 2 Center for Heart Failure Research, University of Oslo, Oslo, Norway 3 Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America 4 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA Background Several Fluorescence Resonance Energy Transfer (FRET) biosensors for cyclic nucleotides have been constructed in the past decade, but there are few sensors for cgmp available that detect low concentrations of cgmp. Currently, only the CFP/YFP sensors Cygnet 2.1, cges- DE5 and cgi-500 (EC 50 ~1.7 μm, 1.5 μm and 500 nm, respectively) and the T- sapphire/dimer2 sensor Red cges-de5 (EC 50 ~40 nm) are available[1-3]. Our aim is to measure subcellular pools of cgmp in single cardiac myocytes, and have previously found that such sensors should have an EC 50 less than 500 nm. The Red cges-de5 has an acceptable EC 50, but modifying this sensor to locate to distinct subcellular compartments within cardiac myocytes yielded sensors with significantly lower response amplitude. We therefore decided to construct novel FRET-based cgmp-sensors with high affinity for cgmp that could be better candidates for subcellular localization. Methods Based on the recent crystallization of Plasmodium falciparum cgmp-dependent Protein Kinase, sensors for cgmp were constructed using the cyclic nucleotide-binding domains flanked with different FRET-pairs (either CFP/Venus or T-sapphire/Dimer2) in its N- and C- terminal to generate two different sensors for cgmp, excitable at various wavelengths. The same was applied to construct two different CFP/YFP sensors with backbone from bovine PKG I and PKG II based on recent crystallization of these cgmp-binding sites. Mutations in the cgmp-binding pocket improved the selectivity towards camp. All sensors were expressed in HEK293 cells and FRET efficacy was determined either in vitro or in intact cells stimulating soluble GC (with the NO donor SNAP) or natriuretic peptide receptor-b (with CNP; C-type natriuretic peptide). Results Three sensors with high affinity ( nm) for cgmp and high selectivity towards camp (up to 500-fold) were designed. All sensors yielded a large response amplitude (10-20 % change in FRET) and responded to SNAP in HEK293 cells and to CNP in cardiomyocytes. Conclusion The novel cgmp FRET biosensors we constructed are good tools for measuring cgmp dynamics in living cells. In addition, one of these sensors appears to be a better candidate for subcellular localization of cgmp than the established biosensors. References 1.Nikolaev, V.O., S. Gambaryan, and M.J. Lohse, Nat Methods, (1): p Russwurm, M., et al. Biochem J, (1): p Niino, Y., K. Hotta, and K. Oka, S. PLoS One, (6): p. e6036. [75]

76 FF5 Characterization of acute cardiac dysfunction caused by calcineurin inhibitors Bernadin Ndongson-Dongmo 1, MarieVictoire Cosson 1, Lise Roman Moltzau 1, Kjetil Wessel Andressen 1, Kurt Allen Krobert 1, Emilio Hirsch 3, Reinhard Bauer 2 and Finn Olav Levy 1. (1) Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway (2) Institute of Molecular Cell Biology, University Hospital of Jena, Jena, Germany (3) Center of Molecular Biotechnology, University of Turin, Turin, Italy Problem: Calcineurin inhibitors (CNI) as cyclosporin A and tacrolimus are the most commonly used immunosuppressive drugs following solid organ transplantation and in various autoimmune diseases. But, CNI therapies are also associated with severe side effects, including cardiovascular disorders like arterial hypertension and atherosclerosis, insulin resistance, brain, liver and renal complications. It s been observed that among the deaths with a functioning graft, 43% of cases are due to cardiovascular events. Whereas metabolism disorder-related cardiovascular complications have been largely explored, the effects of CNI on cardiac contractile function and cardiac rhythm are poorly studied. This study aims to characterize the acute effect of CNI on cardiac contractile function and arrhythmias. Methods: The contractility of the intact heart left ventricle was measured using a pressurevolume-conductance approach. Responses were evaluated in mice 5h after intra-peritoneal injection of CNI in WT, PI3Kgamma KD ("kinase dead"; lacking PI3Kgamma kinase function) and in WT treated with a selective inhibitor of PI3Kgamma. Thereafter, a continuous follow up of ECG using telemetry was performed in mice with similar treatment as mentioned above. Finally, underlying mechanisms associated with observed effects were studied in primary cardiomyocytes using several biochemical approaches with the focus on beta-adrenergic and PI3K signaling. Results: We intriguingly found 5h after CNI injection an important reduction ( 50%) of cardiac contractility (end-systolic elastance; Ees) that was confirmed in vitro with a downregulation of beta-adrenergic signaling upon adult primary cardiomyocyte stimulation with CNI (4h). Interestingly, these effects were completely absent after the same treatment in transgenic mice and cardiomyocytes with inhibited enzymatic function of PI3Kgamma (PI3Kgamma kinase dead ), and in mice and cardiomyocytes treated simultaneously with PI3Kgamma selective inhibitor. Following up these findings, we have also observed arrhythmic events associated with CNI treatment, associated with higher mortality. We further unraveled a not yet reported cellular mechanism of calcineurin in cardiac function. Conclusion: In this study, we have revealed acute cardiac adverse effects of CNI characterized by negative inotropic effect and arrhythmic events. [76]

77 FF6 Extracellular cyclophilin A inhibitor MM284 attenuates intrinsic myocardial contractile dysfunction in endotoxemic mice. Bernadin Ndongson-Dongmo 1, Lang Guangping 2, Marie Victoire Cosson 1, Kurt Allen Krobert 1, Lise Roman Moltzau 1, Michael Brodhun 3, Reinhard Wetzker 2, Gunther Fischer 5, Cordelia Schiene-Fischer 4, Finn Olav Levy 1 and Reinhard Bauer 2 (1) Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway (2) Institute of Molecular Cell Biology, University Hospital of Jena, Jena, Germany (3) Department of Pathology, Helios-Klinikum, Erfurt, Germany (4) Institute for Biochemistry and Biotechnology, Martin Luther University Halle- Wittenberg, Halle, Germany (5) Unit for Enzymology of Protein Folding, Max-Planck-Institute for Biophysical Chemistry Gottingen, Halle, Germany Problem: During systemic inflammatory response syndrome (SIRS) myocardial contractility is disturbed regardless of enhanced adrenergic stimulation and this effect is until now attributed to cytokines and Toll-like receptor signaling. Cyclophilin A (CypA) is secreted under inflammatory and oxidative stress conditions by various cell types and believed to mediate effects through the cell membrane receptor CD147. Whereas a direct impact of intracellular CypA on myocardial hypertrophy has been reported, the effect of extracellular CypA on heart contractile (dys)function has not been investigated yet. This study aimed to determine the specific role of extracellular CypA (ecypa) in the pathogenesis of SIRSinduced septic cardiomyopathy. Methods: Here, we used an endotoxemic LPS mouse model to study the effects of ecypa and its selective blockade by MM284 on in vivo hemodynamics and left ventricular performance, survival and clinical course. Additionally, measurement of contractile force in left ventricular strips was carried out to evaluate possible effects of ecypa on beta adrenergic receptor (βar). For mechanistic analysis, several biochemical approaches in primary adult cardiomyocytes were used to study ecypa effects on relevant players in excitationcontraction coupling of βar signaling including phospholamban and ryanodine receptor activation, camp production and phosphodiesterase (PDE) activity. Expression of CD147 and ERK phosphorylation was measured by western analysis. Results: We found a considerable decrease of myocardial contractility (MC) in mice 6h after LPS administration, which was more pronounced 24h after administration. In line with this, a diminished intracellular Ca 2+ trafficking, leading to reduced myocardial excitationcontraction coupling was indicated by markedly reduced phospholamban and ryanodine receptor activation when directly exposing cardiomyocytes to both cytokines and ecypa. Extent of myocardial depression and reduction of intracellular Ca 2+ trafficking were similarly pronounced in mice treated with cyclosporine A. Strikingly, treatment with the ecypa inhibitor MM284 resulted in markedly improved myocardial performance with concomitantly preserved intracellular Ca 2+ trafficking. CD147 expression was found on cardiomyocytes and ecypa treatment resulted in increased ERK phosphorylation. Conclusion: This study reveals the CD147/eCypA-mediated signal transduction pathway as intrinsic mediator of SIRS-induced septic cardiomyopathy and suggests the inhibition of CD147/eCypA-mediated signal transduction as a potential strategy to improve intrinsic myocardial performance. [77]

78 FF7 Pharmacokinetics of lidocaine infusion in cancer patients during and after surgery Rolf A. Klaasen 1,2, Karen Granheim 3, Andreas Barratt-Due 4,5, Kristoffer Lassen 6,7, Anders M. Andersen 1, Ida Robertsen 8, Anders Åsberg 9, Nils Tore Vethe 1, Audun Stubhaug 10, Stein Bergan 1, Hasse K. Zaré 1 1 Dep. of Pharmacology, Oslo University Hospital 2 Dep. of Medical Biochemistry, Oslo University Hospital 3 Dep. of Anesthesiology, Oslo University Hospital 4 Dep. of Emergencies and Critical Care, Oslo University Hospital 5 Dep. of Immunology, Oslo University Hospital 6 Dep. for Gastrointestinal and Hepatopancreato-biliary surgery, Oslo University Hospital 7 Institute of Clinical Medicine, University of Tromsø The Arctic University of Norway 8 Dep. of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo 9 Dep. of Transplant Medicine, Oslo University Hospital 10 Dep. of Pain Management and Research, Oslo University Hospital Background: Adverse effects of opioid usage can prolong and complicate the recovery and some patients do not attain acceptable pain management. Alternative agents for pain management are therefore needed. Intravenous lidocaine infusion for 24 hours has been shown to be safe and with beneficial effect on postoperative pain, but knowledge about the pharmacokinetics of lidocaine and the metabolites during prolonged infusion is lacking. The aim of this study is to describe the pharmacokinetics of lidocaine and its metabolites during infusion longer than 24 hours. Methods: Patients aged 18 years or older and scheduled for surgery due to liver or pancreatic cancer were included. Lidocaine was given as a bolus (1.5 mg/kg i.v) followed by infusion (1.5 mg/kg/h i.v) with a target therapeutic range of 2-5 mg/l in serum. In the initial phase of the study, the infusion was terminated after 24 hours and frequent serum samples were collected during 24 hours after the infusion was terminated. Lidocaine and metabolites (MEGX and GX) are measured using liquid chromatography and mass spectrometry. Results: Four patients have completed the initial phase. In all patients, serum concentration reached the therapeutic concentration after bolus injection, but fell below 2 mg/l after mean 32 min (range min) with a minimum concentration of mean 1.68 mg/l (range mg/l). Therapeutic concentration was reestablished after mean 4.2 hours (range hours) of infusion. For three patients, the serum concentration persisted within the accepted range during the remaining infusion. One patient had a transient period of serum concentration above the accepted range with a maximum of 8.3 mg/l. None of the patients achieved steady state concentration. After the infusion was ended, the estimated half-life of lidocaine was mean 8.3 h (range h). Maximum MEGX and GX concentrations were mean 1.39 mg/l (range mg/l) and mean 0.29 mg/l (range mg/l). No lidocaine related adverse events were observed. Conclusion: Although the applied regimen resulted in a transient period of subtherapeutic concentration, these were only marginally below the target window. The preliminary data suggest that steady state is not reached after 24 hours for this patient group, requiring a regimen modification to avoid toxic concentrations during prolonged lidocaine infusions. [78]

79 FF8 Interacting proteins of natriuretic peptide receptors Lise Román Moltzau 1, 2, Monica Aasrum 1, Mirjam Damen 3, Maarten Altelaar 3, Finn Olav Levy 1, 2 1 Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway 2 Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway 3 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences and Netherlands Proteomics Centre, Utrecht University, Utrecht, The Netherlands Background and aims Natriuretic peptides (NPs) have lately received much attention as potential heart failure therapy. However the direct cardiac effects are still elusive. Recently, we found that the natriuretic peptides CNP and BNP, both increasing cgmp, affected contractility differently in both normal and failing hearts. CNP, activating the NPR-B receptor, affected contractility both alone and in the presence of camp signaling. This was not shared by the NPR-A agonist, BNP, which had no effect on contractility. This strikingly different response to NPR- A and NPR-B stimulation raised the question as to how these responses are compartmented. In this project we wanted to elucidate a potential role of interacting proteins in regulating the response to NPR-A and NPR-B stimulation. Methods Interacting proteins of the NPRs were identified by pull-down followed by mass spectrometry (MS). Samples for MS and western analysis were prepared using left ventricular cardiomyocytes infected with adeno virus encoding the intracellular part of either NPR-A or NPR-B, tagged with GFP. NPR-A/B and their interacting proteins were pulled down using GFP-trap assay. cgmp measurements were performed in extracts from left ventricular cardiomyocytes. Results More than 100 proteins were identified as potential interacting proteins of the NPRs. Evaluation of proteins binding to NPR-A and NPR-B revealed three proteins from the MS analysis that bound the intracellular part of either NPR-A or NPR-B. Cytohesin-1, a protein in the family of guanine nucleotide exchange factors for ADP-ribosylation factors (ARF- GEFs), was further confirmed in western analysis to interact with the intracellular part of NPR-A and not NPR-B. An inhibitor of cytohesins, SecinH3, concentration-dependently affected the cgmp levels after BNP and CNP differently. SecinH3 increased the cgmp levels induced by BNP through the NPR-A, whereas it reduced cgmp levels induced by CNP through the NPR-B. Conclusion Cytohesin-1 was identified as a potential interacting protein of the NPR-A and not NPR-B. Our results indicate a potential role for cytohesins in the regulation of the cgmp-mediated signaling of natriuretic peptides in the heart. [79]

80 FF9 Significantly higher impact of CYP2D6*41 than *9 and *10 on in vivo metabolizer phenotype in a study of more than 1000 Norwegian patients Tore Haslemo 1 *, Erik Eliasson 2, Marin M. Jukić 3,4, Magnus Ingelman-Sundberg 4, and Espen Molden 1,5 1 Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway 2 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden 3 Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. 4 Department of Physiology, Faculty of Pharmacy, University of Belgrade, Serbia 5 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway Background Knowledge about the actual phenotype effect of so called reduced-function variant alleles of CYP2D6 is lacking. The aim of this study was therefore to clarify the relative impact of the reduced-function variant alleles *9, *10 and *41 on in vivo CYP2D6 metabolizer status in a large cohort of Norwegian patients. Methods The study included 1021 patients (mainly Caucasians) with available CYP2D6 genotype and metabolic ratios (MR) of O/ N-desmethylated venlafaxine metabolites drawn from therapeutic drug monitoring (TDM) analyses, which recently was validated as an excellent CYP2D6 phenotype biomarker. Absence of comedication with CYP2D6 inhibitors or antiepileptic enzyme inducers was confirmed for all patients. The O-desmethyl-to-Ndesmethyl metabolic ratio (MR) of venlafaxine was used as previously validated CYP2D6 phenotype biomarker.mrs were compared between subjects carrying the *1, *9, *10, *41 and null alleles orfunctional gene duplications (UM). MRs in *1/*9 or *1/*10 vs. *1/*41 carriers, and *9/null or*10 /null vs. *41/null carriers, were compared by Mann-Whitney tests. In addition, MR of all genotype subgroups werecompared with null/null carriers by multiple linear regression adjusting for covariates. Results MR was significantly lower in carriers of *41 than in *9 or *10 carriers both in combination with *1 and null alleles (P<0.002). The majority of *41/null carriers (87%) had MRs in the range of null/null carriers, while this was the case for the minority of *9 or *10/null carriers (17.4%). In the multivariate analysis, MR estimates of all subgroups were significantly different from null/null carriers (P<0.001). The MR estimates in carriers of *9 or *10/null (n=17), *41/null (n=30) and null/null (n=95) were 3.55 (95% confidence interval (CI) ), 1.33 ( ) and 0.47 ( ), respectively. Carriers of multiplied functional alleles (*1/*1 x n) had the highest MR estimate (68.2; ). In the multiple regression analysis, CYP2D6 genotype alone explained 60.7% of the overall variability in MR. Conclusions The reduced-function *41 allele, with an allele frequency of 3-13% in different populations, has a significantly greater impact on CYP2D6 metabolizing phenotype than *9 and *10. Patients carrying *41 with null alleles are often to be regarded as poor metabolizers (PMs). Thus, pharmacogenetic assays for clinical routine should include CYP2D6*41 to capture most functional PMs. [80]

81 FF10 Hospitalization of children after prenatal exposure to Methadone and Buprenorphine in pregnancy: National Registry Studies from Czech Republic Blanka Nechanská 1, Milada Mahic 2, Viktor Mravčík 1,3, Roman Gabrhelík 1, Svetlana Skurtveit 2 and Marte Handal 2 1 Charles University in Prague, Czech Republic, 2 Norwegian institute of Public Health, Norway, 3 Czech Monitoring Centre for Drugs and Addiction, Czech Republic Background and Aim WHO strongly recommends opioid dependent women to continue or commence Opioid Maintenance Treatment (OMT) if they become pregnant despite that the evidence behind the recommendation is very low. Long-term effects for the child of OMT during pregnancy are not known. The aim of the study was to examine health outcomes in children prenatally exposed to OMT by studying hospitalizations up to the age of three. Methods We linked data from nationwide registries in the Czech Republic; The National Register of Reproduction Health, The National Register of Addiction Treatment and The National Register of In-patient Treatment. Linkage of data between the registries was based on the personal identification numbers assigned to all individuals in Czech Republic. The study population included all children born during the study period; Data from the National Register of Addiction Treatment was used to identify children prenatally exposed to OMT. These children were compared to children born by women from general population with no recorded history of opioid drugs abuse. Information on hospitalization of children prenatally exposed to OMT drugs was acquired at age of one and three years. Data from NRIT were used to assess information on all in-patient contacts, length of stay, and primary and secondary diagnosis. Diagnosis was classified according to the international classification of disease manual 10 s (ICD-10, mainly on chapter level) Results By 3 years of age, 54.1% of OMT children (n=218) have been hospitalized at least once, compared with 35.8 % of children from the general population. Children prenatally exposed to OMT drugs were more likely to get diagnoses for all main disease groups. During the first three year of life, the most common reason for hospitalisation of OMT children was diseases of the respiratory system and certain infections and parasitic diseases, with 24.3% and 21.6% of children receiving these diagnoses respectively compared to 16.3% and 8.9% in the general population. In the adjusted logistic regression analysis there were still differences in infection and parasitic diseases (OR=2.0 (95% Confidence Interval ); disease of digestive system (OR= 1.7 ( )), and disease of the skin and subcutaneous tissue (OR= 1.9 ( )). Conclusion Based on nationwide data this study provides evidence to suggest that children exposed to OMT in utero more frequently were diagnosed with several somatic diseases during the three first years of life. [81]

82 Postere Toksikologi Postere henges opp på anvist plass i Besseggen 1. Postervisningen ledes av: Hubert Dirven (FHI). Farmakologi Postere henges opp på anvist plass i Besseggen 2. Postervisningen ledes av: Ida Robertsen (UiO) Hver poster får plass tilsvarende en plakat på rundt 80 x 120 cm (bredde x høyde). Alle postere må henges opp med tape. Tape vil bli lagt ut ved de merkede plassene. Presentasjon Posternepresentasjonene innen farmalkologi skjer som en 3-minutters PowerPointpresentasjon med 3-4 lysbilder, hvorav ett tittellysbilde. Unngå bruk av animasjoner. Pek på hovedpoengene og få frem: Problemstilling Hvordan studien er utført Hovedfunn Konklusjon Ta opp hovedtrekkene og unngå detaljer. Dette er ikke et vanlig foredrag og målet er at tilskuerne skal få lyst til å studere posteren nærmere etterpå. Postersesjonen avsluttes med en fri posterdiskusjon. Her går man tilbake til de enkelte posterne og utfolder seg sammen med spesielt interesserte. For postere inne toksikologi er det ingen PowerPoint-presentasjon, bare diskusjon ved posterne NSFTs posterpris 2018 En posterpriskomité vil vurdere alle bidrag og finne en vinner innen henholdsvis toksikologi og farmakologi. Hver vinner får tildelt diplom og en vandreplakett under festmiddagen lørdag 27. januar. Komiteen for bedømming av postere i toksikologi består av Anders Goksøyr (UiB) og Shan Zienolddiny (STAMI). Komiteen for bedømming av postere i farmakologi består av Kjetil Wessel Andressen (UiO), Laila Sortvik Nilssen og Ida Robertsen (UiO). Posterprisvinnere fra 2017: Farmakologi: Henriette Andresen (UiO/OUS) Toksikologi: Solveig Uvsløkk (NIOM) [82]

83 Postere i toksikologi (TP) TP1 Biological effects of environmental contaminants from road runoff on tadpoles of common European frog (Rana temporaria) Amalie Sofie Liane 1, Merete Grung 1,2, Ketil Hylland 1, Sondre Meland 2 1 Department of Biosciences, University of Oslo (IBV/UiO); 2 Norwegian Institute for Water Research (NIVA); Background: Sedimentation ponds are found along roads with high vehicle density in Norway as part of the mitigation action to prevent aquatic contamination of road runoff and tunnel wash water. The ponds are subject to a number of toxic contaminants including organic contaminants, trace metals and NaCl from salting of roads 1,2. The ponds are a habitat for a number of organisms, including amphibians. Frogs may be susceptible to contamination through water, air and nutrition and thus a subject to the contaminants in these ponds 3. The study is associated with the Norwegian Public Roads Administrations (NPRA) project on reducing highway runoff pollution (REHIRUP) and carried out in collaboration with the Norwegian institute for water research (NIVA). Aims of this study: Do organic contaminants from highway runoff have an effect on tadpoles of the common European frog (Rana temporaria) living in sedimentation ponds? Can contaminants cause a change in developmental stages of tadpoles? Are sedimentation ponds a useful measure for protecting the nature around highways? Methods The contamination level is analyzed in the water column, sediment samples and the tadpoles. Samples have been taken from ponds with different levels of contamination and at certain time intervals to cover all life stages of the tadpole. To investigate the developmental stages the morphology and biometrics have been measured and compared. The effects of organic contaminants is covered by measuring cytochrome P-450 concentration and activity, PAH metabolites and the level of DNA damage in the tadpoles. Results The study shows, thus far, an increase in DNA damage in the tadpoles living in sedimentation ponds receiving both road runoff and tunnel wash water. This is also the case for the biometrics and fitness indices, where the results show signs of lower fitness. References: 1.Ranneklev, S. B., et al. (2016). NIVA-rapport; 7029, Norsk Institutt for vannforskning: Meland, S., et al. (2010). Science of The Total Environment 408(19): Sparling, D. W. (2010). Boca Raton, CRC Press. [83]

84 TP2 Occurrence of selected organic contaminants and urban markers in sedimentation ponds Merete Grung 1, Alfhild Kringstad 1, Sondre Meland 1,2, Eirik Fjeld 1, Sissel Ranneklev 1, Jan H. Christensen 3, Linus Malmquist 3 and MajBrit Dela Cruz 3 1 NIVA Norwegian institute for Water Research, Gaustadalléen 21, 3349 Oslo, Norway 2 Norwegian University of Life Sciences, Department of Environmental Sciences, Post box 5003, 1432 Ås 3 Analytical Chemistry Group, Department of Plant and Environmental Science, University of Copenhagen Introduction Sedimentation ponds have been shown to accumulate several groups of contaminants, most importantly PAHs and metals. But also, other urban markers have been shown to be present, including brominated flame retardants (BDEs), organophosphate compounds (OPC) and benzothiazoles (BT) 1. The present investigation aimed at determining the levels of organic contaminant groups in aquatic matrices in sedimentation ponds and determine the potential for bioaccumulation. Method PAHs, including alkylated PAHs, BDE; OPC and BT were determined in water, sediment, plants, dragonfly larvae and fish from sedimentation ponds and reference sites. The analytical methods comprised GC/MS (PAHs and BDEs) and LC/MS (OPCs and BT). PAHmetabolites in bile of fish were determined by means of LC/fluorescence. Results The results showed the presence of all compound groups in one or more of the matrices investigated. PAHs were detected in levels of 2 or 3 µg/g in sediment from sedimentation ponds, while levels in reference sediment was much lower. Interestingly, the levels of alkylated PAHs were up to 16 µg/kg in sediment samples from sedimentation ponds, while below detection limits in reference sediment. BDE47 were shown to bio-magnify with trophic level, however only a limited number of species were investigated. All OPCs investigated were detected in water, fewer in sediments and organisms. The levels in water from the sedimentation ponds were 5 times higher than in reference for many OPCs with log Kow <5. One OPC was detected in fish, and only in fish from sedimentation pond. Two BT were measured in the matrices investigated, and were also detected in fish muscle. BT were not detected in fish from the reference site. Conclusion The analyses of PAHs show the importance of investigating alkylated PAHs in road runoff. Degradation of alkylated PAHs are slower than regular PAHs, thereby prolonging exposure to this hazardous compound group. The presence of BDEs and the urban markers OPCs and BTs show that road runoff is a sink for several contaminants, and thereby constitute a point source of environmental interest. Of the compound groups investigated, only BDEs were shown to bio-magnify. 1 Grung, M. et al. Identification of non-regulated polycyclic aromatic compounds and other markers of urban pollution in road tunnel particulate matter. Journal of Hazardous Materials 323, Part A, (2017). [84]

85 TP3 Persistent Organic Pollutants in Fish from the Mureş River Vidar Berg 1, Angela Curtean-Bănăduc 2, Alexandru Burcea 2, Doru Bănăduc 2, Erik Magnus Ræder 1, Jan Ludvig Lyhce 1. 1 Faculty of Veterinary medicine, Dept. of Food Safety and Infection Biology, Norwegian University of Life Sciences (NMBU), NO-0033 Oslo, Norway. 2 Lucian Blaga University of Sibiu, Ratiu Street, no Sibiu, Romania. Introduction POPs (persistent organic pollutants) are toxic compounds, which are resistant to degradation and accumulate in the environment and biota. Because of little available data on POPs from Romania, there is a need to initiate studies which assess the occurrence of POPs in the country. Norway, Luxenburg and Iceland are funding the EEA Grant Programme. The Lucian Blaga University (LBU), Sibiu in Romania, financed an EEA Grant project with the Laboratory of Environmental Toxicology, NMBU, as a partner: Support instrument for decision making in POP management: case study - Mureș catchment area (SIDPOP). The main aims of the project were: 1. The procurement of an analytical instrument (GC-MS) and laboratory equipment for the analyses of persistent organic pollutants (POPs). 2. Setting up a new laboratory at LBU. 3. Training of personnel from LBU, in Norway and in Romania, to work in the new laboratory at LBU. 4. The procurement of field equipment (such as a car, and equipment for sampling and sample preservation). 5. A sampling programme for collection of fish from the Mureş, invertebrates and sediments for characterization and quantification of POPs. 6. Analyses of fish samples in Oslo and Sibiu for inter laboratory comparison of results. 7. Information work involving central and local administration levels as well as the local population in general about important findings in the project. 8. Scientific publications at different levels, including international journals The freshwater fish common barbell (Barbus barbus). This species is widely distributed in the central and eastern parts of Europe. It was sampled from 9 locations along the Mureş River and tributaries. Muscle and liver samples were analysed for POPs at the Norwegian University of Life Sciences (NMBU) using GC-MS. Results and conclusion. Analyses showed that the levels of POPs were found in some fish samples. In particular, the levels of HCHs were extremely high. We suggest that the high concentrations reflect the historical use and persistence of these compounds. The high levels of HCHs should be followed by actions to identify local sources, and if possible, to remove the sources, and thereby reduce the levels in fish. [85]

86 TP4 Human in vitro liver 3D model in nanotoxicology Elisabeth Elje, Maria Dusinska, Espen Mariussen, Elise Rundén-Pran NILU Norwegian institute for air research, Department for environmental chemistry, Health Effect Laboratory Introduction Two dimensional (2D) monolayer cultures are the standard in vitro models for toxicity testing of nanoparticles (NPs), drugs and chemicals. In accordance with the 3 R s to reduce the use of animals in research, more advanced in vitro human cell models should be developed to predict human toxicity. In this study we have compared the toxic responses in monolayer (2D) and three dimensional (3D) spheroidal cultures of human liver cancer cells, HepG2. Cytotoxicity and genotoxicity were tested for three chemicals and four NPs: colchicine, chlorpromazine hydrochloride, methylmethane sulfonate, Fe x O y -NPs, SiO 2 -NPs, TiO 2 -NPs, or Au-NPs. Methods HepG2 cells were seeded as hanging drops for 4 days, transferred to a spheroid plate (Corning) and cultured for 6 additional days. HepG2 cells in 2D cultures were seeded the day prior to exposure and exposed in parallel with the 3D spheroid cultures. The cells were exposed for 24 hours to colchicine, chlorpromazine hydrochloride, methylmethane sulfonate, Fe x O y -NPs, SiO 2 -NPs, TiO 2 -NPs, or Au-NPs. Cytotoxicity was determined using AlamarBlue assay, and the DNA damage was investigated by the comet assay with and without Fpg enzyme for detection of both DNA strand breaks and oxidized DNA base lesions. Hydrogen peroxide was used as a positive control for DNA strand breaks. Results It was shown that HepG2 spheroids could be disaggregated with trypsinization and centrifugation, and thus be applicable for comet assay. The level of DNA damage in nonexposed 2D and 3D control samples were similar. Exposure with the positive control hydrogen peroxide showed that the hepatocellular 3D spheroid cultures had a higher level of DNA strand breaks compared with the conventional 2D cultures. Cytotoxicity and genotoxicity ranking of the tested chemicals and NPs was performed. Conclusion It was demonstrated that cytotoxicity and DNA damage can be successfully measured by AlamarBlue assay and the comet assay, respectively, in both 2D and 3D human HepG2 cultures. The spheroidal cultures were more sensitive to induction of DNA strand breaks by hydrogen peroxide. Human 3D spheroidal hepatocellular cultures can be successfully applied for genotoxicity testing by the comet assay and represent a promising advanced in vitro model for toxicity testing of chemicals as well as NPs. [86]

87 TP5 Preventive measures to reduce the adverse health impact of traffic-related air pollution (PrevenTAP): An in vitro assessment of the effects of particulate matter on lung cells Vegard Sæter Grytting 1, Magne Refsnes 1, Johan Øvrevik 1, Marit Låg 1 1 Norwegian institute of Public Health, Domain of infection control and environmental health Urban air pollution has been estimated to contribute to 3 million premature deaths worldwide each year and has been linked to several pulmonary and cardiovascular diseases. A major constituent of urban air pollution is traffic-related particulate matter (PM). The toxicity of PM is affected by the size, shape and composition of the PM, and the presence of reactive groups, soluble components and organic contaminants. This thesis will explore the effect of different traffic-related PM (mineral and combustion PM) and combinations of PM on pulmonary and cardiovascular endpoints in vitro, with the aim of identifying the most effective targets for regulatory measures. An initial screening using human cell models will be performed to assess the effects of mineral and stone particles of different composition on inflammatory markers and cytotoxicity. Next, the particles identified as the most potent will be assessed further in co cultures and advanced 3D cell culture models, representing the alveolar region/microvasculature. The pro-inflammatory potential of the selected particles will also be assessed in combination with diesel exhaust particles. Finally, particles of different size collected in situ by project partners from road tunnels with different pavement and particles generated in a road wear simulator will be tested for inflammatory and cytotoxic endpoints in mono- and co-culture cell models. Initial studies indicating that particles of different mineral composition have different effects on inflammatory markers in bronchial epithelial cells and macrophages will be presented. [87]

88 TP6 Effect of silica nanoparticles and diesel exhaust particles in a 3D-triculture lung system involving macrophages, epithelial and endothelial cells T. Skuland 1, BC. Brinchmann 1, M. Låg 1 ; E. Moschini2, AC. Gutleb 2, JA. Holme, J Øvrevik 1 and M. Refsnes 1 1 Norwegian Institute of Public Health, Oslo, Norway; 2 Luxembourg Institute of Science and Technology, Grand Duchy of Luxembourg. Financially supported by: The Norwegian Research Council grant no Introduction: Particulate matter (PM) is a leading environmental cause of cardiovascular disease (CVD), involving inflammatory and pro-thrombotic responses. A critical question is how inhaled PM cause CVD; 1) via pulmonary mediators that have systemic effects, 2) via translocation of the particles or 3) transfer of components adhered to PM. In this study these questions are approached by exposing a 3D-triculture system (mimicking the alveolar barrier), to silica nanoparticles (SiNP) and diesel exhaust particles (DEP). Methods: A 3D tri-culture system consisting of an apical layer of epithelial cells (A549 cells) and macrophages (PMA-differentiated THP-1 cells) separated with a membrane from a basolateral layer of endothelial cells (EA.hy926) (Fig 1), was used. Silica nanoparticles sized 10 nm (Si10) and diesel exhausted particles (DEP) were applied apically, and exposures lasted for 2, 6 and 20 h. Monocultures of endothelial cells were also directly exposed to Si10. The gene expression of different cytokines and cyclooxygenase-2 (COX2) were measured by qpcr after exposure to Si10 and DEP. The release of cytokines from cells exposed 20 h to Si10, was measured by ELISA; and cell viability by Alamar Blue. Results: Si10 exposure induced gene expression of pro-inflammatory cytokines only in the apical cells. An increased release of cytokines in the apical compartment, and a less increase in the concentration of the same cytokines in the basolateral compartment, were observed after 20 h of exposure. In contrast, in the DEP-exposed 3D-tricultures the mrna expression of cytokines (e.g. IL- 1β) and COX2 increased both in the apical and basolateral cells. Notably, the Ea-hy196 cells in monocultures responded to direct Si10 exposure with a marked cytokine release and mrna expression. No changes in viability were observed. Conclusion: As indicated by the Si10 experiments, neither particle translocation across the membrane nor mediators released and transferred from apical cells (epithelial cells/macrophages), seemed sufficient to induce inflammation-associated genes in the basolateral endothelial cells. In contrast, DEP had the potential to induce mrna expression in the endothelial cells of the 3Dtricultures. Overall, this suggests that it was not the particles, nor any mediators, but components leaking from the particles across the epithelial cells and the artificial membrane in the 3D-triculture, that induced gene expression in the endothelial cells. Fig 1: The 3D-triculture [88]

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