Norsk Selskap for Farmakologi og Toksikologi Norwegian Society of Pharmacology and Toxicology Member of EPHAR, IUPHAR, EUROTOX and IUTOX www.nsft.net Vintermøtet på Beitostølen 2017
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Norsk Selskap for Farmakologi og Toksikologi
Norwegian Society of Pharmacology and Toxicology
Member of EPHAR, IUPHAR, EUROTOX and IUTOX www.nsft.net
Vintermøtet
på Beitostølen
2017
[2]
[3]
Sponsorer av NSFTs vintermøte 2017
[4]
[5]
Norsk Selskap for Farmakologi og Toksikologi
Torsdag 26. januar
13:00
-
14:30
Lunsj
14:30 Velkommen
v/ NSFTs leder Jørn A. Holme
BEITOHALLEN
Effects of drugs and environmental
toxicants on CNS Fellessymposium
Møteleder: Jørn A. Holme
BEITOHALLEN
14:40
- 15:10
Effects of pharmaceuticals on human neurotoxicity and
neurodevelopment Hedvig Nordeng (UiO)
15:10 -
15:40
Environmental toxicants and the CNS system – what do we know and what are the knowledge gaps
Oddvar Myhre (FHI)
10 min pause
Priser for årets beste artikler Fellessymposium
Møteledere: Hubert Dirven/Ida Robertsen BEITOHALLEN
15:50
-
16:20
Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human
bronchial epithelial cells Audun Bersaas (STAMI) (Årets artikkel i toksikologi)
16:20
- 16:50
Improved tacrolimus target concentration achievement using computerized dosing in renal transplant recipients – a
prospective, randomized study Elisabet Størset (UiO/OUS) (Årets artikkel i farmakologi)
Kaffe
[6]
Toksikologi:
Kvikksølvforurensing Møteleder: Merete Grung
Besseggen 1
Farmakologi:
Behandlingsprinsipper Møteleder: Sara Bremer
Besseggen 2
17:20
- 17:40
Tidstrender for
kvikksølvkonsentrasjoner i
ferskvannsfisk fra Fennoskandia:
en evaluering av 30 år med data
Hans Fredrik Braaten (NIVA)
Nye behandlingsprinsipper og retningslinjer for behandling av
hjertesvikt Geir Øystein Andersen (OUS)
17:20 -
17:45
17:40
- 18:00
Mercury pollution in China and
implications for human health Yan Lin (NIVA)
PCSK9-hemmere. Virkningsmekanisme, dokumentasjon og mulig plass i
fremtidens lipidsenkende behandling Kjetil Retterstøl (UiO)
17:45 -
18:10
18:00 -
18:20
Dental amalgam – problem for pasient og tannlege?
Jon E. Dahl (NIOM)
Mer enn 25 ulike antidiabetika er tilgjengelige i Norge -
hvorfor? Kåre Birkeland (UiO)
18:10 -
18:35
18:20 -
18:40
Minamatakonvensjonen Eirik Hovland Steindal
(Miljødirektoratet)
19:30 Samling i baren
20:00 Middag
22:00 Kveldsnytt
Besseggen 1 og 2
[7]
Fredag 27. januar
12:30
- 14:00
Lunsj
Obesity – causes and
pharmacological consequences Fellessymposium
Møteleder: Vigdis Aas BEITOHALLEN
14:00
- 14:30
Xenobiotics and obesity Jérôme Ruzzin (UiB)
14:30
- 15:00
Nutrition and obesity Vibeke Telle-Hansen (HiOA)
15:00
- 15:30
The effects of bariatric surgery on the pharmacokinetics of
drugs in patients with morbid obesity Ida Robertsen (UiO)
Kaffe
[8]
Frie foredrag
Toksikologi Møteleder: Hubert Dirven
Beitohallen
Farmakologi Møteleder: Lise Román Moltzau
Besseggen 2
16:00
Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis morphology, epidydimal sperm count and induces sperm DNA fragmentation in mice
Abdolrahman Khezri (NMBU)
Ex vivo CYP-activity analysis in
human tissue samples using a
cocktail approach
Veronica Krogstad (UiO)
16:00
16:10 Mice strain and administration route impact the toxicity of methylmercury
Ole Jakob Nøstbakken (NIFES) Pharmacokinetics of belatacept, a
novel immunosuppressive
therapeutic protein
Erlend J Egeland (UiO)
16:15 16:20
Do silica nanoparticles induce oxidative stress by different
mechanisms in different mammalian cell lines?
Kirsten E. Rakkestad (NIOM)
16:30
Induction of fibrotic responses following injection of multi-walled carbon nanotubes in the pleural cavity and modification by the IL1 genes
Shan Zienolddiny (STAMI)
Schizophrenia Genetics –
identifying variants associated
with clozapine toxicity
Robert Smith (Diakonhjemmet
sykehus)
16:30
16:40
Using time series to identify mechanisms for pollution effects (or lack thereof)
Ketil Hylland (UiO)
Benzodiazepines in Norway
Trine Bjørner (UiO) 16:45
16:50
Polar bear ecotoxicology - establishing understanding through toxicogenomic and ex-situ
approaches
Anders Goksøyr (UiB)
17:00
Integrative transcriptome and proteome analysis reveals perturbation of lipid metabolic pathways in the liver of Atlantic cod (Gadus morhua) treated with PCB
153
Fekadu Yadetie (UiB)
Exposure to mycophenolate and
fatherhood
Anders Åsberg (OUS) 17:00
17:10
Anticoagulant rodenticides in
eagle owls, a non-target raptor
species, in Norway
Aksel Bernhoft (VI)
Frequency of the Low-Expressing Serotonin Reuptake Transporter Genotype in Old Depressed Patients Receiving or Not Receiving
Electroconvulsive Therapy Compared
to Seniors with No History of Mental Illness
Espen Molden (Diakonhjemmet
sykehus)
17:15
17:20
Characterization and pro-
inflammatory responses of
various mould
Elisabeth Oya (FHI)
17:30 Poisoning of dogs with neurotoxin
from molded food or feed
Gunnar Sundstøl Eriksen (VI)
Development of cGMP-sensors
targeted to TnI and PLB reveal
difference in compartmentation
of the natriuretic peptide
receptors A and B
Kjetil Wessel Andressen (UiO)
17:30
[9]
Postervisning
Toksikologi Møteleder: Anders Goksøyr
Beitohallen
Farmakologi Møteleder: Kristine Hole
Besseggen 2 Ecotoxicological responses in Atlantic cod (Gadus morhua) following caging near a previously capped waste disposal site in
Kollevågen, Askøy, Norway Karina Dale (UiB)
Effekt og sikkerhet ved bruk av empagliflozin hos nyretransplanterte pasienter med post-transplantasjons diabetes mellitus
Kine Kvitne (UiO/OUS)
dCod 1.0: decoding the systems toxicology of
Atlantic cod (Gadus morhua) Anders Goksøyr (UiB)
Effect of low calorie diet on the absolute bioavailability of midazolam in patients with severe obesity
Martin Vu (UiO)
Using precision-cut liver slices (PCLS) for
studying effects of environmental
contaminants on the Atlantic cod (Gadus morhua) lipid metabolism Mari F. Kolås (UiB)
Validation of tools for annual adherence
evaluation of kidney transplant recipients
Marte Theie Gustavsen (OUS)
Biological effects of environmental contaminants from road runoff on tadpoles of common European frog (Rana temporaria)
Amalie Sofie Liane (UiO)
Effekt av vitamin D3 på uttrykk, aktivitet og sekresjon av cysteinproteasen legumain studert i ulike cellemodeller
Guro Arnekleiv (UiO)
Peroxisome proliferator-activated receptors (PPARs) as tools for studying effects of contaminants on the Atlantic cod (Gadus morhua) lipid metabolism
Sofie Söderström (UiB)
Diacylglyserol acyltransferase 1 og 2 sin rolle i triglyseridsyntesen i humane
skjelettmuskelceller
Helene Vu (UiO)
Studying estrogenic effects of environmental pollutants by using the Atlantic cod (Gadus morhua) estrogen receptor and a reporter
gene assay
Oline M. Steinkopf (UiB)
Individual dosing of a methadone maintenance patient with reported opioid
withdrawal symptoms
Mimi Stokke (OUS)
Are nanoparticles used in dental materials neurotoxic? Alexandra Isabel Sveinsen Treimo (UiO/NIOM)
Utvikling av en metode for kvantifisering av CYP3A4, CYP3A5 og P-glykoprotein i biopsier
fra nyretransplanterte pasienter
Anne-Marthe Ose (UiO)
Neurotoxicity in rats exposed to exhaust emissions from biodiesel fuels
Renate Valand (HiOA/FHI)
Betydning av kjønn og alder for nivåer av CYP3A4-biomarkøren 4β-hydroksykolesterol hos pasienter behandlet med
enzyminduserbarende antiepileptika
Camilla Nguyen (Diakonhjemmet
sykehus/UiO)
Using precision-cut liver slices (PCLS) and luciferase reporter gene assays to characterise the aryl hydrocarbon receptors
(Ahr) in Atlantic cod (Gadus morhua)
Libe Aranguren (UiB)
Måling av takrolimus i immunceller i løpet av det første året etter nyretransplantasjon
Lina Daleq (OUS/UiO)
Mixture of persistent organic pollutants promotes accumulation of adipose tissue and affects immune system in mice
Martina Galatea Castelli (UiB)
The Proton Pump Inhibitor Lansoprazole Inhibits Protease Activity of Legumain
Paya Diana Hemati (UiO)
[10]
Effects of a mixture of two cyanobacterial
toxins (microcystin-LR and L-BMAA) on spatial learning and memory in adult C57BL/6 mice Tim Hofer (FHI)
Validering av en antistoffbasert metode for
analyse av belatacept i serum
Rolf Anton Klaasen (OUS)
TIPARP and mono-ADP-ribosylation negatively regulate AHR activity and protect against dioxin toxicity
Jason Matthews (UiO)
Identification and characterization of small molecular NPR-A agonists
Henriette Andresen (UiO/OUS)
Relation between in vitro toxicity and thiol-reactivity of HEMA in resin based biomaterials
Bergitte P Olderbø (NIOM)
CYP3A4 phenotype and inflammatory state in patients with rheumatoid arthritis
Birgit M. Wollmann (Diakonhjemmet
sykehus/UiO)
Mechanisms of methylmercury neurotoxicity and their modulation by selenium
Josef D. Rasinger (NIFES)
Comparison of in vitro human cytotoxicity assays for testing of nanomaterials
Elise Rundén-Pran (NILU)
Effects of HEMA on the cytoskeleton in BEAS-2B cells
Solveig Uvsløkk (NIOM)
Effects on human bronchial epithelial cells following low-dose chronic exposure to nanomaterials: a 6-month transformation study
Shan Zienolddiny (STAMI)
Assessing endocrine disruption using larval zebrafish behaviour
Thomas Fraser (NMBU)
Tunnelpartikler inneholder mange ikke-regulerte PAH-lignende forbindelser og andre
urbane markører
Merete Grung (NIVA)
Methylmercury in an Arctic food web – With focus on seabirds
Anders Ruus (NIVA)
Bruk av 3D leverkulturer for å måle DNA-skade ved komet-metoden
Kristine B. Gutzkow (FHI)
Posterdiskusjon
20:00 Middag
[11]
Lørdag 28. 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
Lunsj
Beitoforelesningen 2017 (EPHAR-sponsored) Møteleder: Ola Dale
BEITOHALLEN
14:00
- 14:50
Preventing opioid overdose deaths with take-home naloxone Sir John Strang (King’s College, UK)
Nordic symposium (BCPT-sponsored)
The next generation of alternative methods for drug development and toxicity testing
Fellessymposium
Møteleder: Jørn A. Holme BEITOHALLEN
14:50
-
15:30
Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug
Candidates Tommy B Andersson (Karolinska Institutet & AstraZeneca)
Kaffe
15:45
- 16:25
Use of in vitro testing of epigenetic changes induced by
endocrine disrupting chemicals Joëlle Rügge (Swetox & Karolinska Institutet)
16:25
– 17:05
Organs on chips as predictive in vitro models / three
dimensional (3D) culture of stem cell derived neurons Anna Herland (Karolinska Institutet)
[12]
Kaffe
Toksikologi Luftforurensing
Møteleder: Hubert Dirven
Besseggen 1
Farmakologi Opioid overdoses: Heroin replacement and naloxone
continued Møteleder: Ola Dale
Besseggen 2
17:20
- 17:45
Air pollution – measurements
and modeling Dag Tønnesen (NILU)
Supervised heroin treatment
for the hard-to-treat: positive results from randomised clinical trials
Sir John Strang (King’s College, UK)
17:20 -
17:40
Bystander administered nasal naloxone in Norway:
results from the pilot project Philipp Lobmaier (SERAF; OUS)
17:40
- 18:00
17:45
- 18:10
Urban air particles - in vitro
effects and mechanisms Eleonora Longhin (University of Milano-Bicocca)
Epidemiological aspects of naloxone treatment in Oslo
Ambulance Service 2015-16 Arne Skulberg (NTNU and OUS)
18:00
- 18:20
18:10
- 18:35
Initial triggering mechanisms for cellular effects of
combustion exhaust particles with possible implication for carcinogenesis
Johan Øvrevik (FHI)
Naloxone analysis in overdose victims Åse Marit Leere Øiestad (FHI)
18:20 -
18:40
20:00 Festmiddag
Søndag 29. januar
08:00
- 12:00
Brunsj
[13]
Innholdsfortegnelse
Program 5
NSFTs Vintermøte nr. 45 14
Oversikt over styremedlemmer i NSFT 14
Velkommen til NSFTs vintermøte 2017 15
Praktisk informasjon 17
Årsberetning NSFT for 2016 18
Innkalling til generalforsamling i NSFT 22
Årsberetning 2016 Seksjon for farmakologi 23
Innkalling til årsmøte i Seksjon for farmakologi 26
Årsberetning 2016 Seksjon for toksikologi 27
Innkalling til årsmøte i Seksjon for toksikologi 31
Inviterte foredrag 32
Frie foredrag 55
Frie foredrag toksikologi 56
Frie foredrag farmakologi 66
Postere 73
Postere toksikologi 74
Postere farmakologi 94
Deltagerliste 107
Stipendmottakere 2017 110
[14]
NSFTs Vintermøte nr. 45
Norsk Selskap for Farmakologi og Toksikologi (NSFT) har arrangert vintermøter hvert år siden 1973, det vil si at årets møte er nummer 45 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 104 deltakere til årets møte (ledsagere og barn ikke inkludert), og det er 25 inviterte foredragsholdere fordelt på 9 symposier. Til sammen er det meldt inn 17 frie foredrag og 34 postere fordelt på farmakologi og toksikologi. I år har NSFT mottatt økonomisk støtte fra Basic & Clinical Pharmacology & Toxicology (BCPT) og The Federation of European Pharmacological Societies (EPHAR) 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 NSFTs hovedstyre Leder: Jørn A. Holme Sekretær: Jan Tore Samuelsen Kasserer: Vigdis Aas Styremedlem: Kristine Hole Representant for bedriftsmedlemmer: Pål Falck 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 Solvor Riska 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, Yke Arnoldussen, Gry Koller, Gunnar Sundstøl Eriksen, og Odd Andre Karlsen. Varastyremedlem: Nina Landvik. Kontaktpersoner for seksjon for toksikologi Trondheim: Åse Krøkje Tromsø: Sandra Huber Kristiandsand: Hege Stubberud
[15]
Velkommen til NSFTs vintermøte 2017
Det første vintermøtet, Farmakologisk vintermøte, ble holdt på Rauland Høyfjellshotell i
Telemark i 1973. Norsk Farmakologisk Selskap ble imidlertid stiftet allerede i mai 1936. På
slutten av 1970-tallet dukket toksikologi opp som et eget fagområde. Det var som følge av en
erkjennelse av at kroppsfremmede stoffer (miljøgifter, kjemikalier og forurensning) kan føre
til helseskader, og i 1981 byttet selskapet navn til Norsk Selskap for Farmakologi og
Toksikologi (NSFT). Foreningen og vintermøtene har derfor lange og faglige tradisjoner som
det er svært viktig å ta vare på.
Farmakologi og toksikologi er i en rivende utvikling, men de tilførte ressurser til universitet
og institutter, og fra forskningsråd, blir stadig mer begrensede. Dette krever ny
strategitenkning og satsning. Det er etter min mening viktig i enda større grad å knytte
kontakter med sterke basale medisinske, biologiske og kjemiske fagområder, slik at vi
raskere og mer effektivt kan ta i bruk ny erkjennelse og metodikk innen forskningen.
Mekanistiske studier som belyser sykdomsutvikling utgjør et viktig fundament for både
farmakologisk og toksikologisk forskning, hhv på hvordan legemidler virker og hvordan
toksiske effekter oppstår. Denne typen studier er fremdeles helt sentrale for utviklingen av
fagfeltene.
Det er en økende erkjennelse av at eksponering i embryonalperioden kan fremme
transgenerasjonell sykdom som først kommer til syne i voksen alder. I tillegg manifesterer
epigenetiske endringer seg i vanlige somatiske celler som er terminalt differensiert.
Kjemikalier som påvirker epigenetiske prosesser i somatiske celler kan være knyttet til ikke-
smittsomme sykdommer (NCDs), inkludert kreft, metabolske, immunologiske, hjerte- og
CNS-lidelser. Nylige studier innen miljømedisin tyder på at sykdommer utvikles som følge
av et komplisert samspill mellom kjemikalier og arvet (genetisk) og ervervet (epigenetisk)
følsomhet. Hvorvidt epigenetiske forandringer som kan skyldes ulike typer av sykdom øker
følsomheten for miljøforurensninger trengs å belyses. Økt kunnskap om årsaker og
forandringer under sykdomsutvikling har også implikasjoner for hvordan en skal tenke mht
medikamentell behandling. Omvendt har en økt forståelse av sykdomsutvikling implikasjoner
for hvilke strategier en bør legge for å avdekke nye grupper av miljøgifter. Det kan derfor
virke fornuftig å utvikle samarbeid også mellom kliniske, basale, farmakologiske og
toksikologiske miljøer.
Omic-analyser (genomic, proteomic, adductomic og metabolomic) og analyser av ulike type
epigenetiske forandringer (DNA-metyleringer, histon-moduleringer og non-coding RNA
associated gene silencing) har nyttige anvendelser innen biomonitorering av mennesker og
dyr, i eksperimentelle studier og analyser på cellekulturer. Resultatene kan også knyttes opp
mot systembiologi, ulike typer modelleringer og adverse outcome pathways (AOP). Innen
disse områdene har øko-toksikologien ervervet mye erfaring som kan komme de andre
fagfeltene til gode.
Det er stadig behov for nye legemidler, og det introduseres kontinuerlig nye kjemiske stoffer
i vår hverdag. Nærmere 100 millioner kjemikalier er blitt syntetisert de senere årene, og i
Europa produseres nær 400 millioner tonn fordelt på 140 000 ulike kjemikalier. Ulike in
silico og in vitro high throughput bioscreening modeller benyttes i utvikling av nye
legemidler. Denne type modeller kan med hell også videreutvikles og i enda større grad
benyttes til screening av kjemikalier for toksiske egenskaper.
[16]
Det er et voksende globalt ønske og delt visjon om å skape nye forskningssentre som nettopp
baserer sitt arbeid på prinsippene 3Ms (mekanismer, modeller og markører) og 3Rs (redusere,
avgrense og erstatte). Gode modeller innen stamcelleforskning som bedre forutser
legemiddel-/kjemikalieindusert vevsskade hos mennesker er utviklet. Det er etablert
tredimensjonal (3D) levercellemodeller som er mer sensitive og spesifikke enn klassiske 2D-
kultursystemer mht å oppdage levertoksisitet. Mulige toksiske effekter av partikler på
lungene kan nå studeres ved 3D-tetra-kultursystem av lungeepitel, lungemakrofag og
endotelceller, med muligheter for luft-væske-interfaseeksponering. Det er også nylig utviklet
micro-chip 3D-modeller av den menneskelige blod-hjernebarrieren (BBB). 3D-BBB chip’en
er potensielt en ny metode for å studere human nevrovaskulær funksjon og betennelser in
vitro. Siden skader ofte oppstår som komplekse interaksjoner mellom vevsceller og
immunceller, er det nettopp et stor behovet for å utvikle denne type integrerte coculturer.
Akkurat denne tematikken: The next generation of alternative methods for drug development
and toxicity testing vil være sentral i årets nordiske symposium, som også i år støttes av
Journal of Basic and Clinical Pharmacology and Toxicology (BCPT).
Vi er spesielt stolte over å ha fått professor Sir John Strang (King’s College, UK) til Beito-
forelesningen 2017: Preventing opioid overdose deaths with take-home naloxone.
Forelesningen støttes i år av The Federation of European Pharmacological Societies
(EPHAR).
Ellers vil jeg benytte anledningen til å gratulere Audun Bersaas (STAMI) og Elisabet Størset
(UiO/OUS) som er vinnere av Årets artikkel i hhv toksikologi og farmakologi.
Et viktig mål for vintermøtene er å stimulere til samarbeid på tvers av tradisjonelle fagfelt,
miljøer, alder og kjønn. Spesielt gledelig i år er derfor det store antallet unge studenter. Jeg
håper at studentene vil sette pris på denne fine muligheten til å presentere og diskutere egne
arbeider med andre fagfolk, og at de føler at de får større faglig innsikt og inspirasjon. Videre
at de får etablert nye bekjentskaper som etter hvert kan utvikle seg til varige vennskap og
nyttige nettverk.
Ønsker dere et riktig godt vintermøte og takker for meg som leder av NSFT.
Jørn
Jørn A Holme
[17]
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 2017 totalt 16,5 FEVU-poeng. Farmasøyter som er medlemmer av NFF kan selv registrere deltakelse på vintermøtet ved å logge inn på «Min side» på www.farmaceutene.no i etterkant av arrangementet. For mer informasjon om FEVU-poeng, se: http://www.farmaceutene.no/fevu-hva-er-det. Vintermøtet er også godkjent av Den norske legeforening som valgfritt kurs (17 timer) innen klinisk farmakologi.
[18]
Norsk Selskap for Farmakologi og Toksikologi
Årsberetning 2016
1. Styrets sammensetning Generalforsamlingen i NSFT ble holdt 30. januar 2016 på Radisson BLU Resort Beitostølen. Styrets sammensetning etter valget på generalforsamlingen har vært som følger: - Leder: Jørn A. Holme (2013-2015 og 2015-2017) - Sekretær: Jan Tore Samuelsen (2016-2018) - Kasserer: Vigdis Aas (2013-2015 og 2015-2017) - Styremedlem: Kristine Hole (2016-2018) Vararepresentanter: - Sara Bremer (2016-2018) - Birgitte Lyrån (2016-2018) - Aina Westrheim Ravna (2012-2014, 2014-2016 og 2016-2018) Seksjonene har utpekt følgende representanter til styret: - Toksikologi: Hubert Dirven - Farmakologi: Ida Robertsen Representant for industrien: - Pål Falck (2014-2017) Valgkomité for 2017: - Nils Tore Vethe (2014-2016, 2016-2018) - Jannike Mørch Andersen (2014-2016, 2016-2018) - Vibeke Thrane (2014-2016, 2016-2018) - Eili Tranheim Kase (2016-2018) - Norith Eckbo (2016-2018) Revisor: - Lise Timm Haug (2016- )
2. Styrets arbeid Det har vært avholdt 9 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 og i nyhetsbrev - Europeisk registrert toksikolog (ERT)-registreringer - Etablering av ny ordning for Europeisk sertifisert farmakolog (EuCP) - Finansiering av Selskapets aktiviteter
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3. Økonomi Økonomien til NSFT vurderes som tilfredsstillende. Medlemskontingenten ble på generalforsamlingen i 2016 økt til kr 400,- for vanlige medlemmer og kr 150,- for studenter. Medlemskontingenten for bedriftsmedlemmer er fortsatt kr 3500,-. NSFT har i 2016 mottatt økonomiske støtte fra Basic & Clinical Pharmacology & Toxicology (BCPT) til NSFTs vintermøtet 2016 som gikk til forelesere, da spesielt Beitoforelesningen, Nordisk symposium og støtte til studenter. For Vintermøtet 2017 er det satt av 11.250,- til stipend for studenter som presenterer poster eller fritt foredrag. Stipend og Nordisk symposium støttes også i år av BCPT, og Beitoforelesningen støttes økonomisk av The Federation of European Pharmacological Societies (EPHAR).
4. Faglig virksomhet Vintermøtet Vintermøtet 2016 ble holdt på Radisson Blu Resort Beitostølen 28. januar – 31. januar. Det var påmeldt 118 deltakere (ledsagere og barn ikke inkludert) og det var invitert 25 foredragsholdere fordelt på 9 symposier. Symposiene hadde følgende hovedtema: - Modellering (felles) - Fra individ til populasjon til økosystem (toksikologi) - Immunmodulering ved kreftterapi (farmakologi) - Epigenetikk (felles) - Årets artikkel (Farmakologi & toksikologi) - Bringing the Exposome Concept into Life (Beitoforelesningen, felles) - Nordic Symposium (felles) - Virkning av plastikkforurensning på helse og miljø (toksikologi) - Klassifisering av bivirkninger (farmakologi) Tema for kveldsnytt var: «Sex Drugs, Drugs & Rock ‘n Roll» ved Stein Bergan, Avd for farmakologi, Oslo universitetssykehus. Til sammen var det meldt inn 18 frie foredrag og 32 postere fordelt på farmakologi og toksikologi.
Vårmøter Antibiotikaresistens – et uløselig problem? Tid og sted: 24. mai 2016, OUS-Rikshospitalet. Arrangør: NSFT og Norsk farmasøytisk Selskap (NFS) The Norwegian Research Council program on Environmental Exposures and Health Outcomes: small program with a big impact Tid og sted: 25. mai 2016, Folkehelseinstituttet, Oslo Arrangør: NSFT
Poulssonforelesning og seminar: Poulssonmedaljen 2016 innen basal farmakologi ble tildelt professor Martin J. Lohse ved Max Delbruck Center for Molecular Medicine, Berlin, Tyskland, Medaljeoverrekkelsen og Poulssonseminar ble holdt i Blått auditorium, Rikshospitalet Tid og sted: 24. november 2016, Blått auditorium, Rikshospitalet, Oslo Arrangør: NSFT
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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 2015. Vinner av årets publikasjonspris innen farmakologi er Elisabet Størset (UiO/OUS) for artikkelen «Improved tacrolimus target concentration achievement using computerized dosing in renal transplant recipients – a prospective, randomized study», Transplantation, 2015. Styret mottok til sammen 7 nominasjoner innen farmakologi og komiteen for vurderingen av publikasjonene har bestått av Hege S. Christensen (UiO), Ida Robertsen (UiO), Vigdis Aas (HiOA) og Tore Haslemo (Diakonhjemmet Sykehus). Vinner av publikasjonsprisen innen toksikologi er Audun Bersaas, (STAMI) for artikkelen «Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells». Toxicology in vitro, 2016. Styret mottok 10 nominasjoner av publikasjoner innen toksikologi og komiteen for vurderingen har bestått av Gunnar Sundstøl Eriksen (VI), Anita Solhaug (VI), Odd Andre Karlsen (UiB) og Asbjørn Nilssen (NTNU).
5. Medlemmer Selskapet har 389 medlemmer (per 1.1.2017). Av disse har 100 medlemmer oppgitt tilhørighet til farmakologiseksjonen, 153 til toksikologiseksjonen og 52 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 2016 hadde 47 % av medlemmene betalt medlemskontingenten for 2016. Medlemmer uten funksjonell e-postadresse og manglende medlemskontingent vil etter hvert fjernes automatisk fra databasen. 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), september (nr. 3) og desember (nr. 4). 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: Anna Mehl (Mattilsynet, leder), Christine Bjørge (Miljødirektoratet), Espen Mariussen (FFI), Hege Stubberud (Glencore Nikkelverk AS), Birgitte Lindeman (Folkehelseinstituttet, fungerende leder fra oktober 2016), Åse Krøkje (NTNU), Ketil Hylland, (UiO), Marie Bjørgan (Yara International ASA), Elise Rundén-Pran (NILU). Mer informasjon om ordningen finnes på NSFTs nettsider: http://nsft.net/registrert-toksikolog 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 er i gang med å utarbeide nasjonale retningslinjer for EuCP
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som tilfredsstiller de internasjonale retningslinjene fra The Federation of European Pharmacological Societies (EPHAR). Mer informasjon om ordningen finnes på: www.ephar.org/eucp/ Styret for 2016 takker for seg og ønsker det nye styret lykke til i det videre arbeidet. Oslo, januar 2017
Jørn A. Holme (leder) Jan Tore Samuelsen (sekretær) Vigdis Aas (kasserer) Kristine Hole (styremedlem) Ida Robertsen (leder, Seksjon for farmakologi) Hubert Dirven (leder, Seksjon for toksikologi) Pål Falck (industrirepresentant) Sara Bremer (vara) Birgitte Lyrån (vara) Aina Westrheim Ravna (vara)
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Norsk Selskap for Farmakologi og Toksikologi
Innkalling til generalforsamling i NSFT Beitostølen, 28. januar 2017, 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 2016 - gjennomgang ved Jan Tore Samuelsen
3. Økonomi - gjennomgang ved kasserer Vigdis Aas
a. NSFTs regnskap for 2016 og budsjett for 2017
4. Valg ved valgkomiteen.
a. Nytt styre
b. Ny valgkomité
5. Orientering om status for Europeisk sertifisert farmakolog (EuCP) Laila Sortvik
Nilssen
6. Eventuelt
Oslo, 6. januar 2017 Hovedstyret i NSFT
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Norsk Selskap for Farmakologi og Toksikologi
Årsberetning 2016
NSFT, Seksjon for farmakologi Dette er styrets beretning om aktiviteter i perioden fra 1. februar 2016 til 28. januar 2017. Årsberetningen legges fram for godkjenning på årsmøtet i Seksjon for farmakologi på Beitostølen 28. januar 2017. Styret har hatt følgende sammensetning: Leder: Ida Robertsen (2015-2017) Sekretær: Solvor Riska (2016-2017) Styremedlem: Sigrid Narum (2011-2017) Styremedlem: Lise Román Moltzau (2016-2017) Styremedlem: Kristin Nordal (2016-2017)
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 1.1.2017 100 medlemmer. Av disse er 52 i tillegg medlem av Seksjon for toksikologi. Totalt registrerte medlemmer i NSFT er 389. EPHAR (www.ephar.org) Neste EACPT-møte: The 13th congress of the European Association for Clinical Pharmacology and Therapeutics Prague, Czech Republic, June 24-27 2017 http://www.eacpt2017.org/ 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 2016 Vinner av årets publikasjonspris innen farmakologi er Elisabet Størset (UiO/OUS) for artikkelen «Improved tacrolimus target concentration achievement using computerized dosing in renal transplant recipients – a prospective, randomized study», Transplantation, 2015. Styret mottok til sammen 7 nominasjoner innen farmakologi og komiteen for vurderingen av publikasjonene har bestått av Tore Haslemo (Diakonhjemmet sykehus), Vigdis Aas (HiOA), Hege Christensen (UiO) og Ida Robertsen (UiO).
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Begrunnelse: Prisen for beste publikasjon innenfor fagfeltet farmakologi går til Elisabet Størset og medarbeidere for artikkelen «Improved tacrolimus target concentration achievement using computerized dosing in renal transplant recipients - a prospective, randomized study» Artikkelen er publisert i det anerkjente tidsskriftet Transplantation. Arbeidet har en klar farmakologisk problemstilling og er godt skrevet. Størset og medarbeidere har gjennomført en randomisert, prospektiv klinisk studie hvor en utviklet populasjonsfarmakokinetisk modell blir benyttet til å individualisere legemiddeldoser til nyretransplanterte pasienter. Resultatene fra studien viser at modellen doserer bedre enn erfarne klinikere. Publikasjonen vurderes som svært interessant fordi den viser at det er mulig å implementere avanserte doseringsmodeller i klinikken, og dermed optimalisere farmakologisk behandling av nyretransplanterte pasienter. Arbeidet har en direkte klinisk relevans, og er et fremtidsrettet og utmerket eksempel på individualisering av legemiddelterapi. Vår- og Høstmøte 2016 Seksjonen forberedte og inviterte til Vårmøte sammen med Norsk Farmasøytisk Selskap 24.mai 2016 12.00- 16.00 på Rikshospitalet med tema «Antibiotikaresistens – et uløselig problem?» Møteleder: Trygve Fjeldstad, Daglig leder Norsk Legemiddelhåndbok 12:00 – 12:10 Velkommen til årets vårmøte
Ida Robertsen, Leder seksjon for farmakologi, NSFT 12:10 – 12:40 «One Health»-begrepet
Nasjonal strategi og handlingsplan mot antibiotikaresistens Jørgen W Bjørnholt, Professor dr. med., Avdeling for mikrobiologi, Universitetet i Oslo
12:40 – 13:00 Intervensjoner i allmennpraksis Mark Fagan, PhD, MD, spesialist i allmennmedisin, Tromøy legesenter
13:00 – 13:20 Optimalisert dosering/farmakokinetikk Truls Michael Leegaard, Førsteamanuensis, Klinikk for indremedisin og laboratoriefag, Akershus Universitetssykehus
13:20 – 13:40 Problematiske infeksjoner Jan Erik Berdal, overlege, Avdeling for infeksjonsmedisin, Akershus universitetssykehus
13:40 – 14:00 Hva gjør Legemiddelverket? Seline K. Gustavsen, seksjonssjef, Medisinsk seksjon, Avdeling for legemiddelutredning, Statens legemiddelverk
14:00 – 1430 Pause med enkel servering 14:30 – 14:50 Nye antibiotika Pål Rongved, Professor, Farmasøytisk institutt, Universitetet i Oslo 14:50 – 15:10 Kan fekalterapi være løsningen? Arnold Berstad, Professor emeritus 15:10 – 15:30 Andre resistensdrivende midler
Siamak Yazdankhah, seniorrådgiver, Medisinsk seksjon, Avdeling for legemiddelutredning, Statens legemiddelverk
15:30 – 15:50 Antibiotikaresistens i avløpsvann Henning Sørum, professor, Norges miljø- og biovitenskapelige universitet (NMBU)
15:50 --16:00 Oppsummering/avslutning ------------------------------------------ Arrangementskomite Trygve Fjeldstad, Hege Salvesen Blix, Torill Leirstrand og Ida Robertsen
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Omkostninger ble delt mellom NSFT og NFS. Det var et utmerket fremmøte med over 100 tilhørere. Utdeling av Poulssonmedaljen 2016 Poulssonmedaljen 2016 innen basal farmakologi ble tildelt professor Martin J. Lohse ved Max Delbruck Center for Molecular Medicine, Berlin, Tyskland torsdag 24. november 2016 i blått auditorium på Rikshospitalet.
13:45-14:00
Welcome and short introduction of Poulsson Award Recipient: Prof Martin Lohse Jørn Holme, Leader of NSFT
14:00-15:00 The Poulsson Award Lecture Professor Martin Lohse, Max Delbruck Center for Molecular Medicine, Berlin Receptor signaling in space and time
15:00-15:20 Associate professor Kjetil W. Andressen, Department of Pharmacology, University of Oslo First steps in receptor-activation: how agonist, receptor and G protein interact
15:20-15:40 Professor Finn Olav Levy, Department of Pharmacology, University of Oslo Complex effects of the myosin activator omecamtiv mecarbil on cardiac contractility
15:40-16:00 Professor Ingebrigt Sylte, Department of Medical Biology, The Artic University of Norway Ligand-guided homology modelling and virtual ligand screening of the allosteric GABA-B2 subunit
Vintermøtet 2017 Seksjonen har deltatt i utformingen av programmet for NSFTs vintermøte. Regnskap Regnskapet for seksjonen har i 2016 vært håndtert sammen med regnskapet for NSFT som helhet. For en formell økonomisk oversikt henvises det derfor til NSFTs regnskap. Avslutning Seksjonsstyret for 2016 takker for seg og ønsker det nye styret lykke til med det videre arbeidet. Solvor Riska Sigrid Narum Lise Román Moltzau Kristin Nordal (Sekretær) (Styremedlem) (Styremedlem) (Styremedlem) Ida Robertsen (Leder)
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Norsk Selskap for Farmakologi og Toksikologi
Innkalling til årsmøte i Seksjon for farmakologi, NSFT
Beitostølen, 28. januar 2017, 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 2016
3. Godkjenning av budsjett for seksjon for farmakologi
4. Valg
a. Nytt styre i farmakologiseksjonen b. Ny valgkomité
5. Orienterings- og diskusjonssaker
a. Vår- og høstmøte 2017 b. Innspill til vintermøte 2018
6. Eventuelt
Oslo, januar 2017 Styret i farmakologiseksjonen NSFT
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Norsk Selskap for Farmakologi og Toksikologi
Årsberetning 2016 – seksjon for toksikologi 1. Styrets sammensetning Årsmøtet for toksikologiseksjonen ble avholdt på Vintermøtet 30. januar 2016 på Radisson BLU Resort Beitostølen. Styrets sammensetning for toksikologiseksjonen i året 2016 har vært som følger: Leder - Hubert Dirven (2016-2018) – FHI, Oslo
Merete Grung (2016-2018) – NIVA/UiO, Oslo
Dag Marcus Eide (2016-2018) – FHI, Oslo
Yke Arnoldussen (2016-2018) – STAMI, Oslo
Gry Koller (2015-2017) - Arbeidstilsynet, Oslo
Gunnar Sundstøl Eriksen (2015-2017) - VI, Oslo
Odd Andre Karlsen (2016-2018) - UiB
Vara-medlemmer:
Nina Landvik (2016-2018) – Miljødirektoratet / STAMI
Vidar Berg (2016-2018) - NMBU
Valgkomiteen for 2016-2017: Shan Zienolddiny, Trond Brattelid og Sara Leeves 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 - Rekruttering og utdanning av toksikologer (inkludert Fagrådet i humantoksikologi) - Utgivelse av seksjonens tidsskrift "Toksikologen" - Formidling av informasjon på NSFTs nettsider og i nyhetsbrev - Europeisk registrert toksikolog (ERT)-registreringer 3. Faglig virksomhet Vintermøtet 2017 Styret har foreslått en del temaer til symposia (fedme og miljøkjemikalier, luftforurensning, effekter av miljøkjemikalier på nervesystemet og kvikksølvforurensning) og har vært aktivt med å få program og foredragsholdere på plass. Toksikologiseksjonen fikk inn 23 abstracts for frie foredrag/muntlige presentasjoner og 10 abstracts for postervisninger for Vintermøtet 2017. Dessverre har vi bare plass til 10 foredrag. Resten av foredragsholderne fikk tilbud om en 3 minutters ‘flash presentation’ og poster.
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Vårmøtet Tema for dette møtet: The Norwegian Research Council program on Environmental Exposures and Health Outcomes: small program with a big impact. Welcome – Hubert Dirven Effects of phthalates on human health – Anette Kocbach Bølling (NIPH) Effects of Mycotoxines on human health – Anita Solhaug (VI) Effects environmental Contaminants on autoimmune diabetes development - Johanna Bodin (NIPH) Experimental toxicology data: building stones for human risk assessments – Trine Husøy (NIPH/ EFSA) Miljøforskning fremover – Inger Austrem, Norwegian Research Council Education and training of toxicologists – NSFT is worried and take action – Hubert Dirven Rundt 50 deltakere deltok på dette vårmøtet. Høstmøtet Toksikologiseksjonen har bidratt til NETS2016 (6th Norwegian Environmental Toxicology symposium) som ble arrangert av NIVA i Forskningsparken 26.-27. oktober. Det overordnede tema for møtet var «Assessing and solving environmental challenges in a multiple stressor world», og møtet hadde over 140 deltakere og 100 abstracts. Møtet var godt besøkt av de fleste forskningsmiljøene innen økotoksikologi i Norge, og blant deltakerne fantes både etablerte forskere, forskere i oppstartfasen og studenter. Temaene som ble tatt opp spente også bredt, fra miljøgifter, mikroplast, stråling og multiple stressorer til toksiske mekanismer, overvåkning, risikovurdering og urbane miljøer. De som presenterte foredrag eller poster ble invitert til å publisere materialet i en spesialutgave av Journal of Toxicology and Environmental Health. Mer informasjon om møtet finner du her: http://www.niva.no/nets2016 Nominasjon av NSFT’s publikasjonspris innen toksikologi for 2016 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 2016 har komiteen for vurderingen bestått av Gunnar Sundstøl Eriksen (VI), Anita Solhaug (VI), Odd Andre Karlsen (UiB) og Asbjørn Nilssen (NTNU). Toksikologiseksjonen fikk inn hele 10 nominasjoner til denne prisen. Artiklene kom fra ulike deler av toksikologien, hadde helt ulike tilnærminger og kvaliteten var generelt høy. Årets komité haddde derfor en meget spennende, men svært vanskelig oppgave. Vinner av publikasjonsprisen innen toksikologi 2016 er Audun Bersaas, for artikkelen ‘Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen induced transformation of human bronchial epithelial cells publisert i Toxicol In Vitro. 2016 Sep;35:55-65. Artikkelen ble nominert med følgende begrunnelse: Artikkelen handler om et tema som er og har vært aktuelt i lang tid. Det er formulert en klar problemstilling som ønsket belyst: Kan endret invasiv evne av humane epitelceller fra bronkiene etter eksponering for tobakksrøyk forklares med forandringer i aktivitet av bestemte transkripsjonsfaktorer? Arbeidet har likevel frambragt ny kunnskap om mekanismer involvert i godt kjente effekter. Forfatterne har gjort en systematisk tilnærming med omfattende bruk av ulik, men komplementerende metodikk i tilnærmingen. Bl.a. er det bevisst brukt cellemodeller som ikke inneholder muterte tumor suppressor gener (TP53) eller endret TP53 signalering. Mange tidligere
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studier innen fagfeltet er utført med cellelinjer som inneholder nettopp disse forandringene, noe som kan være systematiske artefakter knyttet til den aktuelle problemstillingen. Det er en omfattende studie med mye eksperimentelle data som gir grunnlag for tolkningen av resultatene og konklusjonene. Hovedfunnene er tydelig epitelial-mesenkymal transisjon av cellene etter eksponering for karsinogener fra tobakksrøyk og nedregulering av viktige DNA transkripsjonsfaktorer (FOXA1 og FOXA2). Alle konklusjoner har godt grunnlag i de framskaffede dataene. Artikkelen er godt skrevet og framstiller data på en forståelig og grei måte, selv for dem som ikke er satt inn i denne problemstillingen fra tidligere. Funnene er også satt naturlig inn i en sammenheng med pågående forskning i en bra diskusjon der relevante siteringer er naturlig diskutert i forhold til artikkelens funn. Europeiskregistrerte toksikologer (ERT)-komitéen Registreringsordning for toksikologer: Den norske komiteen for godkjenning av Europeiskregistrerte toksikologer (ERT) har etter Vintermøtet 2016 bestått av: Anna Mehl (leder), Mattilsynet, Ås (valgt til 2017); Christine Bjørge, Miljødirektoratet, Oslo (valgt til 2019); Espen Mariussen, FFI-Forsvarets forskningsinstitutt, Kjeller (valgt til 2019); Hege Stubberud, Glencore Nikkelverk AS, Kristiansand (valgt til 2017); Birgitte Lindeman, Folkehelseinstituttet, Oslo (valgt til 2017, fungerende leder fra oktober 2016); 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). Informasjon om ERT-ordningen finnes på NSFTs nettsider: http://nsft.net/registrert-toksikolog Oppsummering av ERT-komitéens arbeid i 2016 Komiteen mottok høsten 2016 fire søknader om førstegangs registrering og 18 søknader om re-registrering. Søknadene blir behandlet i ERT-komitéen 11. januar 2017. Registreringskomiteen har vurdert det som naturlig at vi kan ha åpne lister over hvem som er registrert som ERT i Norge, med en reservasjonsrett. Nettsidene trenger oppdatering for å gjøre ordningen med reservasjonsrett tydelig. Eurotox er nå i avslutningen av sitt arbeid med oppdatering av retningslinjer for sertifisering som ERT. Den norske ERT-komiteen har levert kommentarer til arbeidet. Birgitte Lindeman deltok på «5th International Workshop on European Registered Toxicologists (ERT)»-møtet i Paris 2.-3. mai 2016, der retningslinjene og harmonisering av praksis i de nasjonale ERT-komitéene ble diskutert. I etterkant av møtet har ERT-komiteen sendt informasjon om vår praksis for godkjenning som et ledd i arbeidet med harmonisering. Det ble også publisert en artikkel om ERT-ordningen: Wilks MF et al. The European Registered Toxicologist (ERT): Current status and prospects for advancement. Toxicol Lett. 2016. Det er utarbeidet en europeisk standard for utdanning av risikoevaluerere i toksikologi (kursstandard) (CEN TC416) («training of risk assessors»). Nytten av å etablere en CEN-standard også for ERT og i hvilken form en slik sertifisering eventuelt skulle ta, ble diskutert. ERT og utdannelse-gruppene i Eurotox vil jobbe videre med saken. Både i Europa/Eurotox og nasjonalt jobbes det med å fremme toksikologiens stilling i samfunnet, og det å styrke og harmonisere ERT-sertifiseringen blir ansett som et viktig virkemiddel i dette arbeidet. Det er i underkant av 1500 Eurotox-registrerte ERTer og omkring 60 på den norske listen.
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ERT-komiteen er glad for NSFTs initiativ til å dele ut sertifikater til deltagelse på vintermøtet, da dette er et sentralt forum for opprettholdelse av kompetanse i registreringsøyemed.
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) og desember (nr. 4). Lenker til bladet har også blitt publisert på NSFTs nettsider og i nyhetsbrev.
Redaksjonen i Toksikologen i 2016 besto av: Mariell Negård (redaktør, t.o.m. nr. 4), Audun Storset (t.o.m. nr. 4), Iselin Rynning, Elise Skottene (t.o.m. nr. 1) og Ola Tilset (t.o.m. nr. 1.) Nye medlemmer som har kommet inn denne høsten og vinteren er Gunhild Rogne Halland, Pernille Kvernland, Marie Dahlberg Persson og Thomas Aga Legøy (ny redaktør).
5. Andre aktiviteter Fagrådet for humantoksikologi Mange miljøer er bekymret for utdanningstilbudet på MSc, PhD og post-doc nivå innen human toksikologi. UiO og NMBU har varslet om mulig nedleggelse av MSc kurs. Rekruttering til MSc, stipendiater og post-docs er under press. Unge talentfulle forskere innen toksikologi har ikke lenger et godt karriereperspektiv, siden NFRs finansiering til forskningsprosjekter ikke lenger er øremerket. FHI har opprettet et fagråd for humantoksikologi og toks-styret støtter aktivt fagrådets arbeid. BCPT Nordic Prize for 2016 Seksjon for toksikologi/NSFT har spilt inn forslag til BCPT Nordic Prize for 2016. Professor Jan Alexander, fagdirektør ved Folkehelseinstituttet, ble funnet verdig til denne prisen, som for første gang tildeles en fra Norge. Jan Alexander får prisen som en anerkjennelse av hans forskning på mattrygghet og ernæring gjennom mer enn 40 år. Dette er ikke bare en stor ære for Jan Alexander, men for hele det norske fagmiljøet. Seksjon for toksikologi/NSFT skal organisere en award seremoni/symposium 30. mars 2017 for å markere og feire dette. Eurotox award Det er også spilt inn en norsk kandidat til Eurotox award i 2016, som ikke nådde opp.
5. Medlemmer 153 NSFT-medlemmer har oppgitt tilhørighet til toksikologiseksjonen og 52 medlemmer har tilhørighet til begge seksjonene. Oslo, januar 2017 Styret for Toksikologiseksjonen
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Norsk Selskap for Farmakologi og Toksikologi
Innkalling til årsmøte i Seksjon for toksikologi, NSFT
Beitostølen, 28. januar 2017, 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 2016 3. Godkjenning av budsjett for seksjon for toksikologi
4. Valg
a. Nytt styre i toksikologiseksjonen b. Ny valgkomité
5. Møter 2017 – nye forslag og videreføring av idéer
a. Vår- og høstmøte 2017 b. Innspill til vintermøte 2018
6. Eventuelt
a. Fagrådet for humantoksikologi / utdanning av toksikologer b. Behov for toksikologer i de neste 5 år
Oslo, januar 2017 Styret i toksikologiseksjonen NSFT
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Inviterte foredrag (IF)
IF1
Effects of pharmaceuticals on human neurotoxicity and neurodevelopment
HEDVIG NORDENG1,2,3
1Pharmacoepidemiology and Drug Safety Research Group, School of Pharmacy,
University of Oslo, Oslo, Norway 2PharmaTox Strategic Initiative, Faculty of Mathematics and Natural Sciences,
University of Oslo 3Department of Child Health, Institute of Public Health, Norway
E-mail: [email protected]
Web site: www.mn.uio.no/farmasi/english/research/groups/pharmatox
Background and aim: The fetal period is believed to be one of the most sensitive periods for brain
development. During this period, neurons are created, differentiate and migrate to form the various
parts of the brain. The theoretical potential of neurotoxicity of pharmaceuticals is related to their
ability to pass the placenta, the blood-brain barrier and impact on the developing fetal nervous system.
For example, several psychotropic drugs including opioids, antiepileptics, antipsychotics and
antidepressants have been suggested to affect neurotransmitter systems in the growing fetal brain.
Current studies on neurotoxicity of pharmaceuticals are carried out in animals and translated to the
human. But past experience has demonstrated that this approach is often not sufficiently predictive for
human risk assessment, and has become exceedingly expensive due to the increasing amount of
substances to be tested, necessitating a huge increase of animal usage. Therefore, there is a strong
pressure for the development of alternative strategies to study neurotoxicity of pharmaceuticals by
combining experimental data from human cord blood, human embryonic stem cell lines and chick
embryonic model with epidemiological data.
The PharmaTox Strategic Research Initiative at the Faculty of Mathematics and Natural Sciences was
established January 1st 2015 and unites researchers using all these alternative strategies in
combination with advanced statistical methods, medical bioinformatics and microarray technology,
thereby proposing an integrated approach to studying drug neurotoxicity.
A primary data source for the application is genetic and epigenetic data derived from blood samples
of infants in the Norwegian Mother and Child cohort, along with corresponding epidemiological data.
Moreover, to give biological plausible molecular and cellular mechanisms of neurotoxicity, a CNS
pharmacology safety model (chicken embryo) and human embryonic stem cells are used.
The aim of the lecture is to give examples of pharmaceuticals that have been associated with human
neurodevelopmental impairment, to present the PharmaTox initiative and our on-going studies to assess
effects of pharmaceuticals on human neurodevelopment, and to give insight into some of the
methodological challenges in epidemiological studies of medication safety on infant neurodevelopment.
References
1. Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child
neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013; 42: 1702-13.
2. Brandlistuen RE, Ystrom E, Eberhard-Gran M, Nulman I, Koren G, Nordeng H. Behavioural effects of fetal
antidepressant exposure in a Norwegian cohort of discordant siblings. Int J Epidemiol. 2015; 44: 1397-407.
3. Bjornstad S, Austdal LP, Roald B, Glover JC, Paulsen RE. Cracking the egg: Potential of the developing
chicken as a model system for non-clinical safety studies of pharmaceuticals. J Pharmacol Exp Ther 2015;
355: 386-96.
4. Gervin K, Page CM, Aass HC, Jansen MA, Fjeldstad HE, Andreassen BK, Duijts L, van Meurs JB, van
Zelm MC, Jaddoe VW, Nordeng H, Knudsen GP, Magnus P, Nystad W, Staff AC, Felix JF, Lyle R. Cell
type specific DNA methylation in cord blood: A 450K-reference data set and cell count-based validation of
estimated cell type composition. Epigenetics 2016; 1: 690-698.
[33]
IF2
Environmental toxicants and the CNS system – what do we know and what are the
knowledge gaps
Oddvar Myhre, Folkehelseinstituttet, [email protected]
Recent years have seen a pattern of increasing prevalence of neurodevelopmental deficits in
the central nerve system (CNS) including IQ loss, learning disabilities, autism, ADHD, and
developmental delay in the general population, and are reported to affect up to 1 in 6 children
(1). This increasing incidence cannot be explained solely by genetic inheritance. Thus, it is
widely accepted that environmental factors including environmental pollution are involved.
Epidemiological studies suggest that many chemicals and environmental toxicants to which
children and pregnant women are regularly exposed can interfere with normal brain
development and function; some even at extremely low levels of exposure. Research has
identified “critical windows of vulnerability” during embryonic and foetal development,
infancy, early childhood and adolescence (2,3), where environmental toxicant exposures in
particular may cause neurodevelopmental disabilities. Some of the epidemiological studies
are supported by experimental animal and mechanistic studies; and together they provide
rather strong evidence for neurodevelopmental toxicity resulting from exposure to lead,
mercury, organophosphate pesticides, air pollution, PBDEs, and PCBs. Also phthalates are
suspected to interfere with brain development (4). In a review from 2013 it was reported that
a total of 214 industrial chemicals had been reported to be linked to neurotoxic effects in
epidemiological studies (5).
However, there is large knowledge gaps between chemical exposure(s) and associated CNS
effects in epidemiological studies. Only a few of chemicals that are imported into Norway
and EU has been properly evaluated for potential neurotoxic effects in appropriate
experimental models. Even fewer have been evaluated for potential effects on brain
development in children. The cellular mechanisms of toxicity of only a few of the
environmental toxicants are known. Thus, detailed mechanistically studies are highly needed
to support a causal association.
Furthermore, 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. Another regulatory challenge is that when a toxic chemical or
category of chemicals is finally removed from the market, chemical manufacturers often
substitute chemicals that may pose similar concerns or be virtually untested for toxicity. In
conclusion, 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, sophisticated experimental animal studies combined
with detailed and focused mechanistic experimental studies.
1. Boyle et al. 2011. Trends in the prevalence of developmental disabilities in U.S. children, 1997–2008.
Pediatrics 127, 1034–1042.
2. Lanphear 2015. The impact of toxins on the developing brain. Annu Rev Public Health 36, 211–230.
3. Rice & Barone 2000. Critical periods of vulnerability for the developing nervous system: evidence from
humans and animal models. Environ Health Perspect 108, 511–533.
4. Ejaredar et al. 2015. Phthalate exposure and childrens neurodevelopment: a systematic review. Environ Res
142, 51–60.
5. Grandjean & Landrigan 2014. Neurobehavioural effects of developmental toxicity. Lancet Neurol 13, 330–
338.
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IF3
Epithelial-mesenchymal transition and FOXA genes during tobacco smoke carcinogen
induced transformation of human bronchial epithelial cells Audun Bersaas (STAMI) (Årets artikkel i toksikologi)
An in vitro cell transformation study was performed on two different immortalized human
bronchial epithelial cell lines (HBEC2, HBEC12). Exposure to cigarette smoke condensate,
benzo[a]pyrene, and methylnitrosouera for up to 12 weeks resulted in transformed cells with
gained ability to grow anchorage independent in soft-agar. Cells isolated from soft-agar
showed diminished transcription of the FOXA1 and FOXA2 transcription factors. The
transformed cells displayed characteristics of EMT including decreased CDH1 expression,
increased CDH2 expression, and activation of several EMT markers. Moreover, the
transformed cells showed increased invasiveness compared to non-transformed cells in a
matrigel scratch wound healing assay. Chromatin immunoprecipitation revealed increased
binding of histones H3, macroH2A and H2A.Z in regulatory regions of FOXA1 and FOXA2
in transformed cells, indicating compact chromatin. In conclusion, long-term carcinogen
exposure lead to downregulation of FOXA1 and FOXA2 concomitantly with the occurrence
of EMT and in vitro transformation in HBEC cells.
[35]
IF4
Improved tacrolimus target concentration achievement using computerized dosing in
renal transplant recipients – A prospective, randomized study
Elisabet Størset1,2
, Anders Åsberg1,3
, Morten Skauby1, Michael Neely
4, Stein Bergan
3,5, Sara
Bremer6, Karsten Midtvedt
1
1 Department of Transplant Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway
3 School of Pharmacy, University of Oslo, Oslo, Norway
4 Laboratory of Applied Pharmacokinetics, Children’s Hospital Los Angeles, CA, USA
5 Department of Pharmacology, Oslo University Hospital, Oslo, Norway
6 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
Background
Early after renal transplantation, it is often challenging to achieve and maintain tacrolimus
concentrations within the target range. Computerized dose individualization using population
pharmacokinetic models may be helpful. The objective of this study was to prospectively
evaluate the target concentration achievement of tacrolimus using computerized dosing
compared with conventional dosing performed by experienced transplant physicians.
Methods
A single-center, prospective study was conducted. Renal transplant recipients were
randomized to receive either computerized or conventional tacrolimus dosing during the first
8 weeks after transplantation. The median proportion of tacrolimus trough concentrations
within the target range was compared between the groups. Standard risk (target, 3-7 μg/L)
and high-risk (8-12 μg/L) recipients were analyzed separately.
Results
Eighty renal transplant recipients were randomized, and 78 were included in the analysis
(computerized dosing (n = 39): 32 standard risk/7 high-risk, conventional dosing (n = 39): 35
standard risk/4 high-risk). A total of 1711 tacrolimus whole blood concentrations were
evaluated. The proportion of concentrations per patient within the target range was
significantly higher with computerized dosing than with conventional dosing, both in
standard risk patients (medians, 90% [95% confidence interval {95% CI}, 84-95%] vs 78%
[95% CI, 76-82%], respectively, P < 0.001) and in high-risk patients (medians, 77% [95% CI,
71-80%] vs 59% [95% CI, 40-74%], respectively, P = 0.04).
Conclusions
Computerized dose individualization improves target concentration achievement of
tacrolimus after renal transplantation. The computer software is applicable as a clinical
dosing tool to optimize tacrolimus exposure and may potentially improve long-term outcome.
[36]
IF5
A Fennoscandian database of freshwater fish mercury measurements for the evaluation
of air pollution effects on ecosystems
Hans Fredrik Veiteberg Braaten1, Staffan Åkerblom
2, Sigurd Rognerud
1, Espen Lydersen
3,
Jussi Vuorenmaa4, Martti Rask
4, Heleen de Wit
1
1 Norwegian Institute for Water Research, Oslo, Norway
2 Swedish University of Agricultural Sciences, Uppsala, Sweden
3 Telemark University College, Porsgrunn, Norway
4 Finnish Environment Institute (SYKE), Helsinki, Finland
[email protected], [email protected]
Background
Fish in freshwater ecosystems are considered to be critical receptors of long-range
transboundary atmospheric transport of mercury (Hg). Fish constitute an important exposure
pathway of Hg to humans and wildlife. Fish Hg levels even in remote areas commonly
exceed environmental quality standards (EQS) set by the WHO/FAO (0.5 – 1.0 mg kg-1
) and
the EQS set by the water framework directive (0.02 mg kg-1
) is exceeded in nearly all water
bodies. In Scandinavia, monitoring of fish Hg levels have been coordinated locally,
regionally and nationally to support decision and policy making to manage this
environmental problem. Regional and national monitoring programmes have revealed
undulating temporal patterns in fish Hg levels over time, but with no obvious systematic
geographical pattern in the temporal trend.
Methods
An initiative to combine expertise on fish Hg in freshwater ecosystems in Scandinavia and
Russia were taken in 2016 to strengthen the work being done to evaluate fish Hg data from
freshwater ecosystems. This work was done to support the evaluation of efforts being done to
decrease atmospheric emissions of Hg within the UN-ECE Convention on Long-range
Transboundary Air Pollution (CLRTAP). This initiative has resulted in a fish Hg database
that will be used to evaluate spatial and temporal patterns in Fennoscandia.
Results
Individual fish specimen with reported Hg data were retrieved from Swedish (n = 39992),
Finnish (n = 19695), Norwegian (n = 5880) and Russian (n = 225) monitoring databases,
regional survey reports and research projects. The Fennoscandian fish Hg database comprise
a variety of fish species (n : perch ≈ pike >> i.a, brown trout, arctic char, roach) with a
variation in fish species composition within and between lakes. The gathered data is collected
and analysed during the past 6 decades (1967 - 2015). Variation in fish Hg levels is ascribed
to factors affecting Hg cycling and bioaccumulation (e.g., catchment characteristics, water
quality, trophic structure, and climate) but also to atmospheric deposition of Hg.
Conclusion
The fish Hg database will be used in the evaluation of spatial patterns and temporal trends,
and take into account effects from confounding factors from species composition and fish
size-Hg relationships. The efforts to decrease Hg emissions by international agreements
should assist freshwater ecosystems to recover from past Hg contamination, but will also
depend on other factors apart from a decrease in Hg emissions. The results will be
communicated to internal policy bodies focusing on air pollution and mercury contamination.
[37]
IF6
Mercury pollution in China and implications for human health
Yan Lin1, Shuxiao Wang
2, Eirik Hovland Steindal
3, Zuguang Wang
4, Hans Fredrik Veiteberg
Braaten1, Qingru Wu
2, Thorjørn Larssen
1
1 Norwegian Institute for Water Research
2 School of Environment, Tsinghua University 3 Norwegian Environment Agency 4 Renmin University of China
Background: China is the largest user of mercury (Hg) in products and manufacturing
processes, China is also the largest emitter of Hg to the atmosphere. China’s Hg policies have
great implications on the overall success of Minamata Convention on Hg (MC). Fish
consumption is considered the primary pathway of methylmercury (MeHg) exposure for most
people in the world. However, in the inland regions of China, most of the residents eat little
fish, but they live in areas where a significant amount of mercury (Hg) is present in the
environment.
Methods: This study reviews the current Chinese Hg policies under the context of MC. And
we also selected Guizhou Province for our study because it is highly contaminated with Hg
and therefore is representative of other Hg-contaminated areas in China.
Results: Results show that China has considerable compliance gaps for Hg use in products
(medical devices), manufacturing processes (vinyl chloride monomer) and emission (e.g. coal
combustion, smelting and cement). Although the environmental concentration of mercury is
high in China, the probable daily intake (PDI) of MeHg for adult population is not higher
than people from countries with high consumption of fish, e.g. Japan and Norway, except
highly contaminated mining area.
Conclusion: New standards for products and production processes need to be developed and
new emission limits which correspond to the BAT/BEP guidelines need to be set. At the
same time, a consumption advisory based on rice consumption should be developed.
References:
1. Lin, Y.; Vogt, R.; Larssen, T., Environ. Toxicol. Chem. 2012, 31, (11), 2431-2444.
2. Lin, Y.; Wang, S.; Wu, Q.; Larssen, T., Environ. Sci. Technol. 2016, 50, (5), 2337-2344.
3. Hui, M.; Wu, Q.; Wang, S.; Liang, S.; Zhang, L.; Wang, F.; Lenzen, M.; Wang, Y.; Xu, L.;
Lin, Z.; Yang, H.; Lin, Y.; Larssen, T.; Xu , M.; Hao , J., Environ. Sci. Technol. 2016.
4. Zhang, H.; Feng, X.; Larssen, T.; Qiu, G.; Vogt, R. D., Environ. Health Perspect. 2010,
118, (9), 1183-1188.
5. Zhang, H.; Feng, X.; Chan, H. M.; Larssen, T., Environ. Sci. Technol. 2014, 48, (2), 1206-
1212.
[38]
IF7
Dental amalgam – problem for pasient og tannlege?
Jon E. Dahl
NIOM – Nordisk institutt for odontologiske materialer, Oslo
Det Odontologiske fakuletet, Universitetet i Oslo
Amalgam som er en blanding av sølv og kvikksølv, har vært et mye benyttet tannfyllings-
materiale. Gjennom de to siste tiårene før det ble forbudt i 2008, var bruken blitt redusert og
overtatt av plastbaserte materialer. Tidligere ble sølv og kvikksølv blandet slik at spesielt
tannhelsesekretærene var utsatt for eksponering for kvikksølvdamp. En spesiell amalgamtype
krevde dessuten oppvarming før blanding som med tanke på yrkesmessig eksponering for
kvikksølv, var spesielt ugunstig. Det liten tvil om at tannhelsesekretærer som blandet
amalgam uten tilstrekkelig beskyttelse, hadde stor risiko for yrkesbetinget helseskade. For
mange med mulig senskade etter arbeid som tannhelsesekretær har det likevel vært vanskelig
å bli tilkjent erstatning.
I senere tid ble amalgam blandet i lukkede systemer som blandemaskiner og predoserte
kapsler som sterkt reduserte den yrkesmessige eksponeringen. I enkelte studier synes
tannleger å prestere dårligere på hukommelsestester enn kontrollgruppen uten at det var
mulig å korrelere dette til kvikksølveksponering alene. Det ble ikke funnet økt risiko for
fertilitetsproblemer eller økt risiko for spontanabort blant norske kvinnelige tannleger. En
studie fra Finland fant heller ikke økt risiko for spontanabort blant tannhelsepersonell. En
dansk studie konkluderte med at det var ufarlig å arbeide som tannlege.
Pasientene kan eksponeres for kvikksølv fra amalgam under innlegging og utboring i tillegg
til frigjøring i munnen på grunn av korrosjon. Det er vanskelig å bestemme hvor mye
kvikksølv pasientene eksponeres for. Anslag er basert på målinger av kvikksølv i urin som
representerer utskillelse. WHO har antatt at pasienter med amalgamfyllinger kan ha
urinnivåer av kvikksølv på 3-17 µg Hg / g kreatinin. Laveste observerte effektnivå er anslått å
være ved urinverdier på 35-50 µg Hg / g kreatinin.
Lokale forandringer i slimhinnen er observert i tilknytning til amalgamfyllinger. Det er ikke
entydig om dette skylles allergisk eller lokal toksisk reaksjon. Ved utskiftning av amalgam-
fyllingen med annet materiale forsvinner ofte plagene.
Data fra den norske mor-barn studien er blitt koblet med data fra medisinsk fødselsregister.
Det er ingen sammenheng mellom antall amalgamfyllinger hos mor og negativt fødselsutfall.
Enkelte pasienter mener at amalgamfyllinger gir generelle helseplager. Det er ingen
spesifikke symptomer eller funn som kjennetegner disse pasientene, og årsaken til
helseplagene er vanligvis satt av pasienten selv. Hos disse pasientene som skifter ut sine
amalgamfyllinger, er det observert at plagene avtar, men de har likevel flere og kraftigere
plager enn kontrollgrupper.
[39]
IF8
The Minamata Convention – will it make a difference?
Eirik Hovland Steindal1
1 Chemicals and Waste Department, Norwegian Environment Agency
Problemstilling
Mercury is a toxic heavy metal, prone to long-range transport, posing a potential threat to
human health and the environment worldwide. Hence, no country can control transboundary
effects of mercury alone. A key element in Norway's strategy to address mercury pollution is
international cooperation and regulation. In 2009, based on an initiative from Norway and
Switzerland, the Governing Council of UNEP decided to develop a global legally binding
instrument on mercury. Succeeding five intergovernmental negotiating meetings the
Minamata Convention (MC) was agreed early 2013. In total, 128 states signed the agreement
later the same year – confirming their intention to ratify and implement the MC.
The main objective of the MC is to protect human health and the environment from
anthropogenic emissions and releases of mercury. However, in line with other global
instruments, the MC is founded on numerous compromises between states with different
economic and technical capabilities, representing a wide range of different starting points.
Thus, to what extent can such an instrument address the global mercury problem?
Resultater
The MC covers the entire life cycle of mercury, including a range of products, processes and
industries where mercury is used, released or emitted. The treaty also addresses mining of
mercury, export and import, storage and disposal. However, there are still ongoing processes
on supporting guidance material. A guidance document on releases to land and water and
contaminated sites are for example still being processed. Though not obligatory, such
supporting documents are in practice often applied similarly as binding text. In its attempt to
meet the interest of many, the MC also comes with some shortcomings: its soft grip on major
sources such as ASGM and a somewhat lack of holistic control are some examples.
Nevertheless, the true implications of such dynamics remains to be determined and requires
further investigations. To date, 35 countries have ratified, whereas the MC enters into force
once 50 states have ratified, anticipated to occur during the autumn of 2017.
Konklusjon
No doubt, the first new global convention on environment and health in nearly a decade, has
already sent a strong signal to the global market, and will continue to do so as parties start
implementing its provisions. However, even though it is already making a difference the
instrument is not watertight and its success will depend on implementation rate and quality.
Once into force, Norway will aim towards strengthening the convention and push for a tight
implementation of the convention among key parties.
Referanser
UNEP, Minamata Convention on Mercury, official webpage,
http://www.mercuryconvention.org/
[40]
IF9
Pharmacological treatment of heart failure. 2016 ESC Guidelines and new treatment
with angiotensin receptor neprilysin inhibition.
Geir Øystein Andersen
New guidelines for the diagnosis and treatment of acute and chronic heart failure (HF) were
presented from the European Society of Cardiology in 2016. The principles for treatment of
chronic HF will be presented with emphasis on evidenced based pharmacological treatment
indicated in patients with symptomatic HF with reduced ejection fraction. Drugs that are
shown to reduce the morbidity and mortality of chronic HF include the neuro-hormonal
antagonists (ACE inhibitors, mineral receptor antagonists and beta-blockers) and a new
compound LCZ696, which is a first-in-class drug that combine an angiotensin receptor
inhibitor (valsartan) and a neprilysin (NEP) inhibitor (sacubitril). The mechanism of action
and the evidence for its recommendation will be discussed. Other relatively new drugs like
the If-channel inhibitor ivabradine indicated for symptomatic treatment of HF in selected
patients, will also be discussed. Finally, pharmacological treatment of acute HF will be
briefly discussed. Contrary to treatment of chronic HF, medical treatment of acute HF is
almost exclusively based on expert opinion since evidence from randomized trials are
lacking. In short, several vasoactive drugs have been tested for treatment of acute HF, but all
have failed to reduce mortality in randomized controlled trials.
[41]
IF10
PCSK9-hemmere. Virkningsmekanisme, dokumentasjon og mulig plass i fremtidens
lipidsenkende behandling
Kjetil Retterstøl, Lipidklinikken, Medisinsk klinikk, Oslo universitetssykehus og Avdeling for
ernæringsvitenskap, Institutt for medisinsk basalfag, Medisinsk fakultet, Universitetet i Oslo
Høsten 2015 ble to nye kolesterolsenkende medikamenter godkjent for bruk i Norge. Dette er
medikamenter som gis som injeksjon hver 2. eller hver 4. uke og som senker LDL-kolesterol med 50-
60 %, en effekt som er minst like kraftig som effekten av maksimal dose av våre mest potente statiner.
Medikamentene er monoklonale antistoffer, og enzymet som hemmes heter proprotein-convertase
subtilisin/kexin type 9 (PCSK9), som opprinnelig hadde navnet nevral apoptose-regulerende
konvertase 1(NARC-1) (1). Overproduksjon av PCSK9 («gain of function» mutasjon) ga høyt LDL-
kolesterol og prematur kardiovaskulær sykdom (2), og allerede i mai året etter publiserte Trond Leren
funn av mutasjoner som ga økt PCSK9 og forårsaket familiær hyperkolesterolemi hos 3 norske
pasienter (3). Senere fant man mutasjoner i PCSK9 med motsatt effekt, altså redusert PCSK9-nivå
(«loss of function») i en frisk kvinne i 40 års alderen med meget lavt LDL-kolesterol (0,4 mmol/l) og
ikke målbare verdier av PCSK9 i sirkulasjonen (4). Kvinnen hadde egne barn, hun var yrkesaktiv og
velfungerende, noe som inspirerte ytterligere til forskning på PCSK9 som et mulig mål for
kolesterolsenkende behandling. To humane monoklonale antistoffer mot PCSK9 er foreløpig godkjent
for bruk, alirokumab (”Praluent”, Regeneron/Sanofi) og evolokumab (”Repatha”, Amgen).
Legemiddelverket har nylig vurdert at PCSK-9 hemmere ikke er kostnadseffektiv behandling for noen
pasientgrupper, gitt dagens pris på ca. 70 000 kr i året. Resultatene fra endepunktstudiene vil ha
avgjørende betydning for fremtidig klinisk bruk. Disse studiene er i hovedsak sekundærprofylaktiske
studier og bruk i primærprofylakse vil antagelig bli svært begrenset, ikke minst på grunn av høy pris.
Potensielt kan PCSK9-hemmere være til nytte for mange som ikke når LDL-behandlingsmål med
dagens behandling, men effekt på harde kliniske endepunkter mangler, derfor blir også kost-nytte-
beregningene mer presise når resultatene fra endepunktstudiene kommer, sannsynligvis i første
halvdel av 2017.
Referanser
1. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al. The secretory
proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and
neuronal differentiation. Proceedings of the National Academy of Sciences of the United States of
America. 2003;100(3):928-33.
2. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9
cause autosomal dominant hypercholesterolemia. Nature genetics. 2003;34(2):154-6.
3. Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant
hypercholesterolemia. Clinical genetics. 2004;65(5):419-22.
4. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular
characterization of loss-of-function mutations in PCSK9 and identification of a compound
heterozygote. American journal of human genetics. 2006;79(3):514-23.
[42]
IF11
Mer enn 25 ulike antidiabetika er tilgjengelige i Norge - hvorfor?
Kåre Birkeland
Universitetet i Oslo/Oslo Universitetssykehus
Diabetes er en utbredt sykdom i hele verden og prevalensen har økt kraftig de siste 50 år. Vi
regner med at omkring 375 000 personer i Norge har diabetes, og 85% har type 2 diabetes.
Basisbehandlingen er livsstilsrådgivning med fokus på sunn kost, minst 30 min moderat
fysisk aktivitet daglig og 5-19% vektreduksjon ved overvekt. Et flertall av pasientene må i
tillegg ha medikamentell blodsukkersenkende behandling for å nå behandlingsmålet som for
de fleste er HbA1c omkring 7% (53 mmol/mol). Patogenesen for hyperglykemien er
kompleks og sykdommen er progressiv, slik at blodsukkeret stiger etter hvert. Derfor er en
rekke blodsukkersenkende medikamenter med ulike virkningsmekanismer i bruk og ofte
kombineres 2-4 ulike medikamenter. Vi har nylig utarbeidet en ny Nasjonal faglig
retningslinje for diabetes som er tilgjengelig på nett
(helsedirektoratet.no/retningslinjer/diabetes). Foredraget vil gi en oversikt over anbefalingene
for blodsukkersenkende behandling og virkningsmekansismer, bivirkningsprofil og
tilgrunnliggende dokumentasjon for de viktigste midlene (tabell under).
[43]
IF12
Xenobiotics and Obesity
Dr Jérôme Ruzzin
Department of Biology, University of Bergen
The incidence of obesity has increased at alarming rate worldwide creating unprecedented
public health challenges for our societies.
While there may be genetic predisposition, the propagation of obesity is simply too fast to lie
at the feet of genetic changes in the population. Rather, lifestyle factors like sedentariness and
excess energy intake have been considered as primary contributors. However, the view that
these two conventional risk factors are the primary variables explaining the worldwide
explosive rise of obesity is being challenged as far too simplistic. For example, these lifestyle
factors cannot explain why some obese individuals are insulin resistant and at risk for cardio-
metabolic complications whereas other obese subjects are insulin sensitive and without
cardio-metabolic disorders [1]. Nor can they explain the existence of normal-weight
individuals who are metabolically unhealthy [2]. Within the context of the global rise of
metabolic diseases and the poor efficiency of current preventive and therapeutic treatments
[3, 4], there is an urgent need to better understand the underlying causes of obesity.
The post-World War II industrialization has led to the creation and production of an
incommensurable quantity of chemicals that have invaded our environment. Intake of
pharmaceutical drugs has also dramatically increased. As a consequence, xenobiotics (i.e.
chemical compound foreign to a given biological system) are today present in all living
organisms, but surprisingly, the cellular and organismal biological impacts of xenobiotics and
their potential implication in the obesity epidemic have remained poorly identified. This
presentation aims to describe the current state of knowledge about xenobiotics and obesity
and highlights how a better understanding of the mechanisms behind xenobiotic-induced
obesity could contribute to open novel therapeutic directions.
1 Karelis AD. Obesity: To be obese-does it matter if you are metabolically healthy? Nat
Rev Endocrinol 2011; 7: 699-700.
2 Voulgari C, Tentolouris N, Dilaveris P, Tousoulis D, Katsilambros N, Stefanadis C.
Increased heart failure risk in normal-weight people with metabolic syndrome compared
with metabolically healthy obese individuals. J Am Coll Cardiol 2011; 58: 1343-50.
3 Group TS. A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes.
N Engl J Med 2012; 366: 2247-56.
4 Sacks FM, Bray GA, Carey VJ, et al. Comparison of Weight-Loss Diets with Different
Compositions of Fat, Protein, and Carbohydrates. N Eng J Med 2009; 360: 859-73.
[44]
IF13
Nutrition and obesity Vibeke Telle-Hansen, Nutritionist (PhD), Associate Professor, HiOA
The prevalence of obesity is increasing worldwide and nearly doubled between 1980 and 2008.
Obesity is associated with increased mortality as well as being considered an important risk factor for
metabolic diseases, like cardiovascular diseases (CVD) and type 2 diabetes (T2D). Prevention and
treatment of obesity and obesity-related diseases are therefore major public health challenges. Obesity
is a chronic low-grade inflammatory condition which is suggested to play a critical role in the
development of obesity-related metabolic dysfunction. Interestingly, a subgroup of obese individuals
has been described as “metabolically healthy, but obese” (MHO). In contrast to at-risk obese (ARO),
the MHO phenotype is defined by a favorable lipid profile and a normal or only slightly affected
insulin sensitivity, despite the same amount of body fat.
Lifestyle factors such as unhealthy diet and lack of exercise are known to play an important role in the
development and progression of obesity and its comorbidities and non-communicable diseases
(NCDs). Dietary components associated with energy regulation and weight-related diseases includes
fat and fiber. Dietary fat is the most energy dense nutrient and is therefore important in total energy
regulation. The mechanisms behind health effects of fatty acids are however complex. Dietary fatty
acids have been shown to modulate the regulation of inflammatory markers and recent studies have
shown that saturated fatty acids also may affect the nervous regulation of food intake due to increased
inflammation in the brain. Other studies have shown that dietary fatty acids may affect hunger- and
satiety regulating hormones, and hence the risk of developing obesity. Dietary fiber is a heterogenous
group of undigestible carbohydrates that are known to exert different health beneficial effects related
to weight regulation, CVD and T2D. Reduced blood cholesterol and blood glucose are some of the
well known health effects ascribed to fiber, and in particular the soluble fiber beta-glucan. In addition,
dietary fiber has been shown to reduce the risk of obesity by increasing satiety. Interestingly, recent
studies have also shown that dietary components, in particular fat and fiber may affect the
development of obesity and obesity-related diseases by influencing the gut microbiota.
[45]
IF14
The effects of bariatric surgery on the pharmacokinetics of drugs in patients with
morbid obesity
Ida Robertsen
Avdeling for Farmasøytisk Biovitenskap, Farmasøytisk institutt, Universitetet i Oslo
Obesity is a growing global health problem. The prevalence of obesity in the industrialized
world is at an all-time high (>20% in Norway, 36% in the USA), and obesity related
comorbidities contribute significantly to the burden of disease. Although lifestyle
intervention and behavior modification programs are valid options for the treatment of
obesity; bariatric surgery is the treatment modality that can give the best results for long-term
weight reduction. There are several bariatric surgery techniques in use. In general, they
reduce the volume of the gastric ventricle, and/or the absorptive surface in the intestine,
bypassing part of the small gut. Bariatric surgery may hence have an effect on the
bioavailability and pharmacokinetics of various drugs. Possible sources of pharmacokinetics
modifications following bariatric surgery includes changes in drug absorption due to altered
surface area and transit time, changes in drug distribution due to alterations in body size and
composition, and changes in metabolic activity due to changes in enteric or hepatic drug-
metabolizing capacity. However, there is little certainty of whether observed changes in the
pharmacokinetics following bariatric surgery are due to altered gastrointestinal tract anatomy
and physiology, the subsequent weight loss or a combination of both. At present, there is no
single unified model that can predict changes in drug distribution and clearance associated
with either bariatric surgery or the weight loss that is likely to follow. More studies are
needed for optimizing drug treatment in obese individuals in general and also to adjust drug
doses following bariatric surgery.
[46]
IF15
Preventing opiate overdose deaths – mortality matters
Professor Sir John Strang
Director, National Addiction Centre, Kings College London, UK
Risk is not evenly distributed across different drugs of abuse and associated behaviours. In
deaths data, heroin and the opiates loom large. Furthermore, this risk of overdose death also
has times of intense concentration, particularly during transitions between systems. In the
first part of the talk, the distinctive risk of the opiates will be identified, alongside
consideration of implications.
In the second part of the talk, attention will turn to recent novel interventions. In recent years,
the pre-provision of naloxone has been introduced in some areas so that lay first-responders
can give interim emergency care while awaiting the arrival of formal emergency medical care
(similar to interim treatment by family of anaphylaxis with Epi-Pen, etc). Take-home
naloxone schemes now exist, although mostly at local level.
In the third part of the talk, findings from experimental and epidemiological study of fatal
and non-fatal overdoses will be presented, alongside consideration of the limitations of
experimental investigation of these overdose phenomena. Options for new experimental and
epidemiological study will be discussed.
In the fourth and last section of the talk, the options for the future will be examined. This will
include examination of new naloxone auto-injectors, naloxone nasal sprays and also remote
training sites to improve competence at emergency resuscitation. There is much more that
could be done, and options that should form the next wave of innovation and implementation
will be explored.
[47]
IF16
Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the
Hepatotoxicity of Drugs and Drug Candidates
Tommy B. Andersson
Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg,
Sweden
Introduction: The liver is an organ with critical importance for drug treatment as the
disposition and response to a given drug is often determined by its hepatic metabolism.
Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which
constitutes a major risk for drug development programs causing attrition of promising drug
candidates or costly withdrawals in post-marketing stages. 1, 2.
Methods: With the increasing comprehension that 3D cell culture systems more accurately
reflect in vivo physiology, in the recent decade more and more research has focused on the
development and optimization of various 3D culture strategies in an attempt to preserve liver
properties in vitro. Results: Advances in the design of in vitro systems that reliably predict drug metabolism and
drug toxicity in humans have been made. These developments are driven by the
comprehension that culture conditions and cellular architectures, which resemble intact liver
structure in vivo regarding cell-cell and cell-extracellular matrix interfaces as well as
perfusion, facilitate the maintenance of hepatic phenotypes and functionalities. As such, the
rapid dedifferentiation of hepatocytes observed in 2D systems, is decelerated or even
prevented in 3D liver systems.
Conclusion: It is concluded that 3D liver models have hitherto been fruitful and systems are
now at hand whose sensitivity and specificity in detecting hepatotoxicity is superior to
classical 2D culture systems..
Refrences
1. Lauschke VM, Hendriks DFG, Bell CC, Andersson TB, and Ingelman-Sundberg
M Novel 3D Culture Systems for Studies of Human Liver Function and
Assessments of the Hepatotoxicity of Drugs and Drug Candidates (2016) Chem
Res Toxicol, DOI: 10.1021/acs.chemrestox.6b00150
2. Marx U, Andersson TB, Bahinski A, et al. (2016). Biology-inspired
Microphysiological System Approaches to Solve the Prediction Dilemma of
Substance Testing. ALTEX 33: 272-321
[48]
IF17
Use of in vitro testing of epigenetic changes induced by endocrine disrupting chemicals
Ali Alavian-Ghavanini1,2
, Gábor Borbély1, Yun Liu
3, William Duong
4, Joëlle Rüegg
1,2
1Swedish Toxicology Science Research Center Swetox, Södertälje, Sweden
2Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden
3 Fudan University Shanghai Medical College, Shanghai, P.R. China
4University of Basel, Department of Biomedicine, Basel, Switzerland
Purpose
Early life exposure to endocrine disruptive chemicals (EDCs) may be a major contributory
factor in later life diseases. Epigenetic mechanisms such as DNA methylation are most likely
involved in increased disease susceptibility due to developmental exposure. Indeed, growing
evidence from human and animal studies suggest that EDCs induce epigenetic changes.
Therefore, epigenetic marks have a great potential to be used as predictors of possible
adverse health effects caused by early life exposure. However, as yet, there is too little
molecular information and no established test systems to incorporate epigenetic endpoints
into regulatory procedures. The aim of our research is to gain insights into mechanisms
underlying EDC-induced epigenetic changes, link them to relevant outcomes in animals and
humans, and use this information to establish test systems for epigenetic endpoints.
Methods
We mainly use cell-based models to elucidate EDC-induced epigenetic changes and
underlying mechanisms. In mouse embryonic fibroblasts from wildtype (wt) and ERbeta
knock-out mice, we investigated the role of ERbeta to directly regulate DNA methylation by
comparing genome-wide DNA methylation using reduced representation bisulfite
sequencing. Methylation patterns were validated by bisulfite-pyrosequencing and expression
of differentially methylated genes was analysed by qPCR. Further, the interaction between
ERbeta and DNA methylation regulators was analysed using biochemical assays and
chromatin immunoprecipitation. In differentiating mouse hippocampal cells and human
mesenchymal stem cells, we investigate the effect of the EDCs, by themselves or in mixtures,
on differentiation and DNA methylation. These cell models are also used to develop in vitro
assays to measure the interaction between EDC-targets and DNA methylation regulatory
enzymes using fluorescence cross-correlation spectrometry or mammalian-two hybrid assays.
Finally, in different collaborative projects, we analyse epigenetic changes identified in vitro
in animal tissue or human samples and link them to adverse outcomes.
Results
We have found that the EDC target ERbeta is involved in regulating DNA methylation at
specific genomic regions by interacting with TDG, an enzyme involved in DNA
demethylation. We also have indication that this interaction is disturbed by EDCs, thus
providing a mechanism how these chemicals can induce DNA methylation changes. We are
now in the process of developing in vitro assays to monitor this interaction and test how it is
affected by EDCs. Further, in the H2020 funded EDC-MixRisk project, we connect these
molecular findings with effects of mixture exposures on human health.
Conclusions
Our research is contributing to the mechanistic understanding of EDCs mode of actions. Such
insights are of great importance for mechanism-based risk assessment of EDCs and for
developing sensitive methods to include epigenetic endpoints into regulatory processes.
[49]
IF18
Organs on chips as predictive in vitro models Anna Herland
1
1 KTH Royal Institute of Technology, Department of Micro and Nanosystems, Stockholm
Purpose
Improving the effectiveness of preclinical predictions of human drug responses is critical to
reducing costly failures in clinical trials. Since animal models often show poor translation to
human responses, we are developing and evaluating the usability of human micro engineered
cell culture models.
Methods
We are using human primary and stem cell-based culture combined with microfabrication
and microfluidics to mimic functional units of human organs, a concept known as Organs-
on-chips. The micro engineered models are assessed with real-time integrated sensing as well
as conventional molecular biology analysis.
Results
These Organ-on-Chips devices recreate the specialized tissue-tissue interfaces,
physicochemical microenvironments, and vascular perfusion characteristics of the lung (Huh
et al., 2010), liver, gut, kidney, the blood-brain-barrier (Herland et al., 2016) and many other
human organs (Benam et al., 2015). Typically primary human cells are suitable for these
systems, however, in certain cases, primary cells are not accessible or the cells cannot
maintain an in vivo like phenotype in vitro. This is particularly evident in models of the
central nervous system, where iPS-derived cells are an attractive alternative cell source. We
have established a modular system of neurovascular unit, which can recreate physiological
functional barrier alternations and metabolic changes under a challenge of a neurostimulant.
Moreover, the system provided new insight into metabolic interactions between the cell types
in the neurovascular unit.
Conclusion
Organ-on-Chips have been shown to predict efficacy, safety and mechanism of action for
new drugs, chemicals, and cosmetics, as well as providing insight into mechanisms of cell-
cell interactions. However, both further technical and biological development, as well as
rigorous validation, remains to evaluate to what extent organ-on-chip models accurately
represent human-relevant physiology and show predictive capability across broad drug
classes and clinical outcomes.
References
Benam, K.H., Dauth, S., Hassell, B., Herland, A., Jain, A., Jang, K.-J., Karalis, K., Kim, H.J.,
MacQueen, L., Mahmoodian, R., Musah, S., Torisawa, Y., van der Meer, A.D., Villenave, R.,
Yadid, M., Parker, K.K., Ingber, D.E., 2015. Annu. Rev. Pathol. Mech. Dis. 10, 195–262.
Herland, A., Meer, A.D. Van Der, Fitzgerald, E.A., Park, T., Jelle, J., 2016.. PLoS One 11,
e0150360.
Huh, D., Matthews, B.D., Mammoto, A., Montoya-Zavala, M., Hsin, H.Y., Ingber, D.E.,
2010.. Science 328, 1662–8.
[50]
IF19
Air pollution – measurements and modeling
Dag Tønnesen (NILU)
Topics:
Principles for measurements of regulated species.
The regulatory monitoring network in Norway.
Expected development in measurements of air pollution in the future.
Principles for Air Quality models.
Complexity of Air Quality modelling issues.
Example of simplified model for roadside air pollution.
IF20
Urban air particles, in vitro effects and mechanisms
Eleonora Longhin1, Marina Camatini
1, Steen Mollerup
2, Jørn A. Holme
3
1 Polaris Research Centre, University of Milano-Bicocca, Milan, Italy
2 National Institute of Occupational Health, Oslo, Norway
3 Norwegian Institute of Public Health, Oslo, Norway
Background
Urban particulate matter (PM) exposure causes health effects especially on the respiratory
and cardiovascular systems. In vitro research has been used to explore the relative importance
of particles components and the mechanisms involved in PM toxicity.
Methods
Different methods are used to collect and characterize urban particles for biological
investigations. Sampling on filters by gravimetric samplers is the most common. Particles are
then detached from filters and used for cells exposure, by mean of different mono- and co-
culture models. Interesting 3D culture systems are evolving, in combination with advanced
air-liquid-interface (ALI) exposure conditions.
Results
In general, effects on in vitro systems vary in response to different PMs and experimental
models used. Polycyclic aromatic hydrocarbons (PAHs), metals and biological components
are the main chemical classes individuated as important for PM toxicity. In various cellular
models, these compounds were found to be responsible for PM-induced reactive oxygen
species (ROS) and activation of transcription factors such as AhR, NF-kB, Nrf2. These
effects lead to oxidative stress and inflammation, which are important adverse outcomes
arising in the respiratory system following PM exposure (Nemmar et al., 2013).
PAHs seem to play a particular important role for PM carcinogenic effects, causing genotoxic
damages that are important for cancer initiation. PM has also been reported to induce
alterations in cell proliferation, migration/invasion and cell cycle, which may contribute to
various stages of carcinogenesis. Recently more studies used long-term exposure of in vitro
systems to investigate these aspects, reporting significant results on cell transformation.
Systemic inflammation and particles translocation are the main hypothetical pathways
leading to the cardiovascular effects of PM (Stone et al., 2016). Both these theories received
support from in vitro investigations, but the contribution of each to the final outcomes is still
not clear, and likely depends on features as particles properties, endpoint and model
investigated.
[51]
Conclusions
Up to now in vitro investigations helped to individuate the possible mechanisms driving the
PM health effects seen in epidemiological and clinical studies, although several aspects
remain to be clarified. The complexity and variability of urban particles represent a challenge
for these type of investigations, but also an opportunity to clarify effects induced by different
components of PM, if a proper particles characterization is carried out alongside with
biological investigations. The definition of common guidelines for particles sampling and
cells exposure may help to compare results from different studies.
References
Nemmar A et al., 2013, Biomed. Res. Int., 279371
Stone V et al., 2016 Environ Health Perspect DOI: 10.1289/EHP424
IF21
Initial triggering mechanisms for cellular effects of combustion exhaust particles with
possible implication for carcinogenesis
J. Øvrevik1, B. Brinchmann
1, N. Bach
1, J.A. Holme
1, A.I. Totlandsdal
1, A.K. Bølling
1, M.
Refsnes1, M. Låg
1, and P.E.Schwarze
1.
1Department of Air Pollution and Noise, Domain for Infection Control and Environmental
Health, Norwegian Institute of Public Health, Oslo, Norway.
Inflammation is considered to play a central role in a diverse range of disease outcomes
associated with exposure to various types of inhalable particulates. The initial mechanisms
through which particles trigger cellular responses leading to activation of inflammatory
responses are crucial to clarify in order to understand what physico-chemical characteristics
govern the inflammogenic activity of particulate matter and why some particles are more
harmful than others. Recent research suggests that molecular triggering mechanisms involved
in activation of proinflammatory genes and onset of inflammatory reactions by particles or
soluble particle components can be categorized in direct formation of reactive oxygen species
(ROS) with subsequent oxidative stress, interaction with the lipid layer of cellular
membranes, activation of cell surface receptors and direct interactions with intracellular
molecular targets. This presentation will focus on the immediate effects and responses in
cells exposed to particles and central down-stream signaling mechanisms involved in
regulation of proinflammatory genes.
IF22
Supervised heroin treatment for the hard-to-treat: positive results from randomised
clinical trials
Sir John Strang (Kings College, UK)
[52]
IF23
Bystander administered nasal naloxone in Norway: results from the pilot project
Philipp Paul Lobmaier1,2
, Desiree Madah-Amiri1, Thomas Clausen
1
1 Senter for Rus- og Avhengighetsforskning (SERAF), Universitetet i Oslo
2 Søndre Oslo DPS, Klinikk for Psykisk Helse og Avhengighet, Oslo Universitetssykehus
Background
Take home naloxone programs have been successful internationally in training bystanders to
reverse an opioid overdose with naloxone, an opioid antagonist. A multi-site naloxone
distribution program began in Norway in 2014 as part of a national overdose prevention
strategy. The aim of this presentation is to a) describe the program, and b) present findings
from the government-supported intervention.
Material and method
From July 2014 to December 2015, staff from multiple low-threshold facilities trained clients
on how to use intranasal naloxone. Distribution occurred without an individual prescription
or physician present. Questionnaires from initial and refill trainings were obtained, and
distribution rates were monitored.
Results
There were 2,056 naloxone sprays distributed from one of the 20 participating facilities, with
277 reports of successful reversals. In these cases where naloxone was used, the victim
survived in 96% (n=265) of the events, with the remaining outcomes being unknown (1%,
n=3) or missing (3%, n= 9). Participants exhibited known risks for overdosing, with injecting
(p= 0.02, OR= 2.4, 95% CI= 1.14, 5.00) and concomitant benzodiazepine use (p=0.01, OR=
2.6, 95% CI= 1.31, 5.23) being significant predictors for having had high rates of previous
overdoses. Suggested target coverage for large-scale programs was met, with an annual
naloxone distribution rate of 144 per 100,000 population, as well as 12 times the cities mean
annual number of opioid-related deaths.
Conclusion
A government-supported multisite naloxone initiative appears to achieve rapid, high volume
distribution of naloxone to an at-risk population. The target goal for naloxone distribution
was met, and done so for those at greatest risk. The use of the intranasal device resulted in
safe and effective use reported back from the participants.
The abstract above is based on a paper by Madah-Amiri, Clausen & Lobmaier entitled
“Rapid widespread distribution of intranasal naloxone for overdose prevention”, which has
been accepted for publication in Drug and Alcohol Dependence.
[53]
IF24
Epidemiological aspects of naloxone treatment in Oslo Ambulance Service 2014- 15.
Arne Skulberg
Research fellow NTNU
Consultant Anaesthetist, Oslo University Hospital, Air Ambulance Department
The Ambulance Service in Oslo and Akershus treats between 500 and 1000 patients for
opioid overdoses annually. Treatment consist of ventilatory support, often involving bag-
mask ventilation and the administration of naloxone. This is usually given as an IM injection,
sometimes coupled with IV. As a part of the NTNU/ Prof Ola Dales undertaking to develop
naloxone for intranasal administration in overdoses an epidemiological and pharmacological
survey of patients receiving naloxone is on- going from 2014- 18. We will present
epidemiological data on this patient cohort, and on the locations and times at which
overdoses happen. The normal follow up of this patient population is described. The dosing
of naloxone in opioid overdoses vary, the SPC describes a range from 0.4- 2.0 mg injected
with a maximum of 10 mg. Naloxone elicit a state of acute withdrawal, a serious side effect
that influence the ability for other interventions and follow up these patients require. At the
scene of an overdose emergency medical personal does not have the information of the dose,
type or purity of opioid causing the overdose, the individual’s tolerance and general physical
health are unknown, and often other sedating drugs (often benzodiazepines) add to the
clinical presentation of unconsciousness and respiratory depression. We present data on
which doses typically reverse the overdose, key knowledge both for developing treatment
guidelines and future new naloxone products.
[54]
IF25
Naloxone analysis in overdose victims
Åse Marit Leere Øiestad1
1 Oslo University Hospital, Division of Laboratory Medicine, Department of Forensic
Sciences.
Aim
Present the routine analysis of samples from overdose victims at the Department of Forensic
Sciences at Oslo University Hospital and the possibilities for naloxone analysis.
Methods
Approximately 1800 - 2000 post mortem blood samples from legal autopsy cases are
analysed annually at The Department of Forensic Sciences. Screening of blood samples from
these cases, which includes overdose victims, is done by ultra-high performance liquid
chromatography tandem mass spectrometry (UHPLC-MS/MS) and quadrupole time-of-flight
mass spectrometry (LC-Q-TOF-MS). Confirmatory analysis is then performed with UHPLC-
MS/MS.
Results
High concentrations of naloxone can be found with the present methods of analysis.
However, for the low concentrations believed to be relevant in cases where naloxone has
been administered to overdose victims, other possibilities would have to be explored and
naloxone analysis asked for specifically. A change of extraction method is already planned
for, which could make more routine detection possible.
Conclusion
Naloxone is not routinely screened for in overdose victims, but can be analysed upon
request.
[55]
Frie foredrag
De frie foredragene i farmakologi er pa 15 minutter hver, hvorav 12 minutter er til foredraget
og 3minutter er til spørsmål og diskusjon. Frie foredrag i toksikologi er på totalt 10 minutter,
hvorav 8 minutter til foredraget og 2 minutter til spørsmål og diskusjon.
NSFTs pris for beste frie foredrag 2017 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 28.
januar. Priskomiteen for frie foredrag i toksikologi 2017 består av Erik Ropstad (NMBU) og
Merete Grung (NIVA). Priskomiteen for frie foredrag innen farmakologi 2017 består av:
Vigdis Aas (HiOA), Sara Bremer (OUS) og Lise Román Moltzau (UiO).
Vinnere av pris for beste frie foredrag 2016 var: Farmakologi: Ole Kristian Forstrønen Thu (NTNU)
Toksikologi: Thomas Fraser (NMBU)
[56]
Frie foredrag i toksikologi (TF)
TF1
Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis
morphology, epidydimal sperm count and induces sperm DNA fragmentation in mice
Abdolrahman Khezri1* ; Birgitte Lindeman2 ; Anette K. Krogenæs3 ; Hanne F. Berntsen4 ; Karin E. Zimmer1 ; Erik Ropstad3
1 Department of Basic Science and Aquatic Medicine, Norwegian University of Life Science
2 Department of Toxicology and Risk, Norwegian Institute of Public Health
3 Department of Production Animal Clinical Science, Norwegian University of Life Science
4 National Institute of Occupational Health
Problemstilling
Persistent organic pollutants (POPs) are widespread throughout the environment and some
are suspected to induce reproductive toxicity. As animals and humans are exposed to
complex mixtures of POPs, it is reasonable to assess how such mixtures could interact with
the reproductive system.
Metode
Our aim is to investigate how maternal exposure to a mixture of POP based on the levels in
the food basket of the Scandinavian population, could alter reproductive endpoints. Female
mice were exposed via feed 3 exposure groups (control (C), low (L) and high (H)). Testicular
morphometric endpoints, epididymal sperm concentration and sperm DNA integrity were
assessed in adult male offspring.
Resultater
We found that the number of tubules, proportion of tubule compartments and epididymal
sperm concentration significantly decreased in both POP exposed groups. Cauda and vas
deferens sperm showed different trends in the sperm chromatin structure assay. Nevertheless,
epididymal sperm from both POP exposed groups showed increased DNA fragmentation.
Konklusjon
It is concluded that maternal exposure to a defined POP mixture relevant to human exposure
can affect testicular development, sperm production and sperm chromatin integrity.
Keywords: Persistent organic pollutants (POPs), reproductive toxicity, testis morphology,
sperm count, Sperm Chromatin Structure Assay (SCSA)
[57]
TF2
Mice strain and administration route impact the toxicity of methylmercury.
Ole Jakob Nøstbakken,1
, Lene Secher Myrmel1, Lise Madsen
1,2, Trond Brattelid
3
1 Nasjonalt institutt for Ernæring og Sjømatforsking (NIFES)
2 Universitetet i København
3 Høgskolen i Bergen
Problemstilling
Our understanding of methylmercury (MeHg) toxicity is largely based on studies with
animals exposed to MeHg through either feed, gavage, or intraperitoneal injection. The
manner and frequency of administration of MeHg may affect the: toxicological evaluation,
the tissue distribution of MeHg, and eventually the outcome of experiments. Furthermore, the
choice of animal model, and even choice of mice strain may affect the final outcome of such
experiments. This study evaluate the toxicity of MeHg in two mouse strains of different
origin exposed to MeHg at different frequencies via diet or gavage.
Metode
The main aim of our study was to evaluate the impact of administration route and genetic
background on the tissue distribution and toxicology of MeHg. Two mice strains, C57BL/6
and BalbC, were used to reveal the importance of genetic background on the uptake,
distribution and toxicological response to MeHg. To evaluate route of administration and
exposure frequency of MeHg BalbC mice was exposed to MeHg on a daily basis (chronic),
twice a week (pulsed) via diet, or twice a week via gavage. All high dose exposure groups
were exposed to the same relative amount of MeHg in the course of a week. In addition two
groups of each mice strain were exposed to a chronic low dose of MeHg.
Resultater
In the high MeHg dose exposure groups the amount of measured Hg in feces were
strain independent, whereas Hg accumulated at significant higher levels in brain, liver, RBC
and muscle in BalbC compared to C57BL/6. For the low MeHg dose exposure groups the
level of Hg in RBC and kidney were higher in BalbC than in C57BL/6. Administration of
MeHg via gavage significantly reduced the amount of Hg measured in all tissues analyzed.
No significant differences were observed between accumulation of Hg in the mice given the
chronic and pulsed dosage.
There was a decreased weight gain in BalbC mice exposed to the high MeHg dose
compared to the control group, which was not observed for the C57BL/6 mice. In addition,
mouse under pulsed high dose MeHg exposure regime tended to decrease bodyweight at the
final stage of the study compared to chronic high MeHg dose exposure. The difference in
weight gain was mainly due to a reduction in body fat level.
The mice were also assessed using behavioral tests in the final stage of the study. No
clear differences were observed in the behavior of the mice, except for an indication of
reduced grip strength in the pulsed dosage group.
Konklusjon
Route of MeHg administration and strain of mice is of major importance for Hg distribution
and toxic responses. These strain differences should be considered in the experimental set-up
of animal studies concerning MeHg.
[58]
TF3
Do silica nanoparticles induce oxidative stress by different mechanisms in different
mammalian cell lines?
Kirsten E. Rakkestad1, Jon E. Dahl
1, Ragnhild E. Paulsen
2, Marit Låg
3 and Jan T.Samuelsen
1
1)Nordic Institute of Dental Materials, Oslo, Norway;
2)University of Oslo, School of
Pharmacy, Oslo, Norway; 3)
Norwegian Institute of Public Health, Oslo, Norway.
Nanoparticles (NPs; particles ≤ 100nm) have become popular in use for a wide array of
applications, including dental materials, as they can provide a very desirable combination of
properties. By far, the largest application in dentistry has been in dental composites, although
several unique adhesive systems containing NPs have also been commercialized. However,
with increased use come increased exposure, and an increased risk of unwanted health
effects. Dental technicians, dentists, researchers, and patients are all exposed to dental NPs.
In a clinical setting the NPs will be applied directly in the mouth cavity and/or in the
maxillofacial area. Thus inhalation, swallowing and absorption through mucosal membranes
are all possible exposure routes.
We have chosen to compare three different mammalian cell lines in this study; the human
alveolar epithelial cells A549, the human bronchial epithelial cells BEAS-2B, and the PC12
cell line which is derived from a pheochromocytoma of the rat adrenal medulla. This is both
to compare the NP’s lung-toxicity potential to their neurotoxic potential, and to compare cell
lines with known differences in their oxidative defense systems.
One of the most frequently reported nanoparticle-associated toxicities is generation of
reactive oxygen species (ROS). We have therefore measured cellular ROS production,
cellular glutathione levels, and expression levels of proteins that are affected by oxidative
stress, i.e. heme oxygenase (HO) and glutamate cysteine ligase (GCL) in all three cell lines
after exposure to silica nanoparticles ≤ 10 nm (Si10) in various concentrations.
Our results show that that the same particles induce different patterns of oxidative stress in
the three different cell lines. The results further imply that different cellular mechanisms are
involved.
[59]
TF4
Induction of fibrotic responses following injection of multi-walled carbon nanotubes in
the pleural cavity and modification by the IL1 genes
Yke Jildouw Arnoldussen1, Mona Aleksandersen
2, Kristine Haugen Anmarkrud
1, Vidar
Skaug1, Cesilie Granum
2, Fang Chin-Lin
1, Elin Einarsdottir
1, Mayes Kasem
1, Einar
Eilertsen1, Ron N. Apte
3, Erik Ropstad
2, Shan Zienolddiny
1#
1Department of Biological and Chemical Work Environment, National Institute of
Occupational Health, Oslo, 2Department of Production Animal Clinical Sciences, Norwegian
University of Live Sciences, NMBU-School of Veterinary Science, Oslo, 3The Shraga Segal
Department of Microbiology, Immunology and Genetics, Ben Gurion University of the
Negev, Beer Sheva 84105, Israel
Presenting author. Email: [email protected]
Introduction: We have investigated induction of fibrotic responses in the pleural cavity and
the lung, and a role for Interleukin-1 (IL-1) in CNT-induced fibrosis in mice following intra-
pleural injection of two different multi-walled CNTs and crocidolite asbestos fibers.
Methods: IL-1 wild type (IL1-WT) and IL-1 knock out (IL1-KO) mice were injected in the
pleural cavity with 50 or 100 µg/mouse. The mice were sacrificed 28 days post injection and
pleura and lungs were harvested. Histopathological analysis was performed in addition to
expression analysis of 84 fibrosis-specific genes and miRNAs from the lungs and pleura.
Results: Histopathological analysis showed that CNT-1 had the highest effect on inducing
fibrosis, changing the mesothelium and increasing leukocyte infiltration both in the pleura
and lungs. IL1-WT mice were significantly more prone to development of fibrosis and
leukocyte infiltration than IL1-KO mice. Among the genes with significant changes in
expression, twelve genes (Ccl12, Ccl3, Col1a2, Col3a1, Cxcr4, Lox, Mmp13, Mmp9,
Serpin1a1, Timp1, Timp4 and Bcl-2) were chosen for further analysis in each individual
mouse. CNT-1 had the greatest impact on gene and miRNA expression in the pleura, closely
followed by CNT-2. Furthermore, the CNTs and asbestos induced more significant changes
in the pleura than lung tissue. Fewer significant gene changes were observed between IL1-
WT and IL1-KO mice. Conclusion: The present study is the first study to include IL1-KO
mice and investigate the effects of two different CNTs when comparing these to the effects
crocidolite asbestos. CNTs induce fibrotic molecular responses depending on their physico-
chemical properties, but the responses are not very dependent on IL-1 signaling.
[60]
TF5
Using time series to identify mechanisms for pollution effects (or lack thereof)
Ketil Hylland1, Dag Ø. Hjermann
1,2, Norman Green
2 og Anders Ruus
1,2
1 Department of Biosciences, University of Oslo, PO Box 1066, Blindern, NO-0316 Oslo
2 Norwegian institute for water research (NIVA), Gaustadalléen 21,NO- 0349 Oslo
Coastal marine ecosystems receive contaminant inputs from a range of sources and some
Norwegian industrial fjords have been heavily polluted. From its peak in the 1970-1980s this
contamination has decreased markedly, providing a change over time against which effects
on local populations of marine organisms can be compared.
Biological effects have been implemented in marine monitoring programmes in European
countries in the past couple of decades. Such sub-lethal contaminant-related responses, also
called biomarkers, have been a part of the Norwegian coastal monitoring programme for over
20 years. As part of this programme, the concentration of selected contaminants (metals,
organochlorines) have been determined in blue mussels and cod tissues in both unpolluted
and polluted areas. The same cod were analysed for biomarker responses: delta-
aminolevulinic acid dehydratase (ALA-D) activity in red blood cells, PAH metabolite
concentrations in bile and cytochrome P4501A (CYP1A) activity and concentration in liver,
and also assessed for general condition. Both genders were included, and only cod in a
predetermined size range was used.
The aim of this study was to clarify the extent to which industrial pollution affects resident
cod populations and whether reduced contamination inputs would also lead to decreased
exposure and improved health. Exposure was both assessed through tissue residues and
through concentrations in blue mussels collected from the same areas. The chosen study areas
were Sørfjord, with known inputs of metals, PAHs and organochlorines, and as a reference
the outer Hardangerfjord. There was reduced exposure to all contaminants in Sørfjord over
the 20-year period. ALA-D was clearly inhibited in cod from Sørfjord early in the period and
this impact decreased with decreasing exposure to lead. There was a substantial variability
within and between years which could to some extent be explained by individual lead
exposure. PAH exposure decreased through the period studied, but there was no obvious
association with hepatic CYP1A activity or concentration. Cod in Sørfjord had lower values
for indices of condition that cod from the outer Hardangerfjord and other coastal areas. The
lack of clear correspondence between exposure and biomarker responses through the period
suggest that non-contaminant factors are at least partly to blame for the health status of cod in
Sørfjord.
[61]
TF6
Polar bear ecotoxicology - establishing understanding through toxicogenomic and ex-
situ approaches
Anders Goksøyr1,*, Roger Lille-Langøy1, Lene Øygarden1,2, Odd André Karlsen1
Mari K. Berg1,2, Mikael Harju3 & Heli Routti2
1Department of Biology, University of Bergen, Norway; 2The Norwegian Polar Institute,
Tromsø, Norway; 3Norwegian Institute of Air Research, Tromsø, Norway
Ecotoxicology involves studying the behaviour of contaminants in the environment but also
organismal and ecosystem responses to such compounds. Organisms at the top of the food
chain are especially susceptible to the effects of lipophilic, persistent organic pollutants
(POPs) and other emerging contaminants. In the Arctic, many species, e.g. the polar bear
(Ursus maritimus), are vulnerable to such effects, accumulating high levels of POPs through
their diet, mainly being seal blubber. Polar bears are not amenable to experimental studies,
and only tissue or blood samples are available for laboratory analyses. These provide a basis
for correlation analyses between contaminants, physiological parameters and specific gene
responses, but mechanistic understanding is more difficult to obtain. We have developed a
strategy where we clone the genes of representative target receptors found in the defensome
of the polar bear, e.g. the pregnane X (or promiscuous xenobiotic) receptor, PXR, and the
peroxisome proliferator activated receptors (PPARs), and study their ligand binding ability in
a cell-based luciferase reporter assay. These studies indicate which compounds that are able
to activate these receptor pathways in the polar bear, and may be performed in direct
comparison with human and other species’ receptors. An additional approach for studying
cellular responses of the adipogenic pathway in the polar bear has also been established. By
culturing mesenchymal stem cells from polar bear fat biopsies, adipocyte differentiation can
be studied in the laboratory. A number of emerging contaminants have been shown to be able
to interfere with adipogenesis in murine and human systems. With these approaches, we have
investigated whether contaminants found in Arctic biota and polar bear tissue can affect
toxicological pathways in the polar bear.
The study was supported by the Norwegian Research Council (181888/Miljø 2015), the Fram
Centre Hazardous Substance Program and the Norwegian Polar Institute.
[62]
TF7
Integrative transcriptome and proteome analysis reveals perturbation of lipid metabolic
pathways in the liver of Atlantic cod (Gadus morhua) treated with PCB 153
Fekadu Yadetie1,*
, Marta Eide1, Eystein Oveland
2, Anne Døskeland
2, Frode Berven
2, Christer
Hogstrand3, Anders Goksøyr
1, Odd André Karlsen
1
1Department of Biology, University of Bergen, Norway
2Department of Biomedicine, Proteomics Unit (PROBE), University of Bergen, Norway
3Diabetes and Nutritional Sciences Division, King's College London, London, UK
Background
Many environmental chemicals, particularly persistent organic pollutants (POPs) are
implicated in metabolic disruption, possibly contributing to development of metabolic
diseases. PCB 153 is a legacy pollutant that is one of the most abundant PCB congeners
detected in biological samples. To study mechanisms of toxicity of PCB 153, we exposed
Atlantic cod (Gadus morhua) to increasing doses (0, 0.5, 2 and 8mg/kg BW) of PCB 153 and
examined the effects on the liver transcriptome and proteome.
Method
Atlantic cod oligonucleotide arrays were used for gene expression analysis and label-free
quantitative proteomics was used for proteomics analysis of liver samples. Integrated
transcriptomics and proteomics data was analyzed using various bioinformatics tools.
Results
Both transcriptomics and proteomics analyses showed that PCB 153 modulates many
pathways, mainly related to lipid metabolism. Measurement of triglycerde levels showed a
significant increase in plasma. Integrative analysis of the transcriptomics and proteomics data
revealed significant effects of PCB 153 on many cellular processes, particularly lipid
metabolism and related pathways. A coordinated up-regulation of genes and enzymes in the
de novo fatty acid synthesis pathway, and increased levels of plasma triglycerdes suggest
overall lipogenic effects of PCB 153.
Conclusions
Our integrative analysis of transcriptomics and proteomics datasets suggests perturbation of
lipid metabolism by PCB 153. The results are consistent with the hypothesis that POPs may
disrupt energy metabolism.
The project is funded by the Norwegian Research Council grants iCOD (project no. 192441),
iCOD 2.0 (project no. 244564) and dCOD (project no. 248840).
[63]
TF8
Anticoagulant rodenticides in eagle owls, a non-target raptor species, in Norway
Knut Madslien1, Turid Vikøren
1, Morten Sandvik
1, Cecilie M. Mejdell
1, Aksel Bernhoft
1
1 Norwegian Veterinary Institute, Oslo
E-mail: [email protected]
Approach:
Eagle owl (Bubo bubo) is one of the largest owl species in the world and classified as an
endangered species in Norway. They are predominantly found along the coastline in Norway,
but also in remote inland regions. Eagle owls are mostly nocturnal predators, hunting for a
range of different prey species, predominately small mammals like rodents, hare and young
foxes, birds like various seabirds and crows, as well as amphibians like frogs.
Second generation anticoagulant rodenticides, with long half-lives, may pose a threat
to the survival and welfare of non-target raptor species, since these substances are persistent
and may accumulate at higher trophic levels. The legitimacy of this concern has been
confirmed by previous studies of a limited number of eagle owls in Denmark and Norway.
Methods:
The quantitative levels of anticoagulants in the livers of 64 eagle owls were determined by
LC-MS. The birds were found dead between 1998 and 2014 and submitted for necropsy, and
subsequently, anticoagulant determination, at the Norwegian Veterinary Institute.
Results:
The second generation anticoagulants were detected and quantified in the livers of the
majority of eagle owls examined. Furthermore, a substantial proportion of the birds exceeded
a lower limit for potential mortality as indicated in the literature.
Conclusion:
Our results confirm that exposure to anticoagulant rodenticides is very common in eagle owl
in Norway. Efforts to ensure safe utilisation and limited use of such compounds are important
to ensure viable populations of eagle owls in Norway in the future.
[64]
TF9
Characterization and pro-inflammatory responses of various mould Øya E
1, Afanou AKJ
2, Malla N
4, Uhlig S
2, 3, Rolen E
3, Skaar I
3, Straumfors A
2, Winberg JO
5, Bang
BE4,5
, Schwarze PE1, Eduard W
2, and Holme JA
1§
1Department of Air Pollution and Noise, Norwegian Institute of Public Health, Oslo, Norway
2Department for the Chemical and Biological Work Environment, National Institute of Occupational
Health, Oslo, Norway 3Norwegian Veterinary Institute, Toxinology Research Group, Oslo, Norway
4Department of Occupational and Environmental Medicine, University Hospital of North Norway,
Tromsø, Norway 5Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway,
Tromsø, Norway
Background:
Mould particles from Aspergillus fumigatus (AF), Penicillium chrysogenum (PC), Aspergillus
versicolor (AV) and Stachybotrys chartarum (SC) have been linked to respiratory-related
diseases. Here we characterized the morphology, mycotoxin and β-glucan content, protease
content and activity of X-ray-inactivated aerosolized and washed/non-aerosolized spores, and
mycelial fragments/hyphae from these species. Their toxicity and pro-inflammatory
properties were examined in human bronchial epithelial cells (BEAS-2B) and human
monocyte leukemia THP-1 monocytes and phorbol 12-myristate 13-acetate (PMA)-
differentiated THP-1 macrophages.
Results:
The spore-preparation from PC and SC contained a mixture of spores and mycelial
fragments, while the rest were evident spore or hyphae preparations as judged by scanning
electron microscopy analysis. Gelatin degrading proteases were produced by the hyphae of
all species except AV and only by the spores of the SC. Each mould species produced mainly
one gelatin degrading protease that was either of the metallo or serine type while one remains
unclassified. Although some mycotoxins were found in the PC and AV preparations, their
levels were in general low. Detectable levels of β-glucans were found in the aerosolized
spores and hyphae particle preparation. Pro-inflammatory effects were tested up to highest
non-cytotoxic concentrations. At these doses, none of the preparations induced increased
secretion of interleukin (IL)-1β or tumor necrosis factor alpha (TNF-α) in BEAS-2 cells. In
THP-1 monocytes AF and PC hyphae fragments as well as washed spores from AF and AV
elicited pro-inflammatory effects. Further, in the by far most sensitive cell model, PMA
differentiated THP-1 macrophages, there were large differences in the potency of the hyphae
preparations, with AF>PC>AV>SC. In addition, several of the spore preparations induced
cytokine responses. Most interestingly, while the hyphae preparations of AF and PC were
more potent than the respective spore preparations, the opposite seems to be true for AV and
SC. In longer incubations, the hyphae fragments of AF, PC and AV induced metalloprotease
most likely pro-MMP-9 in both the THP-1 models.
Conclusions:
Both spores and hyphae fragments are inducers of pro-inflammatory mediators and should be
incorporated in epidemiological studies of indoor environments. There was, however, no
clear link between various sample characteristics and the observed pro-inflammatory
response, illustrating the complexity of the mechanisms involved in such immune responses.
[65]
TF10
Poisoning of dogs with neurotoxin from molded food or feed
Gunnar Sundstøl Eriksen
Veterinærinstituttet, Oslo
Introduction
The Norwegian Veterinary Institute (NVI) has during some years received samples from 20-
30 dogs with classic symptoms of poisoning with neurotoxins. Symptoms include shivering,
lack of coordination, vomiting, nystagmus (involuntary eye movements), increased
salivation, and increased heart rate. In severe cases, even severe muscle spasms have been
reported. On several intoxications, the dogs have apparently recovered, but the clinical
symptoms reappeared after external stimuli such as sounds or change in light. Some dogs did
not respond to treatment with muscle relaxants and the dogs were euthanized by
veterinarians. One surviving dog has permanently impaired coordination of hind legs
Methods
NVI received material available for analysis from several poisonings. The available material
varied from case to case and included feed, vomit, plasma, and tissue samples from
euthanized or dead dogs. The relevant material was subject to mycological examinations and
all material was analyzed for Penicillum toxins by LC-MS.
Penicillum crustosum was cultivated and penitrem analogues were purified from the extracts.
Mice were given a single oral dose and ataxia was scored. Synaptosomes were isolated from
mice and the affinity to the GABA receptor was tested by radioligand binding assays.
Results
Significant amounts of the fungus Penicillium crustosum was detected in feed waste, vomit
and stomach contents from intoxicated dogs. This species is known to produce a wide variety
of bioactive compounds and two particularly two of them, roquefortine C and penitrem A has
been associated with nerve poisonings in dogs previously. In addition, it is demonstrated that
the fungus produces several other penitrems and the analog thomitrems. Several of the
bioactive compounds were found in the material from the intoxicated dogs, including in
vomit, plasma and tissue samples. The analogues are less potent than penitrem A in mice. We
have also been shown in vitro that penitrem A acts as a modulator of the GABA receptor in
mice. Previously, it has been shown that penitrem may inhibit the presynaptic calcium-
regulated potassium channels (BK channels).
Conclusions
This possible poisoning of dogs with mycotoxins is apparently still little known among dog
owners and veterinarians. Dog owners should keep rotten apples, food waste and compost out
of reach for their dogs.
[66]
Frie foredrag i farmakologi (FF)
FF1
Ex vivo CYP-activity analysis in human tissue samples using a cocktail approach
Veronica Krogstad1, Alexandra Peric
2, Ida Robertsen
1, Philip Carlo Angeles
3,4, Rune
Sandbu3,4
, Line Kristin Johnson3, Jøran Hjelmesæth
3,5, Cecilia Karlsson
2, Shalini Andersson
2,
Anders Åsberg1, Tommy B. Andersson
2, Hege Christensen
1
1Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway
2Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden
3The Morbid Obesity Center, Vestfold Hospital Trust, Tønsberg, Norway
4Department of Surgery, Vestfold Hospital Trust, Tønsberg
5Department of Endocrinology, Morbid Obesity and Preventive Medicine,
Institute of Clinical Medicine, University of Oslo, Norway
E-mail: [email protected]
Introduction
The bioavailability of orally administered drugs is restricted by first-pass metabolism in the gut
wall and liver. This is largely due to cytochrome P450 (CYP) enzymes known to be expressed in
both intestinal mucosa and liver cells. However, there is limited data describing the relative
contribution of the hepatic and intestinal CYP-activity to the overall first-pass metabolism. More
detailed information on these processes will help with advanced modelling of drug bioavailability
and also better predict drugs vulnerability to specific drug-drug interactions. In a clinical study in
patients with morbid obesity undergoing gastric bypass surgery, paired biopsies from jejunum
and liver were obtained from each patient. The aim of this project was to analyse the activity of
seven CYP-enzymes in these samples using a cocktail of CYP-probes.
Methods
The tissue samples were homogenized using a Potter-Elvehjem homogenizer. Subcellular
fractionation was performed by ultra-centrifugation and the microsomal fractions containing the
CYP-enzymes were isolated. Microsomes from liver and jejunum were incubated for 20 minutes
with a cocktail of seven substrates (bupropion, midazolam, bufuralol, amodiaquine, diclofenac,
phenacetin and S-mephenytoin) in eight concentrations, acting as probes for CYP2B6, CYP3A4,
CYP2D6, CYP2C8, CYP2C9, CYP1A2 and CYP2C19, respectively. After incubation, the
samples were subject to protein precipitation using a mix of acetonitrile and internal standard.
The chosen metabolite for each substrate was quantified with UPLC-MS/MS and interpolated
against calibration curves for each metabolite. The results were analysed using Microsoft Excel
and GraphPad Prism 7.
Results
Liver and jejunum samples from six patients were analysed. The hepatic CYP-activity was as
expected higher than the intestinal CYP-activity overall when normalized for total protein
concentration in the microsomal fractions. Of interest, the jejunum showed, in addition to
CYP3A4 and CYP2C9 activities, also significant CYP2C8 and CYP2D6 activities. Different
enzyme kinetic models were used based on goodness-of-fit evaluations of substrate concentration
versus velocity curves for each metabolite. Enzyme kinetic parameters and the variation in
activity between patients and tissue samples for each CYP-enzyme will be presented.
Conclusion
Activities of seven CYP-enzymes were assessed in paired biopsies from jejunum and liver from
six patients with morbid obesity. The results can provide important information about the impact
of liver- and intestine CYP metabolism on first-pass metabolism of drugs. The data can further be
utilized in physiology-based pharmacokinetic modelling.
[67]
FF2
Pharmacokinetics of belatacept, a novel immunosuppressive therapeutic protein
Erlend Johannessen Egeland1, Rolf Klaasen
2, Veronica Krogstad
1, Monica Hermann
3 Joe
Chan4, Anders Åsberg
1.5
1 Seksjon for Farmasøytisk Biovitenskap, Farmasøytisk Institutt, UiO
2 Avdeling for Farmakologi, OUS Rikshospitalet
3 Høgskolen på Vestlandet
4 Klinikk for indremedisin of laboratoriefag, Akershus universitetssykehus
5 Nyrefysiologisk laboratorium, OUS Rikshospitalet
Introduction
Renal transplant recipients need life-long immunosuppression to avoid rejection of the
transplant. Belatacept (Nulojix©
, Bristol-Myers Squibb, USA) is a novel immunosuppressant
available for use in clinical practice, replacing the nephrotoxic calcineurin inhibitors
(Vincenti). Belatacept is a therapeutic protein which is dose-individualised according to
body-weight (5 mg/kg). The manufacturer claims that no dose adjustment is needed after
initiation of therapy, even though it is known that higher doses, and thus higher serum
concentrations, lead to a higher risk of serious side-effects (Grinyo). Serum concentrations
within the four-week dosage intervals have only been published on a 14-patient cohort
(Shen). We aimed to investigate the pharmacokinetic aspects of belatacept in renal transplant
recipients.
Methods
Renal transplant recipients enrolled in the belatacept arm of a study comparing
cardiovascular side-effects of belatacept and tacrolimus were eligible for inclusion in this
sub-study. All patients received intravenous belatacept in four-week intervals in combination
with daily mycophenolate mofetil and prednisolone. Blood samples for belatacept
concentration measurement were collected 10, 40, 70 and 100 minutes after the end of the 30-
minute belatacept infusion. Samples were also collected 1 to 2 days, and 7 to 14 days after
the infusion day, and immediately before the next infusion. Serum concentrations were
determined with a time-resolved immunofluorometric assay (Klaasen).
Results
At present, two renal transplanted male patients have been included in the study. Patient 1
and 2 were administered doses of 550 mg (bodyweight 112 kg) and 315 mg (bodyweight 65
kg) belatacept, respectively. Patient 1 had a trough concentration of 3.3 mg/L and Cmax of 110
mg/L, while the corresponding values for patient 2 were 1.9 mg/L and 68 mg/L. More results
and analyses will be presented.
Conclusion
Our preliminary results indicate that patients may have a greater variability in Cmax than the
manufacturer claims, and that body-weight adjusted doses of belatacept are not necessarily
optimal for all patients.
Grinyo J, Charpentier B, Pestana JM et al, 2010, Transplantation 90, 1521-7
Klaasen R, Bergan S, Bolstad N et al, 2017, abstract NSFTs vintermøte
Shen J, Townsend R, You X et al, 2014, Clin Drug Investig 34, 117-26
Vincenti F, Rostaing L, Grinyo J et al, 2016, N Engl J Med 374, 333-4
[68]
FF3
Schizophrenia Genetics – identifying variants associated with clozapine toxicity
Robert L Smith1, Tore Haslemo1, Francesco Bettella2, Ole A Andreassen2, Espen Molden1,3
1. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
2. NORMENT Centre of Excellence, Department of Medical Genetics, OUS, Norway
3. Department of Pharmaceutical Biosciences, School of Pharmacy, UiO, Norway
Aim
The atypical antipsychotic drug, clozapine (Leponex®), is by far the most effective
antipsychotic drug to treat schizophrenia. However, the use of clozapine is limited by its
serious adverse effects such as agranulocytosis and tonic-clonic seizures. The aim of this
study is to identify genetic variants associated with the pharmacokinetics and toxicity of
clozapine.
Methods
Schizophrenia patients were included if they had recorded at least one clozapine serum
concentration measurement and had conducted a genome-wide association study (GWAS)
analysis. The patients were divided into two subgroups based on clozapine ‘switching’
history, i.e. patients that had either switched from clozapine to another antipsychotic drug(s)
(1; cases) or not (2; controls). The cases (1) most likely represent patients which have
experienced unsatisfactory clozapine response, such as toxicity, lack-of-effect or compliance
issues. The data was analyzed using linear-mixed model, adjusted for smoking habits, age,
gender, and sampling time.
Results/conclusion
In total, 318 patients with measured clozapine serum concentration were identified. Among
the included patients, 281 patients had more than one serum concentration measurements. In
the mixed model analyses, 3833 clozapine serum concentration measurements were included.
From the GWAS file, 533 single nucleotide polymorphisms (SNPs), located on exons or
nearby the exon/intron junctions, of 45 various candidate genes were extracted. Of these
SNPs, 3.7% were in disequilibrium according to the Hardy-Weinberg equation (p<0.05).
Furthermore, 103 patients (32.4%) were confirmed ‘switch’ cases, whereas the remaining
patients were controls (67.6%). Among the ‘switch’ cases, 39 patients (37.9%) switched to
long-acting injection(s) probably due to compliance issues with clozapine tablets, whereas 60
patients (58.3%) continued on oral administration. Also, the majority of patients in the cases
switched to either olanzapine (n=25, 24.2%), risperidone (n=15, 15.5%), or quetiapine (n=12,
11.6%). No differences in geometric C:D ratios of clozapine between the cases (3.6
nmol/mL/mg, 2.2-5.0) and the controls (4.4 nmol/mL/mg, 3.8-5.1) were observed (p=0.29).
Further association of the extracted SNPs, clozapine pharmacokinetics and clozapine
‘switching’ history will be presented at the conference.
[69]
FF4
Benzodiazepines in Norway
Ingunn Fride Tvete 1, Trine Bjørner
2, Tor Skomedal
3, Ivar Aursnes †
1 The Norwegian Computing Center, Oslo
2Department of General Practice/Family Medicine, University of Oslo
3Department of Pharmacology, University of Oslo
Background
Benzodiazepines and Z-hypnotics are frequently prescribed, and problems with dependency
and abuse are well known. Studies of risk for dose escalation have been performed. (1,2)
Mental disorders are in many countries a major cause for disability pension. We wanted to
study the use of these drugs when disability pension was granted.
Methods
Prescription fulfilments data from Norwegian Prescription database (NorPD) linked with
socio-economic data and data on disability status from Statistics Norway (SSB).
Analyses were conducted using the statistical software R.
Results
Among new users of BZD only, of combined BZD and Z-hypnotics or of Z-hypnotics only,
12.29%, 13.96% and 8.65%, respectively, became disability pensioners. Those who used Z-
hypnotics only had thus a lower risk for becoming disability pensioners compared to users of
BZDs either way. Women had higher risk than men to become disability pensioners. Higher
ages, lower education, previous drug use and psychiatrist as first prescriber were risk factors.
Comparing first BZD redeemed; clonazepam initiators had higher risk for becoming
disability pensioners compared to diazepam initiators. No differences between other BZD
users were found. For most disability pensioners the amount of drug use did not change after
being granted disability pension. Anyway, among those with previously low use nearly 20%
increased their consumption. Young disability pensioners had a higher risk of dose escalation
compared to the elder pensioners.
Conclusions
Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to
benzodiazepine users for receiving disability pension, while combined use increased the risk.
Clonazepam initiators were especially at risk. These findings might be helpful for clinicians
to identify and guide individuals at risk for becoming disability pensioners. The finding of
dose escalation among young people might indicate that becoming a disability pensioner is a
burden. The finding does not give support to relief from work as a health initiative.
References
1) Tvete IF, Bjørner T, Aursnes IA, Skomedal T:A 3-year survey quantifying the risk of dose
escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more
rationale prescribing. BMJ Open 2013;vol.3.
2) Tvete IF, Bjørner T, Skomedal T: Risk factors for excessive benzodiazepine use in a
working age population: a nationwide 5-year survey in Norway. SJPHC 2015;vol33(4)
[70]
FF5
Exposure to mycophenolate and fatherhood
Anders Åsberg1,3,4
, Anna V. Reisæter1,3
, Stein Bergan2,4
, Bjørn Egil Vikse
5,6, Karsten
Midtvedt1
1 Department of Transplant Medicine,
2 Department of Pharmacology and
3 Norwegian Renal
Registry, Oslo University Hospital, Rikshospitalet 4
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo 5
Department of Clinical Medicine, University of Bergen 6
Department of Medicine, Haugesund Hospital
Background
Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) are immunosuppressive
drugs used after organ transplantation. The active substance of both drugs, mycophenolate
(MPA), may influence spermatogenesis and there is a lack of knowledge regarding outcome
of pregnancies fathered by males exposed to MPA. We compared outcomes in pregnancies
fathered by renal transplant males that either were exposed to MPA or not exposed to MPA at
time of conception and pregnancy.
Method
A nation-wide population-based retrospective cohort study was performed. Data from the
Norwegian Renal Registry including all renal transplanted men alive between January 1st
1995 and December 31st 2015 was linked with data from the Medical Birth Registry of
Norway.
Results and conclusion
During the given time period a total of 230 immunosuppressed renal transplanted males have
fathered 350 children (157 on MPA/193 not on MPA). There were no significant increased
risk of congenital abnormalities, preterm birth or small for gestational age in MPA exposed
vs. unexposed cohorts of children.
Conclusion
When comparing paternal exposure vs. no exposure to MPA we find no increased risk of
adverse birth outcomes. These results are reassuring and support the continuation of paternal
MPA treatment both during and after conception.
[71]
FF6
Frequency of the Low-Expressing Serotonin Reuptake Transporter Genotype in Old
Depressed Patients Receiving or Not Receiving Electroconvulsive Therapy Compared to
Seniors with No History of Mental Illness
Robert Løvsletten Smith1, Reidun Koppen Barstad
1,2, Torfinn Gaarden
2, Tor-Magne
Bjølseth2, Espen Molden
1,3*
1Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway;
2Department of Geriatric Psychiatry, Diakonhjemmet Hospital, Oslo, Norway;
3Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo,
Norway
The low-expressing serotonin reuptake transporter (SERT) genotype (SLC6A4 short/short)
has been associated with insufficient antidepressant response of selective reuptake inhibitors
(SSRIs). As therapeutic failure of pharmacological treatment is an indication for
electroconvulsive therapy (ECT), we hypothesized that the proportion of SLC6A4 short/short
carriers is increased among older ECT-treated patients. In the present study, the SCL6A4, as
well as CYP2D6 and CYP2C19 variant alleles encoding deficient or ultra-rapid metabolism,
were genotyped in i) hospitalized, elderly, depressed patients receiving (n=70; cases) or not
receiving ECT (n=30; depressed controls), and ii) seniors with no history of mental illness
(n=20; healthy controls). The average Montgomery and Aasberg depression rating scale
(MADRS) scores were 30.2 (95% confidence interval (CI), 28.8-31.7), 24.0 (20.5-31.7), and
3.3 (1.7-4.8) in ECT cases, depressed controls, and healthy seniors, respectively. The
frequency of SCL6A4 short/short carriers was lower in ECT cases (7.1%) compared to
depressed (20%, P=0.082) and healthy controls (30%, P=0.013). Frequencies of CYP2D6 and
CYP2C19 variant genotypes did not differ between the various subgroups (P>0.1). Opposite
to our hypothesis, the present study suggests that frequency of the SCL6A4 short/short
genotype is reduced in older, ECT-treated patients. This finding, which should be replicated
in larger populations, might indicate that low SERT expression actually protects against
severe/major depression possibly due to reduced reuptake and hence sufficient, synaptic
serotonin levels in SCL6A4 short/short carriers.
[72]
FF7
Development of cGMP-sensors targeted to TnI and PLB reveal difference in
compartmentation of the natriuretic peptide receptors A and B
Ornella Manfra1,2
, Gaia Calamera1,2
, Nicoletta C. Surdo3, Silja Meier
1,2, Manuela Zaccolo
3,
Finn Olav Levy1,2
and Kjetil Wessel Andressen1,2
1 Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo
University Hospital, P.O.Box 1057 Blindern, 0316 Oslo, Norway 2 K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of
Medicine, University of Oslo, Oslo, Norway 3
Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK
Rationale
Natriuretic peptide receptor-B (NPR-B) stimulation by C-type natriuretic peptide (CNP)
causes a lusitropic and negative inotropic response, through cGMP-mediated phospholamban
(PLB) and troponin I (TnI) phosphorylation. Despite similar increases in cGMP, these effects
are not mimicked by NPR-A-stimulation by atrial (ANP) or brain natriuretic peptides (BNP).
Thus, the mechanisms of the differential cGMP signalling and compartmentation remain
unclear.
Objective
Clarify the organization of functional cGMP compartments and the role of
phosphodiesterases (PDEs) in both neonatal and adult rat cardiomyocytes.
Methods and Results
We constructed Fluorescence resonance energy transfer-based sensors for cGMP
subcellularly targeted to proteins that regulate inotropic responses: TnI and PLB.
Measurements of subcellular changes in single cardiomyocytes revealed that sGC-, NPR-A-
and NPR-B-stimulation increased cGMP near PLB, whereas only NPR-B-stimulation
increased cGMP near TnI. The phosphodiesterases PDE2 and PDE3 regulated cGMP in both
compartments.
Conclusions
The cGMP functional response generated by CNP in cardiomyocytes is compartmentalized
near TnI and PLB/SERCA2. Although both NPR-A and NPR-B receptors increase cGMP
near PLB, a concurrent increase of cGMP near TnI is required for regulation of inotropic
responses. The targeted sensors are novel tools to investigate the cGMP compartments that
are critical to understand how CNP influence the cardiac system.
[73]
Postere
Toksikologi
Postere henges opp pa anvist plass i Beitohallen. Postervisningen ledes av: Anders Goksøyr
(UiB).
Farmakologi
Postere henges opp pa anvist plass i Besseggen 2. Postervisningen ledes av: Kristine Hole
(Diakonhjemmet sykehus)
Hver poster far plass tilsvarende en plakat pa rundt 80 x 120 cm (bredde x høyde). Alle
postere ma henges opp med tape. Tape vil bli lagt ut ved de merkede plassene.
Presentasjon Posternepresentasjonene skjer som en 3-minutters PowerPoint-presentasjon med 3-4
lysbilder, hvorav ett tittellysbilde. Unngå bruk av animasjoner.
Pek pa hovedpoengene og fa frem:
Problemstilling
Hvordan studien er utført
Hovedfunn
Konklusjon
Ta opp hovedtrekkene og unnga detaljer. Dette er ikke et vanlig foredrag og malet er at
tilskuerne skal fa lyst til a studere posteren nærmere etterpa. Postersesjonen avsluttes med en
fri posterdiskusjon. Her gar man tilbake til de enkelte posterne og utfolder seg sammen med
spesielt interesserte.
NSFTs posterpris 2017 En posterpriskomite vil vurdere alle bidrag og finne en vinner innen henholdsvis toksikologi
og farmakologi. Hver vinner far tildelt diplom og en vandreplakett under festmiddagen lørdag
28. januar. Komiteen for bedømming av postere i toksikologi består av Ketil Hylland (UiO)
og Oddvar Myhre (FHI). Komiteen for bedømming av postere i farmakologi består av
Kristine Hole (Diakonhjemmet sykehus), Kjetil Wessel Andressen (UiO) og Ida Robertsen
(UiO).
Posterprisvinnere fra 2016: Farmakologi: Leung Ming Yu (UiO)
Toksikologi: Pål A. Magnusson (FHI)
[74]
Postere i toksikologi (TP)
TP1
Ecotoxicological responses in Atlantic cod (Gadus morhua) following caging near a
previously capped waste disposal site in Kollevågen, Askøy, Norway
Karina Dale1, Odd André Karlsen
1, Fekadu Yadetie
1, Marta Eide
1, Siri Øfsthus Goksøyr
1,
Libe Aranguren1, Roger Lille-Langøy
1, Jan Ludvig Lyche
2, Mette Bjørge Müller
2, Ketil
Hylland3, Zhanna Tairova
3, Merete Grung
3,4 & Anders Goksøyr
1
1Department of Biology, University of Bergen, Thormøhlensgate 53B, Bergen, Norway.
2Department of Food Safety and Infection Biology, Norwegian University of Life Sciences,
Oslo, Norway 3Department of Biosciences, University of Oslo, Oslo, Norway
4Norwegian Institute for Water Research, Oslo, Norway
Waste from garbage disposal can affect our environment. Kollevågen, a bay situated in
Askøy outside of Bergen, was utilized as a waste disposal from 1930 to 1975. After
terminating the disposal, the garbage was covered by sand and stone and a recreational area
was opened in 1983. However, in 2005, sediment pollution was discovered in the Kollevågen
area due to disturbance of the capping. Actions to repair the capping are being prepared. In
the dCod 1.0 project, we wanted to investigate the environmental effects of the pollution on
Atlantic cod prior to and after improvements performed in Kollevågen. Groups of Atlantic
cod (n=22) were placed in cages in different locations in Kollevågen and at a reference
location from August to October 2016. After six weeks the fish were collected, euthanized
and sampled. Bile were analyzed for PAH metabolites using HPLC. Mucus and blood plasma
are being analyzed for the presence of vitellogenin (VTG), a common biomarker for
endocrine disrupting compounds (EDCs), using ELISA. The liver tissue is being utilized for
qPCR analysis to assess gene expression of common biomarkers involved in contaminant
exposure (VTG, CYP1A), in addition to other genes known to be affected by relevant
contaminants such as PCBs. The liver transcriptome will be analyzed by RNA sequencing
methodology. Liver samples were also taken for analysis of chemical contaminants using
target and non-target analyses.
In total, more than 1000 samples were collected from 82 fish during the sampling campaign
on board R/V Hans Brattstrøm. Results so far indicate a gradient of exposure to
contaminants, reflected in increased PAH-metabolites (phenanthrene, pyrene,
benzoapyrene). LSI and condition factor were lower in fish from the innermost station.
Results from ongoing analyses by qPCR and ELISA, as well as contaminant levels, will be
presented.
The Kollevågen study is part of dCod 1.0 (Project no. 248840), a large project initiated
through Center of Digital Life Norway (DLN), a national center for biotechnology research
and innovation financed by the Research Council of Norway (NFR). The field work in
Kollevågen was also financed by Bergen Kommune.
[75]
TP2
dCod 1.0: decoding the systems toxicology of Atlantic cod (Gadus morhua)
Anders Goksøyr1,*
, Odd André Karlsen1, Fekadu Yadetie
1, Marta Eide
1, Karina Dale
1, Siri
Øfsthus Goksøyr1, Libe Aranguren
1, Roger Lille-Langøy
1, Dorothy J. Dankel
1, Guttorm
Alendal2, Morten Brun
2, Hans J. Skaug
2, Nello Blaser
2, Shirin Fallahi
2, Håvard Frøysa
2, Inge
Jonassen3, Eileen Hanna
3, Fatemeh Ghavidel
3, Xiaokang Zhang
3, Augustine Arukwe
4, Essa
Ashan Khan4, Malin Celander
5, Nancy Denslow
6, Bjørn Einar Grøsvik
7, Ketil Hylland
8,
Zhanna Tairova8, Jan Ludvig Lyche
9, Ian Mayer
9, Mette Bjørge Müller
9, Pål Olsvik
10,
Daniela Pampanin11
, Cinta Porte12
, Jed Goldstone13
, John Stegeman13
1Department of Biology, University of Bergen, Norway;
2Department of Mathematics,
University of Bergen, Norway; 3Computational Biology Unit, Department of Informatics,
University of Bergen, Norway; 4Department of Biology, NTNU, Trondheim, Norway;
5Department of Biological and Environmental Sciences, University of Gothenburg, Sweden;
6University of Florida, Gainesville, FL, USA;
7Institute of Marine Research, Bergen,
Norway; 8Department of Biosciences, University of Oslo, Norway;
9Department of Food
Safety and Infection Biology, NMBU, Norway; 10
National Institute for Nutrition and Seafood
Research (NIFES), Bergen, Norway; 11
International Research Institute (IRIS), Stavanger,
Norway; 12
Institute of Environmental Assessment and Water Research, CSIC, Barcelona,
Spain; 13
Woods Hole Oceanographic Institution, Woods Hole, MA, USA.
*[email protected]; dcod.no
Digital Life is a strategic research initiative by the Research Council of Norway to foster
convergence and cross-disciplinarity between life sciences, computation, modelling and
engineering. Six large research projects and a Center for Digital Life Norway were funded in
the first round of this initiative with a total of 250 MNOK. dCod 1.0 is one of the research
projects funded. The goal of the dCod-project is to combine competencies in environmental
toxicology, biology, bioinformatics and mathematics across the traditional department
boundaries, to create a deeper understanding of the Atlantic cod's adaptations and reactions to
stressors in the environment. Building on thorough studies and mapping of the cod genome
and long research traditions on the physiology, toxicology and reproduction biology of cod,
the dCod project will expand our knowledge with genomics based methods, where studies of
how the cod genome responds under different environmental conditions will be investigated.
The project aims to generate large amounts of experimental data to be the basis of topological
data analysis and mathematical models that can describe these responses based on different
scenarios. Overall, the goal is to create a tool for environmental monitoring and risk
assessment that can be used in assessing the impacts of for example the oil industry, sewage
discharge into harbours and industrial discharge into Norwegian fjords. Climate change and
ocean acidification, in addition to cocktail effects of several stressors, will also be
studied. Initial results will be presented.
the dCod 1.0 project is funded under the Digital Life Norway initiative of the BIOTEK 2021
program, the Research Council of Norway (project no. 248840).
[76]
TP3
Using precision-cut liver slices (PCLS) for studying effects of environmental
contaminants on the Atlantic cod (Gadus morhua) lipid metabolism
Mari F. Kolås1, Libe Aranguren
1, Fekadu Yadetie
1, Odd Andre Karlsen
1, Anders Goksøyr
1
1Department of Biology, 5006, University of Bergen
Anthropogenic pollutants are increasingly being detected far from where they are produced
and released. The findings of emerging pollutants in the Arctic and polar regions confirm
their ability to travel long distances. For many emerging pollutants, such as perfluorinated
chemicals as PFOS and PFOA, potential toxic effects and mechanisms involved have not
been well studied in fish. Some of these compounds are known to activate the transcription
factor peroxisome proliferator-activated receptor alpha (PPARα), which is one of the major
regulators of genes involved in the lipid metabolism. PPARα is primarily activated through
binding of ligands in the form of various fatty acids. However, it has been shown that the
PPARα also can be activated through the binding of compounds that structurally resemble
their endogenous ligands. Atlantic cod (Gadus morhua) is an economically important fish in
the north Atlantic. It is also ecologically important, and it is used as a sentinel species for
environmental monitoring. Importantly, the genome of the Atlantic cod was sequenced in
2011 (Star et al., 2011), providing more possibilities when it comes to mapping the possible
effects of emerging pollutants on different cellular pathways. This project will use precision-
cut liver slices (PCLS) obtained from Atlantic cod to investigate the effects of various
pollutants (e.g. PFOS, PFOA, and phthalates) on the expression of selected genes in the lipid
metabolic pathways. These results will be compared with the gene expression data from
exposures of PCLS to WY-14643 (Pirinixic acid), a well-known model compound PPARα-
agonist. PCLS will be exposed to pollutants at different concentrations for 48 hours (Eide et
al., 2014). Viability tests, such as release of lactate dehydrogenase (LDH) to the medium and
the MTT assay will be conducted to assess the quality of the PCLS during the exposure.
Quantitative PCR (qPCR) will be used to investigate potential exposure effects on PPARα-
target genes (such as acox1 and cpt1) and also other candidate biomarker genes, such as vtg.
Acknowledgements
This project is supported by the two projects; “iCOD 2.0: (Project no. 244564) and “dCOD
1.0: (Project no. 248840), financed by the Research Council of Norway (NFR) and
University of Bergen.
References
Eide, M., Karlsen, O.A., Kryvi, H., Olsvik, P.A., and Goksoyr, A. (2014). Precision-cut liver
slices of Atlantic cod (Gadus morhua): an in vitro system for studying the effects of
environmental contaminants. Aquatic toxicology (Amsterdam, Netherlands) 153, 110-115.
Star, B., Nederbragt, A.J., Jentoft, S., Grimholt, U., Malmstrom, M., Gregers, T.F., Rounge,
T.B., Paulsen, J., Solbakken, M.H., Sharma, A., et al. (2011). The genome sequence of
Atlantic cod reveals a unique immune system. Nature 477, 207-210.
[77]
TP4
Biological effects of environmental contaminants from road runoff on tadpoles of common
European frog (Rana temporaria)
Amalie Sofie Liane1, Merete Grung
1,2, Ketil Hylland
1, Sondre Meland
3
1Department of Biosciences, University of Oslo (IBV/UiO);
2Norwegian Institute for Water Research (NIVA);
3Norwegian Public Road Administrations;
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. The ponds work as a filter for road
runoff and tunnel wash water with the aim to limit the environmental impact of contaminants. The
ponds are subject to a number of toxic contaminants including organic contaminants, trace metals, as
well as NaCl from salting of the roads1,2
. The ponds are a habitat for a number of organisms that may
be affected by the contaminant levels in the ponds. Amphibians are susceptible to contamination
through water, air and nutrition and thus a subject to the contaminants in these ponds3.
The objective of this thesis is to measure and investigate how and whether tadpoles are affected by
toxicants in highly contaminated ponds in comparison to naturally occurring ponds. 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).
This MSc-project aims to examine the effects of road runoff on tadpoles in sedimentation ponds from
highways in the southeastern part of Norway. Questions that will be addressed include:
Do frog larvae of the common European frog (Rana temporaria) living in sedimentation
ponds accumulate organic contaminants?
Do organic contaminants from highway runoff have an effect on tadpoles of the common
European frog (Rana temporaria) living in sedimentation ponds?
Do developmental stages of tadpoles differ, and if so can contaminants cause this difference?
Are sedimentation ponds a useful measure for protecting the nature around highways?
The ponds will be characterized by taking measurements of the ionic substances and eutrophic status
in the water column. The contamination level will be analyzed in the water column, sediment samples
and the tadpoles. This will be done at several stages during the field study. Measurements of
developmental stages, morphology, nutritional levels, and effects of contaminants in the tadpoles will
be performed.
1.Ranneklev, S. B., et al. (2016). Vannforekomsters sårbarhet for avrenningsvann fra vei
under anlegg og driftsfasen. NIVA-rapport; 7029, Norsk Institutt for vannforskning: 45.
2. Meland, S., et al. (2010). "Chemical and ecological effects of contaminated tunnel wash
water runoff to a small Norwegian stream." Science of The Total Environment 408(19):
4107-4117. 3. Sparling, D. W. (2010). Ecotoxicology of amphibians and reptiles. Boca Raton, CRC Press.
[78]
TP5
Peroxisome proliferator-activated receptors (PPARs) as tools for studying effects
of contaminants on the Atlantic cod (Gadus morhua) lipid metabolism
Sofie Söderström1, Roger Lille-Langøy
1, Fekadu Yadetie
1, Anders Goksøyr
1, Odd André
Karlsen1
1
Dept. of Biology, University of Bergen, Norway
[email protected] Background: The Atlantic cod (Gadus morhua) is a common teleost in the North Atlantic.
Due to its habitats near offshore oil platforms, petroleum recovery facilities, as well as
coastal industries and municipal wastewater treatment plants, Atlantic cod must cope
with both legacy and emerging environmental contaminants. Peroxisome proliferator-
activated receptors (PPARs) are ligand-activated transcription factors in the superfamily of
nuclear receptors. Upon activation by either natural ligands (e.g., fatty acids and lipid
derivatives) or contaminants of certain structures, PPARs control the expression of genes
involved in lipid- and carbohydrate metabolism. Three different subtypes of PPARs have
been described in vertebrates, denoted as PPARα, PPARβ/δ, and PPARγ. These subtypes
differ in their tissue distribution, ligand specificity, and target genes. In addition, teleosts
have been shown to possess two isoforms of PPARα (PPARαa and PPARαb). By studying
how PPAR subtypes can bind and be activated by contaminants, especially by the
emerging and far less documented contaminants, it may provide valuable insight into how
the lipid metabolism in Atlantic cod can be modulated by environmental pollutants.
Methods: RNA extraction from cod tissue, cDNA synthesis, PCR amplification, and TA
cloning was performed to obtain the ligand-binding domains (LBDs) of the different cod
PPAR subtypes. The different PPAR LBDs were further used in an in vitro luciferase
reporter gene assay (LRA) in COS-7 cells for ligand-activation analyses. Sequence
homology and phylogenetic analysis of PPAR-encoding genes from Atlantic cod and other
teleosts were performed in silico.
Results: All the LBDs of the PPAR subtypes were successfully cloned and incorporated
into the LRA. Agonists, to be used as positive controls for ligand activation, were established for
cod PPARαa, PPARαb, and PPARβ/δ respectively. However, none of the typical
mammalian PPARγ agonists tested were able to active the cod PPARγ construct. Among the
15 pollutants tested in the LRA, only long-chained (8 and 9 carbon long) perfluoroalkyl
carboxylic acids (PFCAs) were able to activate the PPARαb receptor. Results from
phylogenetic studies indicate the highest degree of similarity in the PPARαb subtype
between teleosts, while PPARγ exhibits highest degree of sequence variation.
Conclusions: The same agonist was used for both PPARα subtypes, where of αb
exhibited higher sensitivity compared to the αa subtype. PFCAs between 8 to 9 carbons long were the
only pollutants able to activate any of the PPARs, specifically the PPARαb. Meanwhile,
perfluoroalkyl sulfonic acids (PFSAs), that are rather similar to PFCAs, were not able to activate any of the PPAR subtypes. Our results therefore indicate that long-
chained compounds harboring a carboxyl-group are potential agonists to the PPARαb subtype in Atlantic cod.
The project is funded by the Research Council of Norway grant iCod 2.0 (project no.
244564)
[79]
TP6
Studying estrogenic effects of environmental pollutants by using the Atlantic cod
(Gadus morhua) estrogen receptor and a reporter gene assay
Oline M. Steinkopf, Siri Ø. Goksøyr, Roger Lille-Langøy, Fekadu Yadetie, Anders Goksøyr
and Odd A. Karlsen
Department of Biology, University of Bergen, Norway
Estrogen receptors (ERs) are transcription factors that belong to subfamily 3 of the nuclear
receptor superfamily. They are activated by endogenous estradiol, but may also be activated
by other compounds, e.g. environmental contaminants such as bisphenol A and phthalates.
Activation of ER in fish leads among other things to sexual maturation and the production of
vitellogenin, a yolk precursor protein that is produced in female fish during maturation.
Importantly, exposure to estrogenic compounds may cause feminization of male fish, which
can have a dramatically impact on fish populations. In Atlantic cod (Gadus morhua) two
subtypes of ERs are present; ER (esr1) and two paralogs of ER (esr2a and esr2b), and
their tissue distribution and expression pattern during the reproductive cycle were recently
published. In this work, which is part of a master thesis, we want to clone ER from Atlantic
cod, and use a luciferase based gene reporter assay to study potential activations of the
estrogen receptor signalling pathway by various environmental pollutants..
RNA and cDNA has been prepared from Atlantic cod liver tissue, and Rapid Amplification
of cDNA Ends (RACE) will be used to unveil the unknown 3´-end of the ER transcript.
This is necessary for guiding the design of primers that should be used for cloning ER. The
ligand-binding domain of ER will be further used in a galctosidase 4 DNA-Binding-Domain
(GAL4-DBD) based luciferase gene reporter assay in COS7 cells, for studying potential
activation of ER by a selected set of environmental contaminants. These include, among
others, PFOS, PFOA, endosulfan, chlorpyrifos, and siloxanes.
Acknowledgements
This project is supported by the two projects; iCOD 2.0 (Project no. 244564) and dCOD 1.0
(Project no. 248840), financed by the Research Council of Norway (NFR) and University of
Bergen.
[80]
TP7
Are nanoparticles used in dental materials neurotoxic?
Alexandra Isabel Sveinsen Treimo1, Katrine Borgå
1, Jan Tore Samuelsen
2, Ragnhild E. Paulsen
3,
Kirsten Eline Rakkestad2
1Department
of Biosciences, University of Oslo (IBV/UiO);
2Nordic Institute of Dental Materials
(NIOM); 3School of Pharmacology, University of Oslo; [email protected]
Nanoparticles are defined as particles ranging from 1 nm to 100 nm in size. In this study, silica
particles that are respectively <10 nm and <50 nm will be used. Nanoparticles are widely used in
production of dental materials, such as coating materials for dental implants and mouthwashes among
others (Feng, X. et al 2015). Although the use of nanomaterials has a positive effect on clinical
treatments, the biosecurity of the use of nanomaterials are yet not fully understood. Nanoparticles are
similar in size to important components of the cell such as DNA, proteins and other biological
molecules (Feng, X. et al 2015). Substances that do not have any toxic effect at a certain size can have
toxic effects when they become the size of nanoparticles.
Research indicates that nanoparticles can pass the blood-brain barrier (BBB) and thereby locate in the
central nervous system (CNS). Research could reveal if nanoparticles used in dental treatments are
neurotoxic (Feng, X. et al 2015).
This master thesis will use in vitro studies to get a better understanding of the possible
neurotoxic effects of nanomaterials from dental treatments. Rat PC12 cells are commonly used for
assessment of nanoparticle-induced neurotoxicity (Feng, X. et al 2015). The PC12 cells are collected
from adrenal glands in Rattus norvegicus (rat). There will be used one original cell line and one sub
clone of this original PC12 cell line. In the first step, after exposing the cells for silica particles, the
following aspects will be studied: changes in the morphology of the cell (herein neurite outgrowth)
and cell death. In the second step, the effects nanoparticles have on oxidative stress will be
investigated. A change in the function in the cell could indicate a neurotoxic effect of the
nanoparticles from dental treatments (Wang, F. et al 2011). Research has shown that exposure of
nanoparticles can enhance the levels of reactive oxygen species (ROS) in PC12 cells (Wang, F. et al
2011). The production of ROS can lead to the production of radicals. These radicals can end up
damaging tissue because the detoxification processes are overloaded by the toxicant.
The aims of this master thesis are to
Identify and describe effects of the nanoparticles on cell morphology
Establish dose-response relationship between nanoparticle exposure and cell death
Study the potential of the nanoparticles to induce oxidative stress and generate cellular ROS
Quantify differences in toxic potential of nanoparticles of different size
Compare the effects of similar exposure in two different batches of the same cell line
Results show that the response differs between the two size ranges of the nanoparticles and the dosage of
these. Higher concentrations of nanoparticles show lower cell viability. Cells were exposed for 24 hours and
48 hours and viability was measured using MTT assay. Differences in particle induced cell viability between
the two PC12 cell batches are also found.
Feng, X., Chen, A., Zhang, Y., Wang, J. Shao, L., & Wei, L. (2015).
Application of dental nanomaterials: potential toxicity to the central nervous system. International Journal
of Nanomedisine 10 (1), 3547-3565. doi: https://dx.doi.org/10.2147/IJN.S79892
Wang, F., Jiao C., Liu, J., Yuan, H., Lan, M., Gao, F. (2011). Oxidative mechanisms contribute to
nanosize silican dioxide-induced developmental neurotoxicity in PC12 cells. Toxicology in vitro, 25
(8), 1548-1556. Doi: http://dx.doi.org/10.1016/j.tiv.2011.05.019
[81]
TP8
Neurotoxicity in rats exposed to exhaust emissions from biodiesel fuels
Renate Valand1,2
, Pål Amdal Magnusson2, Johan Øvrevik
2, Joanna Gromadzka-Ostrowska
3,
Anna Lankoff4,5
, Oddvar Myhre2
1Oslo and Akershus University College of Applied Sciences, Norway;
2Norwegian Institute of
Public Health, Norway; 3Warsaw University of Life Sciences, Poland;
4Center for
Radiobiology and Biological Dosimetry, Poland; 5Jan Kochanowski University, Poland
Introduction
Road traffic is the most important source of local air pollution and accounts for about 20% of
greenhouse gas emissions in Norway. Introducing carbon-neutral alternatives to conventional
fossil fuels may be a way of reducing greenhouse gas emissions, but the knowledge regarding
health impacts of engine emissions from such fuels is presently limited. The aim of the
project is to elucidate neurotoxic effects in rat brain hippocampus after exposure to diesel
exhaust emissions (DEE) containing varying percentages of 1st and 2
nd generation biodiesel
compared to conventional diesel exhaust, both in the presence and absence of a diesel particle
filter (DPF).
Methods
Gene expression analysis of the hippocampus were performed on adult male Fischer344 rats
(n=7/group) previously exposed to DEE generated both in the presence and absence of a
DPF. DEE were generated from a Euro 5 engine (Fiat Panda 2014) running on conventional
fossil fuel with varying contents of biodiesel. B7 and B20 with respectively 7% and 20% 1st
generation biodiesel and SHB20 containing 7% 1st generation biodiesel and 13% 2
nd
generation biodiesel. Unexposed rats were included as controls. The rats were exposed in
whole-body exposure chambers with a temperature of 22°C, a humidity of 50% and a CO2
concentration of 2000ppm, 6h/day, 5 days/week (7 and 28 days exposure).
Levels of gene expression of about 30 genes tied to cognition, inflammation and oxidative
stress are currently studied in the hippocampus by real-time qPCR using CFX384 Touch real-
time PCR detection system from BioRad. Statistical analysis will be performed with
Microsoft Excel 2010 and JMP Pro 11 software.
Results (expected results)
Previous studies have shown associations between air pollution and acceleration of cognitive
decline in the elderly and neurodevelopmental effects in children (1,2). Rodent models have
shown inflammatory responses in several brain areas after exposure to air particulate matter
(3). However, knowledge from controlled experimental inhalation studies on DEE exposure
and effects in rat brain cognitive domains are lacking. Therefore, levels of genes from rat
hippocampus tied to cognition, inflammation and oxidative stress in the hippocampus will be
presented.
References 1. Ailshire, Jennifer A., and Eileen M. Crimmins. “Fine Particulate Matter Air Pollution and Cognitive
Function Among Older US Adults.” American Journal of Epidemiology 180.4 (2014): 359–366. PMC.
Web. 12 Dec. 2016.
2. Calderón-Garcidueñas, Lilian et al. “Air Pollution and Detrimental Effects on Children’s Brain. The
Need for a Multidisciplinary Approach to the Issue Complexity and Challenges.” Frontiers in Human
Neuroscience 8 (2014): 613. PMC. Web. 12 Dec. 2016.
3. Cheng, Hank et al. “Nanoscale Particulate Matter from Urban Traffic Rapidly Induces Oxidative Stress
and Inflammation in Olfactory Epithelium with Concomitant Effects on Brain.” Environmental Health
Perspectives 124.10 (2016): 1537–1546. PMC. Web. 12 Dec. 2016.
[82]
TP9
Using precision-cut liver slices (PCLS) and luciferase reporter gene assays to
characterise the aryl hydrocarbon receptors (Ahr) in Atlantic cod (Gadus morhua)
Libe Aranguren1, Alexander K. Madsen
1, Pernille Iden
1, Marta Eide
1, Roger Lille-Langøy
1,
Anders Goksøyr1 and Odd André Karlsen
1
1Department of Biology, University of Bergen, Thormøhlensgate 53B, 5006, Bergen, Norway
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). The teleost species Atlantic cod (Gadus
morhua) is potentially exposed to such pollutants. Atlantic cod is important to fisheries
industry, and is also commonly used as a monitoring species in marine waters. Thus,
increased knowledge of Ahr mediated xenobiotic responses in Atlantic cod is important. The
use of ex vivo and in vitro techniques, such as precision-cut liver slices (PCLS) and reporter
gene assays allow an efficient and high throughput analyses of an increased number of
compounds.
The Ahr1b and Ahr2 receptors were cloned from Atlantic cod, and further used in luciferase
reporter gene assays for studying Ahr-ligand activation. Four well-known AhR model-
compounds, including 6-formylindolo(3,2-b) carbazole (FICZ), 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD), polychlorinated biphenyl (PCB) PCB 126 and benzo(a)pyrene (B(a)P) were
used as agonists in the reporter gene assay. In addition, PCLS were exposed ex vivo to the
same compounds, and the expression levels of the Ahr target gene, cyp1a, were followed by
quantitative real time PCR (qPCR).
Both Ahr1b and Ahr2 were activated in a very similar manner in the luciferase reporter gene
assay by FICZ, TCDD, PCB126 and B(a)P. FICZ and TCDD were found to be the most
potent Ahr1b/2 agonist. cyp1a1 mRNA expression increased significantly when PCLS were
exposed to the same compounds. In accordance with the luciferase reporter assay, FICZ and
TCDD appear as the most potent ligands, while B(a)P demonstrated a very high efficacy ex
vivo.
The Ahr model compounds acted as agonists of both Atlantic cod Ahr1b and Ahr2 receptors
in vitro. Activation of the Ahr pathway was also confirmed ex vivo with PCLS. Hence, Ahr-
mediated toxicity can be mediated through both Ahr1b and Ahr2 in Atlantic cod.
iCod2.0 is funded by the Research Council of Norway, project no. 244564/E40
[83]
TP10
Mixture of persistent organic pollutants promotes accumulation of adipose tissue and
affects immune system in mice
Martina Galatea Castelli1, Emmanuelle Fouilloux-Meugnier
2, Bérengère Benoit
1, Florian
Dingreville2, Sandra Pesenti
2, Hubert Vidal
2, Jérôme Ruzzin
1
1 University of Bergen
2 Unité 1060 INSERM CarMen, Université Lyon 1, Lyon F-69008, France
E-mail to: [email protected]
Background
The mechanisms by which endocrine-disrupting chemicals, like persistent organic pollutants
(POPs), can induce metabolic disorders remain poorly known. Recently, immunometabolism,
the interaction between immune system and metabolism, has emerged as an important
contributor to metabolic disease. In this study, we investigated the impact of POPs on
immunometabolism homeostasis in mice.
Methods
Three-week-old male C57BL6 mice were fed with a chow diet (control group) or a high-fat
diet without (HF) or with a mixture of POPs including 9 polychlorinated biphenyls and 11
organochlorine pesticides (HF + POPs) for 15 weeks. Body weight, food intake and faecal
output were assessed during the study. At 18 weeks of age, inguinal and epididymal white
adipose tissues, small intestine, spleen and mesenteric lymph nodes were collected for
immune cells (flow cytometry) and gene expression (microarray) analysis.
Results
Compared to control group, both HF- and HF+POPs-fed mice showed increased body
weight. Despite similar food intake, mice exposed to POPs had increased inguinal and
epididymal adipose tissues compared to HF-fed mice. Interestingly, HF+POPs-fed mice had
significant increased faecal output compared to HF-fed mice. In addition, POPs induced an
increase in neutrophiles and B cells whereas both CD4+ and CD8+ T cells were decreased in
the spleen. In mesenteric lymph nodes, CD4+ T cells were decreased in HF+POPs-fed mice
compared to HF-fed mice.
Conclusion
These data indicate that POPs stimulate the accumulation of white adipose tissue and, in
parallel, disrupt the mouse immune system. The increased faecal production observed in mice
exposed to POPs may further suggest an intestinal dysfunction. We are currently using
transcriptomic analysis to reveal potential signalling pathways affected by POPs in the
intestine1, an organ with critical immunological function.
1 These data should be available in January 2017
[84]
TP11
Effects of a mixture of two cyanobacterial toxins (microcystin-LR and L-BMAA) on
spatial learning and memory in adult C57BL/6 mice
Oddvar Myhre1, Dag Marcus Eide
1, Synne Kleiven
2, Hans Christian Utkilen
2, Tim Hofer
1
1 Department of Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo
2 Department of Natural Sciences and Environmental Health, University College of Southeast
Norway, Bø.
E-mail: [email protected]
The cyanobacterial toxins β-methylamino-L-alanine (L-BMAA) and microcystin-LR (MC-
LR) are suspected to cause human developmental and degenerative neurological diseases.
MC-LR is in addition a potent liver toxin. Here, male adult C57BL/6JOlaHsd mice (ex-
breeders) aged approximately 11 months were treated with L-BMAA and microcystin-LR
alone, or in combination. A dose-range study determined a tolerable daily dose of 30 µg MC-
LR/kg BW when administered subcutaneously for 5 consecutive days. The L-BMAA (not
acute toxic) dose and latency time prior to behavioral testing was based upon published
results from others. Thus, the mice were given 30 µg MC-LR/kg BW and/or 30 mg L-
BMAA/kg BW, either alone or in mixture for five consecutive days (cumulative doses were
150 µg MC-LR/kg BW, 150 mg L-BMAA/kg BW, or 150 µg MC-LR +150 mg L-BMAA/kg
BW). After 4 weeks, spatial learning and memory performance of exposed mice was
compared to controls using a Barnes maze with video tracking during three days. After 8
weeks, anxiety, general locomotor activity, willingness to explore, hippocampal and peri-
postrhinal cortex dependent memory was investigated using Open Field combined with
Novel Location/Novel Object Recognition tests. The mice were also re-tested for long-term
memory effects 10 weeks after exposure using the Barnes maze on one day. Several
parameters were evaluated and will be presented
TP12
TIPARP and mono-ADP-ribosylation negatively regulate AHR activity and protect
against dioxin toxicity
Jason Matthews
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates
the toxic effects of the environmental contaminant, dioxin. Dioxin causes a range of toxic
responses in laboratory rodents, including steatohepatitis and a lethal wasting syndrome;
however, the mechanisms are still unclear. In humans, AHR activation is associated with
increased risk for diabetes. AHR regulates the expression of many genes including TCDD-
inducible poly(ADP-ribose) polymerase (TIPARP/PARP7/ARTD14). TIPARP is a member
of the PARP family of enzymes that use NAD+ as a substrate to catalyse the transfer of single
units of ADP-ribose or long chains of ADP-ribose onto themselves and onto their protein
substrates in processes referred to as mono- or poly-ADP-ribosylation, respectively. I will
present our recent studies characterizing TIPARP activity and its role in AHR-dependent
transcription and function. We have shown that TIPARP is mono-ADP-ribosyltransferase and
as part of a negative feedback loop regulates AHR activity. Tiparp-/-
and hepatocyte specific
[85]
TiparpHep-/-
mice show increased sensitivity to dioxin-induced gene expression, toxicity,
steatohepatitis and lethality. Tiparp-/-
or TiparpHep-/-
mice given a single injection of 10 ug/kg
dioxin did not survive beyond day 7 and 9, respectively; all Tiparp+/+
mice survived the 30
day treatment. This supports the notion that TIPARP is a negative regulator of AHR activity.
The mono-ADP-ribosylase, MacroD1, reversed TIPARP-dependent ADP-ribosylation of
AHR and the repressive effects of TIPARP on AHR activity. Collectively, these data reveal
previously unidentified roles for TIPARP, MacroD1, and ADP-ribosylation in AHR-
mediated steatohepatitis and dioxin-induced lethality, implicating TIPARP and mono-ADP-
ribosylation as key regulators of AHR signalling.
TP13
Relation between in vitro toxicity and thiol-reactivity of HEMA in resin based
biomaterials
Bergitte P Olderbø1, Rune Becher
1*, Håkon Valen
1, Jan Tore Samuelsen
1
1 Nordic Institute of Dental Materials, Oslo, Norway
* Norwegian Institute of Public Health, Oslo, Norway
Introduction
Resin based dental biomaterials consist of methacrylate monomers that are polymerized in
situ, but the conversion to polymer is never complete. Consequently, dental patients are
exposed to monomers such as 2-hydroxyethyl methacrylate (HEMA). In addition, dental
personnel are exposed every day due to work with uncured materials. In vitro, methacrylates
are shown to be cytotoxic in a dose-dependent manner. HEMA spontaneously adduct with
the cysteine-thiol of glutathione (GSH), thereby causing GSH depletion. The following
increase in cellular reactive oxygen species (ROS) is hypothesized as a key event leading to
the toxic response. In this study we aim to compare the effects of methacrylate exposure and
GSH depletion by inhibition of GSH synthesis to test this hypothesis.
Methods
The human bronchial epithelial cell line BEAS 2B was exposed to varying concentrations of
HEMA and buthionine sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase (GCL;
the rate limiting enzyme in cellular GSH synthesis). The viability, ROS levels and cellular
GSH levels after exposure were measured using MTT assay and flow cytometry,
respectively. Western blotting was used to measure the levels of proteins known to be
affected by HEMA exposure.
Results
Exposure to both HEMA and BSO resulted in GSH-depletion and increased ROS-levels. As
previously shown, exposure to HEMA resulted in increased levels of proteins associated with
increased ROS-handling capacity, increased thiol-reducing capacity, increased protein
degradation and increased capacity to detoxify lipid peroxidation products. In BSO-exposed
cells, only increased levels of proteins with ROS-handling capacity was observed.
Conclusion
This study does not support the hypothesis suggesting the main mechanism of methacrylate
toxicity to involve GSH-depletion and increased oxidative load. Our study may suggest that
methacrylate toxicity involves direct interactions with proteins and lipids.
[86]
TP14
Mechanisms of methylmercury neurotoxicity and their modulation by selenium
Josef D. Rasinger1, Anne-Katrine Lundebye
1, Ståle Ellingsen
1 and Heidi Amlund
1
1 Nasjonalt institutt for ernærings- og sjømatforskning
Background: Methylmercury (MeHg) is a toxicant of concern for aquatic food chains and
human health. Selenium (Se) is an abundant nutrient in fish, and a known antagonist of
MeHg toxicity. Ameliorating effects of Se on MeHg toxicity have been described; yet little is
known about the mechanisms behind the interactions between these two compounds. The
present study used zebrafish (Danio rerio) as a model species to investigate the influence of
dietary Se on the accumulation of MeHg in brain. Proteomic and bioinformatics tools were
used to study the mechanisms underlying MeHg induced neurotoxicity and their modulation
by Se.
Methods: Employing a full factorial design, adult zebrafish were fed a commercial zebrafish
diet enriched with MeHg (as methylmercury-cysteine, 10 mg Hg/kg) and/or Se (as
selenomethionine; SeMet, 5 mg Se/kg) or a control diet (commercial zebrafish diet). After
eight weeks of exposure, pooled samples of brain (n=3/pool) were subjected to microwave-
assisted digestion and analysed for total mercury (Hg) and Se by inductively coupled plasma
mass spectrometry. Brains of individual fish (n=12, 3 per treatment) were prepared for
proteomics profiling using quantitative intact proteomic tools followed by causal network
analysis.
Results: At the end of the feeding trial, Hg concentrations were higher in brain of MeHg
exposed fish compared to non-exposed fish, demonstrating that MeHg crosses the blood-
brain barrier. Lower levels of Hg were found in brain of zebrafish fed MeHg and SeMet
compared with fish fed MeHg alone, suggesting that dietary Se reduces the accumulation of
MeHg in brain. In addition, the expression levels of neuronal proteins associated with gap
junction signalling, oxidative phosphorylation and mitochondrial dysfunction were found to
be altered significantly (p<0.05) after exposure to MeHg, SeMet, and MeHg and SeMet,
respectively. Analysis of upstream regulators revealed these changed to be linked to Target of
Rapamycin (TOR) signalling, which was disrupted by MeHg and modulated by SeMet
through differential activation of Rictor.
Conclusion: Our findings suggest that SeMet reduces MeHg accumulation in the brain, and
indicate that SeMet is neuroprotective, modifying MeHg induced neurodegeneration through
TOR dependant pathways.
[87]
TP15
Comparison of in vitro human cytotoxicity assays for testing of nanomaterials
Elise Rundén-Pran, Naouale El Yamani, Maria Dusinska
NILU- Norwegian Institute for Air Research, Department of environmental chemistry, Health
Effects Laboratory, Kjeller, Norway
Introduction: Development of alternative testing strategies for potential human toxicity is
important to accomplish with the 3R´s to refine, reduce and replace animal studies. For safe
applications of nanomaterials, it is important to standardize and validate in vitro toxicity
methods. The methods should be time- and cost effective, and preferably have a high-
throughput content, as toxicity of nanomaterials is strongly dependent upon physio-chemical
properties. Toxicity testing is not straight forward when it comes to nanomaterials, due to
extreme reactivity of the particles and thus potential interference with the test system.
Aim: Our aim was to compare two different in vitro cytotoxicity test method with dissimilar
readout on the same cell line, human lung epithelial A549 cells, and to test and rank a battery
of nanomaterials for potential cytotoxicity. Additionally we wanted to test how
physiochemical properties influence on the toxicity by testing different size or shape of some
of the nanoparticles.
Method: Cytotoxicity testing was performed by Alamar blue (AB) assay and Colony forming
efficiency (CFE). AB is a colorimetric assay, while CFE is a clonogenic assay measuring the
ability of single cells to survive and form colonies after exposure.
We tested potential cytotoxicity for a range of different types of nanoparticles: Ag, TiO2,
SiO2, ZnO, BaSO4, CeO2 and carbon nanotubes (CNT). For Ag, TiO2 and SiO2 different sizes
or shapes were also tested to see how this influence upon toxicity. Physiochemical
characterization was performed with NanoSight for size, size distribution and stability in
dispersion.
Results: Our results show that toxicity was dependent upon type of nanomaterial as well as
size and shape, and not all nanoparticles tested was found to be cytotoxic. Concentration
dependent cytotoxicity was measured for Ag, ZnO and CNT. Both of the cytotoxicity assays
have clear advantages, however our data indicate that the CFE assay might be more sensitive
and less prone to interference than the AB assay. Additionally, the CFE assay has two
endpoints, measuring both cell survival and cytostatic effect.
Conclusion: Ag, ZnO and CNT were found to be cytotoxic, and shape influenced upon toxic
potential. Both assays were able to detect cytotoxic effect of NPs for determination of LC50,
and our validation of the chronic exposure approach of single cells by CFE assay shows that
this is a good and reliable assay for assessment of toxicity of NPs.
Supported by NANoREG (EC FP7, 310584) and NorNANoREG (Norwegian Research
Council, 239199/070)
[88]
TP16
Effects of HEMA on the cytoskeleton in BEAS-2B cells
Solveig Uvsløkk, Ida S. R. Stenhagen, Jan T. Samuelsen
Nordisk institutt for odontologiske materialer, Oslo
Introduction
Resin-based biomaterials are routinely used in different medical applications. Generally, the
resins are composed of methacrylate monomers. The polymerization of the resins is never
complete and patients are exposed to methacrylate monomers leaking from the cured
material. In dentistry, patients are exposed to 2-hydroxyethylmethacrylate (HEMA) after
common dental procedures, such as bonding of orthodontic brackets. HEMA is a known
allergen and has a well-known toxic potential in vitro. The molecular mechanism responsible
for the observed toxicity is not known in detail, but glutathione (GSH) depletion caused by
adduct formation with HEMA and increased oxidative load is suggested events of
importance.
One major component of the cytoskeleton is actin, a protein which is modified by glutathione
conjugation. Protein S-glutahionylation (PSSG) is the reversible post-translational
modification of protein cysteines (PSH) with the addition of glutathione (GSH) (PSH-
GSHPSSG). This glutahionylation is suggested to affect the dynamics of the
cytoskeleton. In this study, the aim was to investigate if exposure to HEMA alters PSSG in
bronchial epithelial cells and affects the structure and dynamics of the cell’s cytoskeleton.
Methods
The bronchial epithelial cell-line BEAS-2B was chosen as a model. Cells were grown in
Lechner and LaVeck (LHC-9) medium and exposed to HEMA. Specific antibodies were used
to detect actin and the changes in PSSG after exposure to HEMA. The changes were
quantified using Western blotting and the Odyssey CLx Infrared Image System. Fluorescence
microscopy of fixed cells stained with DAPI and phalloidin was used to observe f-actin in the
cells after exposure to HEMA. Observations during wound-healing assays were examined
using light microscopy. A “scratch” was made with a pipette tip and photographs were taken
at different times of the cells invading the “scratch”.
Results
Western blotting detected several S-glutahionylated proteins with a predominant band around
42 kDa. In cells exposed to HEMA the intensity of this band decreased significantly.
Fluorescent microscopy of cells incubated with phalloidin and DAPI showed a change in
organisation of cellular f-actin after exposed to 2mM HEMA for 6h. The wound-healing
assay showed less movement of the cells across the “scratch” in cultures exposed to 2mM
HEMA.
Conclusion
This study has shown that exposure to HEMA alters the organisation of the cytoskeleton,
reduces the level of protein S-glutationylation and reduces migration of the BEAS-2B cells.
[89]
TP17
Effects on human bronchial epithelial cells following low-dose chronic exposure to
nanomaterials: a 6-month transformation study
Santosh Phuyal1, Mayes Kasem
1, Laura Rubio
2, Hanna L. Karlsson
4, Ricard Marcos
2,3, Vidar
Skaug1 and Shan Zienolddiny
1*
1Department of Biological and Chemical Work Environment, National Institute of
Occupational Health, Pb 8149 Dep, N-0033, Oslo, Norway; 2Grup de Mutagènesi,
Departament de Genètica i de Microbiologia, Facultat de Biociències , Universitat
Autònoma de Barcelona , Bellaterra , Spain; 3CIBER Epidemiología y Salud Pública,
Instituto de Salud Carlos III, Madrid, Spain; 4Unit of Biochemical Toxicology, Institute of
Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden
Presenting author. Email: [email protected].
The most plausible exposure route to manufactured nanomaterials (MNM) remains
pulmonary inhalation. Yet, few studies have attempted to assess carcinogenic properties in
vitro following long-term exposure of human pulmonary cells to low and occupationally
relevant doses. The most advanced in vitro tests for carcinogenicity, the cell transformation
assay (CTA), relying mostly on rodent cells and short-term exposure. We hypothesized that
long-term exposure of human bronchial epithelial cells with a normal phenotype could be a
valuable assay for testing carcinogenicity of nanomaterials. Therefore, this study, performed
within the framework of the FP7-NANoREG project, assessed carcinogenic potential of
chronic exposure (up to 6 month) to low doses of multi-walled carbon nanotubes (MWCNT,
NM-400 and NM-401) and TiO2 materials (NM62002 and KC7000). In order to harmonize
and standardize experiments, standard operating protocols of MNM dispersion
(NANOGENOTOX) were used by three different NANoREG project partners. All
nanomaterials showed low cytotoxicity in short-term tests for the tested doses (0.96 and 1.92
g/cm2). During long-term exposure, however, NM-401 clearly affected cell proliferation. In
contrast, no cell transformation was observed for NM-401 by any of the partners. NM-400
and NM62002 formed some colonies after 3 months. We conclude that agglomerated NM-
401 in low doses affect cell proliferation but do not cause cell transformation in the CTA
assay used.
[90]
TP18
Assessing endocrine disruption using larval zebrafish behaviour
Thomas Fraser1, Abdolrahman Khezri
2, Erik Ropstad
1
1 Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences
2 Department of Basic Science and Aquatic Medicine, Norwegian University of Life Sciences
Problemstilling
The larval zebrafish model is as a screening tool to identify neurotoxic or neuroactive
compounds. However, there is little knowledge as to whether these behaviours are sensitive
to endocrine disruption. This information is important, as behavioural effects in larval
zebrafish are typically assumed to be related to previously identified mechanisms of action in
other model systems without verification.
Metode
We investigated how different hormones and model endocrine disruptors influence larval
behaviour in a standardised protocol. Zebrafish embryos were exposed to a range of sub-
teratogenic concentrations from 8 hfp onwards, kept on a day/night regime, and their
locomotor activity was recorded during a light/dark test at various times between 96 and 120
hours post fertilisation.
Resultater
Estrogens, androgens, anti-androgens, cortisol, and thyroid hormones all influenced larval
behaviour. However, the behavioural test appears a less sensitive method to detect estrogenic
and androgenic compounds compared to gene expression analyses. We were also unable to
demonstrate a role of the nuclear receptors in behavioural responses to 17α-ethinyl estradiol
(EE2) or testosterone exposure. In addition, thyroid disruptors had no effect on behaviour at
levels that abolished thyroxine production within the thyroid follicles. Finally, although
known to be neuroactive, progesterone had no effect on behaviour.
Konklusjon
Zebrafish larval behaviour does respond to hormones and endocrine disruptors, but the
protocol used appears less sensitive as a method to detect endocrine disruption compared to
other molecular or immunohistochemical analyses. We were also unable to provide evidence
that an estrogenic compound (EE2) and testosterone were acting on behaviour via nuclear
receptors. Therefore, further work is required to understand what larval zebrafish behaviour
can tell us about endocrine disruption.
[91]
TP19
Tunnelpartikler inneholder mange ikke-regulerte PAH-lignende forbindelser og andre
urbane markører
Merete Grung1, Alfhild Kringstad1, Kine Bæk1, Ian Allan1, Kevin V. Thomas1, Sondre Meland2,3,
og Sissel Ranneklev1
1 NIVA – Norwegian institute for Water Research, Gaustadalléen 21, 3349 Oslo, Norway 2 Norwegian Public Roads Administration, Post box 8142 Dep, 0033 Oslo, Norway 3 Norwegian University of Life Sciences, Department of Environmental Sciences, Post box 5003,
1432 Ås,
Problemstilling
Norge har om lag 1000 tuneller, og disse vaskes 2-12 ganger i året. Vaskevannet slippes ut til
akvatisk miljø, og utgjør dermed en punktkilde for forurensning. Forurensninger i
tunnelvaskevannet kan sees på som en proxy for lokal vegforurensning siden dette materialet ikke
er forventet å inneholde lang-transporterte foruresninger eller være påvirket av aktiviteter i
nedbørsfeltet. Det er kjent at avrenning fra vei og tunnelpartikler har høye nivåer av PAH og
metaller. I dette prosjektet ønsket vi imidlertid å undersøke forekomsten av komponenter det
vanligvis ikke analyseres for i tunnelpartikler.
Metode
Vi brukte passiv prøvetaker av silikon for å ekstrahere organiske komponenter fra tunnelpartikler
fra Norby-tunnelen som ligger ved en høyt traffikert innfartsåre til Oslo. Analysemetodene vi
brukte var todelt: En såkalt non-target analyse som er en hypotesefri analyse som søker å
bestemme hvilke forbindelser som finnes i prøven som undersøkes. I tillegg brukte vi en suspect
screening, som vil si at vi ser etter et utvalg av forbindelser som vi mistenker at er tilstede i
prøven. Begge teknikkene er avhengig av avansert utstyr med nøyaktig masse-bestemmelse, og
fordrer i tillegg en god kvalitetssikring av identifikasjoner som foretas.
Resultater
Resultatene2 viste at poly-aromatiske komponenter (PAC) utgjorde hovedvekten (50) av de
nesten 70 ulike forbindelsene som ble identifisert i ekstraktet av tunnelpartiklene. Men bare 5 av
de 50 PAC som ble identifisert er blant de som vi vanligvis analyserer for (PAH-16). Majoriteten
av identifiserte PAC var alkylert og/eller inneholdt et heteroatom, noe som gjør at toksisiteten og
egenskapene til disse forbindelsene er annerledes enn PAH-16-forbindelsene som vi kjenner godt.
I tillegg ble det påvist urbane markører som organofosfat flammehemmere, ftalater,
benzotiazoler, musk komponenter og en plastmykner. Påliteligheten til analysene er svært god, og
for 16 av komponentene gjennomførte vi ko-kromatografering med innkjøpt standard for å være
sikre på korrekt identifikasjon.
Konklusjon
Tunnelpartikler inneholder mange ikke-regulerte PAC-forbindelser. Majoriteten av disse har
egenskaper og toksisitet som ikke er undersøkt til nå. Eksponering for disse forbindelsene vil
derfor sannsynligvis ha mange av de toksiske effektene som er kjent for flere PAH-forbindelser,
men i ukjent størrelsesorden. Alkylering og innhold av heteroatomer gjør at komponentene
oppfører seg annerledes enn de PAH som er undersøkt, og heteroatomene kan for eksempel gjøre
forbindelsene mer vannløselige. I tillegg er det kjent at nedbrytningstiden for alkylerte PAH er
lenger enn ikke-alkylerte PAH.
2 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, 36–44 (2017).
[92]
TP20
Methylmercury in an Arctic food web – With focus on seabirds
Anders Ruus1,2
, Ida B. Øverjordet3,4
, Hans Fredrik V. Braaten1, Anita Evenset
5,6, Guttorm
Christensen5, Eldbjørg S. Heimstad
7, Geir W. Gabrielsen
8, Katrine Borgå
1,2
1. Norwegian Institute for Water Research (NIVA)
2. University of Oslo, Department of Biosciences
3. Norwegian University of Science and Technology, Department of Biology
4. SINTEF Materials and Chemistry, Marine Environmental Technology
5. Akvaplan-niva
6. University of Tromsø. The Arctic University of Norway
7. Norwegian Institute for Air Research (NILU)
8. Norwegian Polar Institute
Mercury (Hg) is a toxic natural element, however, anthropogenic activities have increased its
release and dispersal in the environment. Emitted gaseous Hg enters the Arctic from lower
latitudes by long-range transport. In aquatic systems, anoxic conditions favour the bacterial
transformation of inorganic mercury to methylmercury (MeHg), which is the most toxic form
of Hg, and has a greater potential for bioaccumulation than the inorganic form.
We quantified the biomagnification of MeHg in a marine pelagic food web, comprising
species of zooplankton, fish and seabirds, from the Kongsfjorden system (Svalbard, Norway),
by use of Trophic Magnification Factors (TMFs). Furthermore, we quantified the
accumulation of MeHg in black-legged kittiwake (Rissa tridactyla) and common eider
(Somateria mollissima), focusing on possible seasonal changes in MeHg accumulation, as
well as possible differences between bird tissues. We also quantified the relationship between
total Hg (TotHg) and MeHg, as well as between TotHg and selenium (Se) in the different
species and tissues, to better understand Hg dynamics and the role of Se in Hg detoxification,
respectively.
Tissue concentrations of MeHg increased with increasing trophic level in the food web,
however, at greater rates than observed in several earlier studies, especially at lower latitudes.
Concentrations of MeHg in kittiwake decreased from May to October, resulting in seasonal
differences in TMFs. Moreover, seasonal changes in MeHg, TotHg and Se accumulation, as
well as differences between tissues, were shown in birds. The seasonal differences in Hg
concentrations appeared as conspicuous as geographical differences, e.g. from seabirds from
Canada. MeHg, TotHg and Se all showed declining concentrations from May to October in
both species. However, the decrease was not as prominent for Se, as for TotHg, which was
reflected by an increase in the Se:Hg molar ratio from May to October.
A significant linear relationship was observed between concentrations of selenium (Se) and
total mercury (TotHg) in birds but not in zooplankton, suggesting the importance of Se in Hg
detoxification for individuals with high Hg concentrations.
[93]
TP21
Bruk av 3D leverkulturer for å måle DNA-skade ved komet-metoden
Birgitte Lindeman, Kristine B Gutzkow, Edel Lilleaas, Marit Låg
Norwegian Institute of Public Health; Infection Control and Environmental Health
Problemstilling
Humane 3D leverkulturer (sferoider) opprettholder et høyt nivå av fase I og II enzymer i
kultur og er dermed et attraktivt modellsystem for å måle induksjon av DNA-skade og DNA-
reparasjon etter eksponering for fremmedstoffer. Leversferoider er små (ca 1000 celler per
sferoide) og krever dermed analyser som kan tilpasses lavt celleantall. Enkelt-celle
gelelektroforese, den såkalte kometmetoden, krever kun få celler og er en aktuell metode for
å analysere leversferoider. Utfordringen er å isolere enkeltceller fra sferoidene med god
bevaring av DNA-integritet ved å unngå DNA-skade eller reparasjon under prepareringen. I
denne posteren vil vi beskrive vårt pågående arbeid med metodologiske tilpasninger av lever-
sferoider til kometmetoden.
Metode
Både mekaniske og enzymatiske prosedyrer for å isolere enkelt-celler fra sferoidene har blitt
forsøkt. Som modellstoff har vi benyttet røntgenstråling og arsentrioksid og målt DNA
trådbrudd, alkalilabile seter og oksidative skader ved bruk av den bakterielle glykosylasen
Formamidopyrimidine-DNA-glykosylase (Fpg).
Resultater
Vi har benyttet to sferoider per prøve for å sikre nok celler til å kunne avlese 150 celler både
med og uten Fpg. Foreløpige resultater viser en forventet respons på røntgenstråling og en
dose-respons for arsen trioksid induserte DNA trådbrudd med doser som er humant relevante.
Tilsvarende tendens finner vi for Fpg-følsomme lesjoner. Imidlertid er bakgrunnsnivået for
oksidative DNA-skader høyere enn ønskelig og vi jobber med å redusere dette.
Konklusjon
Forsøkene så langt tyder på at humane lever-sferoider er et attraktivt modellsystem for å
analysere induksjon av DNA-skader. Ved bruk at komet-metoden som ikke krever mer enn
150-200 celler per prøve er 1-2 sferoider tilstrekkelig. Foreløpige resultater viser fin
følsomhet i standard komet-metode, mens bruk av glykosylasen Fpg viser at det blir dannet
noe oksidative DNA-skader under prepareringen. Videre optimalisering pågår.
[94]
Postere i farmakologi (FP)
FP1
Effekt og sikkerhet ved bruk av empagliflozin hos nyretransplanterte pasienter med
post-transplantasjons diabetes mellitus
Kvitne K1, Åsberg A
1, Jenssen T
1, Hartmann A
1, Midtvedt K
1, Müller S
1, Ravnskog H
1,
Sørhøy H1, Halden T
1.
1Avdeling for transplantasjonsmedisin, Seksjon for nyremedisin, Oslo universitetssykehus
Rikshospitalet
Problemstilling
Pasienter med kronisk nyresykdom har økt risiko for prematur kardiovaskulær sykdom og
død. Etter nyretransplantasjon reduseres risikoen, men den er fremdeles tre til fem ganger
høyere enn i den generelle befolkningen. I Norge utvikler 10-13 % av nyretransplanterte
pasienter post-transplantasjons diabetes mellitus (PTDM). Det er en selvstendig risikofaktor
for kardiovaskulær sykdom. Forebygging og behandling av PTDM er derfor viktig for å
bedre langtidsutsiktene til denne pasientgruppen. Få antidiabetika er imidlertid egnet til
pasienter med PTDM, blant annet på grunn av redusert nyrefunksjon, bivirkninger som kan
øke deres kardiovaskulære risiko og interaksjoner med de immunsuppressive legemidlene.
Hensikten med denne studien er å undersøke om SGLT2-hemmeren empagliflozin
(Jardiance®) sikkert og effektiv bedrer glukosemetabolismen og gir vektnedgang hos
nyretransplanterte pasienter med PTDM.
Metode
Studien er en prospektiv, placebokontrollert, dobbeltblindet, randomisert studie over 24 uker.
Totalt skal 50 nyretransplanterte pasienter diagnostisert med PTDM inkluderes. Pasientene
randomiseres 1:1 til empagliflozin 10 mg / placebo en gang daglig i 24 uker. Det vil være to
sikkerhetskontroller underveis, ved uke 8 og 16. Kosthold, fysisk aktivitet og andre medisiner
skal holdes uforandret under studieperioden. Pasienter transplantert for > 1 år siden med
stabil nyrefunksjon, eGFR > 30 mL/min/1,73m2 og PTDM i henhold til WHO definisjonen
(FPG > 7,0 mmol/L og/eller 2hPG > 11,1 mmol/L) vil bli inkludert. Det primære endepunktet
i studien er endring i kontinuerlig vevsglukose (målt over 3 dager med iProTM
2) fra baseline
til uke 24 sammenlignet med placebo. Det vil også utføres måling av kontinuerlig
vevsglukose i forbindelse med 8-ukerskontrollen. Sekundære endepunkter inkluderer endring
fra baseline i fastende plasmaglukose, 2-timers plasmaglukose etter oral glukose
toleransetest, HbA1c, kroppsvekt, waist-hip-ratio, blodtrykk (inkludert ortostatisk blodtrykk),
karstivhet, kroppssammensetning (inkludert visceralt fett) og eGFR. Demografiske data og
bivirkninger vil registreres i CRF, og adherence kontrolleres ved tablettelling ved uke 24.
Resultater
Så langt er 8 pasienter inkludert, 6 menn og 2 kvinner, med gjennomsnittsalder på 59±12 år.
7 av 8 pasienter har høyt blodtrykk og gjennomsnittlig BMI er 29,3±5,7 kg/m2.
Konklusjon
Endring i kontinuerlig vevsglukose, fastende plasmaglukose, HbA1c, vekt, waist-hip-ratio,
eGFR og blodtrykk frem til 8-ukerskontrollen vil bli presentert på møtet.
[95]
FP2
Effect of low calorie diet on the absolute bioavailability of midazolam in patients with
severe obesity
Martin Vu1, Veronica Krogstad
1, Line Kristin Johnson
2, Philip Carlo Angeles
2, Grete
Hasvold1, Monica Hermann
3, Cecilia Karlsson
4, Shalini Andersson
4, Tommy B Andersson
4,
Rune Sandbu2,5
, Jøran Hjelmeseth2,6
, Anders Åsberg1, Hege Christensen
1, Ida Robertsen
1
1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
2 The Morbid Obesity Center, Vestfold Hospital Trust, Tønsberg
3 Stord/Haugesund University College
4Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden
5Department of Surgery, Vestfold Hospital Trust, Tønsberg
6Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical
Medicine, University of Oslo, Norway
Background
Obesity is an increasing global health problem and is associated with serious comorbidity and
patients with severe obesity frequently use a variety of drugs. In a previous study in this
patient population it was indicated that CYP3A expression decreased with increasing body
weight1. In the current study we investigated the effect of weight reduction on CYP3A
activity in vivo, by measuring the absolute bioavailability of the CYP3A probe substrate
midazolam prior to and after intake of a low calorie diet in patients with severe obesity.
Method
A 24-hour pharmacokinetic investigation of midazolam was performed on patients with
severe obesity, before and after 3 weeks on a low calorie diet (<1200 kcal). All patients
received 1.5 mg oral and 1.0 mg intravenous midazolam separated by 4 hours. Per patient and
per occasion, 18 samples were collected in which midazolam and the metabolite 1-hydroxy
midazolam were measured using a validated liquid chromatography tandem mass
spectrometry (LC-MS/MS) method2. Standard non-compartmental methods were used to
determine pharmacokinetic parameters and the absolute bioavailability of midazolam in each
individual.
Results and conclusion
Nine patients with a mean BMI of 47.0 ±5.1 kg/m2 were included in this preliminary
analysis. The 3-week low calorie diet induced a mean weight loss of 7.3 ±2.4 kg (5.1 ±1.2%).
The absolute bioavailability of midazolam was 17.8 ±5.8% before and 14.2 ±3.5% after the
3-week low calorie diet, a mean change of -3.6% ±7.6% (P=0.19). These interim results
indicate that a moderate weight loss in patients with severe obesity do not impact CYP3A
activity.
1Ulvestad, M., et al., Clin Pharmacol Ther, 2013. 93(3): p. 275-82.
2 Le, P.H.V., et al., Master thesis, 2016.
[96]
FP3
Validation of tools for annual adherence evaluation of kidney transplant recipients
Marte Theie Gustavsen1, Thea Jacobsen
2, Kjersti Lønning
1, Karsten Midtvedt
1, Anna V.
Reisæter1, Anders Åsberg
1,2
1Department of Transplant Medicine, Section of Nephrology, Oslo University Hospital,
Rikshospitalet
2Department of Pharmaceutical Bioscience, School of Pharmacy, University of Oslo
Background
Adherence to immunosuppressive therapy is crucial for long-term kidney graft function. For
capture of adherence data it is recommended to use a combination of several subjective and
objective tools. We aimed to validate the questionnaire “Basal Assessment of Adherence to
Immunosuppressive Medication Scale” (BAASIS®
) in kidney transplant recipients (KTx).
Comparative validation-tools were clinician’s collateral reports scoring recipients as
poor/suboptimal/ excellent, pill count over a two weeks period, variation in concentration of
immunosuppressive drugs (tacrolimus; Tac) and clinical outcome at 1 year. The primary
objective of this ongoing study is to validate a tool for annual capture of adherence data in
KTx recipients.
Method
A total of 300 KTx recipients using Tac as part of their immunosuppressive therapy were
included in this single center open randomized prospective trail. Two third of the recipients
were included between one and four weeks after transplantation and followed for 1 year, the
other third were included at the 1-year control. All recipients completed the BAASIS® at
inclusion and an additional 2-8 times. The recipients were grouped as adherent (Ad-
group)/non-adherent (non-Ad group) according to the BAASIS® answers. Results from the 2
groups were then compared to the response from treating physicians, pill count, and variation
in Tac concentrations measured from 1 to 12 months post transplant.
Results
All recipients in the study have been included. Some 1-year follow-up data and data on
clinical outcomes are not yet obtained. Preliminary results tend to show an increasing number
of non-ad recipients with increasing time after transplantation. The results also indicate that
grouping of the patients according to the BAASIS® questionnaire did not seem to coincide
with the other adherence measurement tools. Data set including analysis will be shown at the
meeting.
Conclusion
Non-adherence seems so increase as times goes by in the post-transplant phase. Interim data
indicate that the combination of BAASIS® and Clinician´s score can identify risk patients,
and that these scores are collectable on annual basis. Long-term outcomes are needed to fully
validate the tools against each other.
[97]
FP4
Effekt av vitamin D3 på uttrykk, aktivitet og sekresjon av cysteinproteasen legumain
studert i ulike cellemodeller
Guro L. Arnekleiv1, Hilde Nilsen
1, Ngoc Nguyen Lunde
1, Rigmor Solberg
1, Harald
Thidemann Johansen1
1Avdeling for farmasøytisk biovitenskap, Farmasøytisk Institutt, Universitetet i Oslo,
Problemstilling
Aktivt vitamin D (1,25-dihydroksyvitamin D3; VD3) er blant annet viktig for
beinhomeostasen og inngår både direkte og indirekte i beinmetabolismen. Legumain er en
lysosomal cysteinprotease som spalter proteiner ved aminosyren asparagin. Ved aktivering av
legumain avspaltes et C-terminalt peptid uten enzymaktivitet, og dette peptidet er
karakterisert som ”osteoklast-inhibitorisk peptid 2” (OIP-2). I isolerte humane
beinmargsceller behandlet med antistoff mot legumain er det sett en induksjon i dannelsen av
osteoklaster, og etter stimulering med VD3 hemmer legumain dannelsen av osteoklast-
lignende celler. Legumain produseres og sekreres under differensieringsprosessen av disse
cellene, og utøver trolig en negativ regulatorisk funksjon. Legumain påvirker også
differensiering av stamceller fra beinmarg til henholdsvis osteoblaster eller adipocytter. Det
er beskrevet at legumain i nyrer degraderer vitamin D-bindende protein (VDBP),
transportproteinet for VD3 i blodet, og dette innebærer en ytterligere kobling mellom
legumain og beinhomeostasen. I denne studien studeres uttrykk, aktivitet og sekresjon av
legumain i humane cellekulturer etter eksponering for ulike konsentrasjoner av VD3, samt
direkte effekter av legumain på degraderingen av VDBP.
Metode
Humane embryonale nyreceller, HEK293 (ATCC; CRL-1573), monoklonale HEK293 celler
som overuttrykker legumain, M38L og humane monocytter, THP-1 (ATCC; TIB-202) ble
brukt som cellemodeller. Cellene ble eksponert for ulike konsentrasjoner av VD3 (1, 5, 10, 50
og 100 nM) og legumain ble analysert i cellelysater ved immunoblotting, protein- og
enzymaktivitetsmåling. Legumainsekresjon ble målt i kondisjonerte medier ved ELISA.
VDBP ble inkubert med renset aktivt legumain for å studere proteinets egenskaper som
substrat for legumain.
Resultater
Ved økende konsentrasjoner av VD3 viser foreløpige data en tendens til nedregulert aktivitet
av legumain i cellelysat fra HEK293 og M38L, og en svak økning i PMA-stimulerte THP-1-
celler. Videre ble det sett en tendens til økt sekresjon av legumain fra celler med lavt uttrykk
av legumain (HEK293 og THP-1), mens celler med høyt uttrykk av legumain (M38L)
derimot viste redusert legumainsekresjon.
Konklusjon
Innledende resultater viser at VD3 påvirker både aktivitet og sekresjon av legumain i ulike
cellemodeller.
[98]
FP5
Diacylglycerol acyltransferase 1 og 2 sin rolle i triglyseridsyntesen i humane
skjelettmuskelceller
Helene L. N. Vu1, Nils Gunnar Løvsletten
1, Eili T. Kase
1, G. Hege Thoresen
1,2, Victor A.
Zammit3, Arild C. Rustan
1
1Seksjon for farmasøytisk biovitenskap, Farmasøytisk Institutt, Universitetet i Oslo
2Avdeling for farmakologi, Institutt for klinisk medisin, Universitet i Oslo og Oslo
universitetssykehus 3Division of Metabolic and Vascular Health, Warwick Medical School, University of
Warwick, Coventry, UK
Problemstilling
Diacylglycerol acyltransferase (DGAT) 1 og 2 katalyserer det siste trinnet i
triglyseridsyntesen; dannelsen av triacylglycerol (TAG) fra diaglycerol. Enzymene har ulike
egenskaper og deler ingen felles homologi med hverandre. Dette kan tyde på en
heterogenisitet av intracellulært TAG. Akkumulering av TAG i skjelettmuskel, som er
assosiert med fedme og type 2-diabetes, kan føre til ugunstige effekter på
energimetabolismen. Vi ønsker å studere om DGAT1 og DGAT2 har ulike spesialiserte roller
i humane skjelettmuskler (myotuber) ved å bruke selektive hemmere av DGAT1 og DGAT2.
Metode
Humane satelittceller ble isolert fra skjelettmuskelbiopsier, dyrket og differensiert til
myotuber. Disse ble behandlet med DGAT1- eller DGAT2-hemmer. Dose-respons ble studert
ved å benytte ulike konsentrasjoner av DGAT1-hemmer. Energimetabolismen ble deretter
undersøkt ved å benytte radiomerket [1-14
C]oljesyre og D-[14
C(U)]glyserol.
Lipiddistribusjonen, ved hjelp av inkorporering av radiomerket oljesyre og glyserol i TAG,
ble bestemt ved tynnsjiktkromatografi.
Resultater
Dose-respons kurve med DGAT1-hemmer viste at 1 μM gav en effektiv hemming av
dannelsen av TAG. Ved bruk av DGAT1-hemmer reduseres inkorporeringen av 14
C-oljesyre
i ulike lipidklasser, men denne effekten ble ikke observert ved å hemme DGAT2.
Preliminære data viser at inkorporering av 14
C-glyserol i ulike lipidklasser reduseres i større
grad ved DGAT2-hemming sammenlignet med DGAT1-hemming.
Konklusjon
Selv om DGAT1 og DGAT2 katalyserer samme reaksjon, kan de ha ulike spesialiserte roller
i skjelettmuskulatur. Foreløpige resultater antyder at DGAT1 er ansvarlig for inkorporering
av eksogene fettsyrer til TAG, mens DGAT2 potensielt spiller en viktigere rolle ved
lipogenese (fettsyresyntese) og inkorporering av endogene fettsyrer i TAG.
[99]
FP6
Individual dosing of a methadone maintenance patient with reported opioid withdrawal
symptoms
Mimi Stokke Opdal and Peter Krajci
Department of Pharmacology and Department of Substance Use Disorder Treatment, Oslo
University Hospital (OUS) and Institute of Clinical Medicine, University of Oslo.
Background
The average daily methadone dose used in opioid maintenance treatment in Norway is 95 mg
(1). Methadone is metabolized by CYP3A4, CYP2B6 and to a lesser degree by CYP2C19,
CYP2D6 and CYP2C9. This case describes a 42-year old opioid addicted male, experiencing
insufficient relief of abstinence symptoms on a daily maintenance dose of 140 mg
methadone. Our aim was characterize his methadone pharmacology before further dose
increase.
Method
Degree of abstinence was scored using the standardized Clinical Opioid Withdrawal
Symptom questionnaire (COWS) (2). We inspected the patient’s drug list for possible
interactions (3). We looked for polymorphisms of cytochromes (CYPs) and measured serum
concentrations of methadone before and at four time points after intake of methadone.
Standard biochemical tests were performed to exclude somatic disease.
Permission to publish this case report has been obtained from the patient and from the
Privacy Ombudsman at OUS.
Results
Table 1 shows changes in abstinence symptoms based on COWS score before and after
dosing adjustments. Table 2 lists the medications, CYP-screening data and relevant
pharmacokinetic variables. The methadone Cmin was 772 nanomol/L (the therapeutic range
600-1200 nanomol/L). The half-life of methadone was calculated to 8.6 hours (Figure 1). The
results of biochemical tests were within normal ranges.
Conclusion
The reduced half-life of methadone corresponds with the early development of opioid
abstinence symptoms. The symptoms improved after dose adaptation from 140 mg x1 to 150
mg (90 + 60 mg) daily. The increased methadone metabolism could rely upon CYP2C19
polymorphism (4) and/or methadone autoinduction of CYP3A4. Literature search did not
reveal reports that the co-medications induced the metabolism.
References
1. Seraf rapport nr 1/2016-Statusrapport 2015
2. Wesson, DR and Ling, W. Journal of Psychoactive Drugs, 2003, 35(2): 253-259.
3. http://interaktionsdatabasen.dk/
4. Shirasaka Y et al. Pharmacogenomics Journal, 2016, 16, 375-387.
[100]
FP7
Utvikling av en metode for kvantifisering av CYP3A4, CYP3A5 og P-glykoprotein i
biopsier fra nyretransplanterte pasienter Ose A
1, Krogstad V
1, Hasvold G
1, Robertsen I
1, Egeland E
1, Monica Hermann
2, Skauby M
3,
Åsberg A1,4
, Christensen H1
1Seksjon for farmasøytisk biovitenskap, Farmasøytisk institutt, Universitetet i Oslo
2Høgskolen Stord/Haugesund
3Avdeling for transplantasjonskirurgi, Oslo universitetssykehus, Rikshospitalet
4Nyrefysiologisk laboratorium, Oslo universitetssykehus, Rikshospitalet
Problemstilling
Takrolimus er en kalsineurinhemmer som hemmer proliferasjonen av T-celler, ved å
nedregulere syntesen av IL-2 og ekspresjonen av cellenes IL-2-reseptorer, og brukes derfor
etter transplantasjon av organer. Legemiddelet har et smalt terapeutisk vindu, og utviser stor
intra- og interindividuell variasjon i respons. Til tross for at blodkonsentrasjonen av
takrolimus blir monitorert hos pasientene, er nyretoksisitet en vanlig bivirkning. Takrolimus
metaboliseres i stor grad av CYP3A4/5 og er samtidig substrat for P-glykoprotein. Det
diskuteres hvorvidt uttrykket av disse proteinene kan påvirke intrarenale nivåer av
takrolimus. Hensikten med denne masteroppgaven er å optimalisere Western blot-metoder til
å kvantifisere CYP3A4, CYP3A5 og P-gp i biopsier fra nyrevev i den hensikt å studere
mulige assosiasjoner mellom intrarenal konsentrasjon av takrolimus og uttrykk av disse
proteinene i nyrevev.
Metode
Nyrevev fra fem pasienter som har gjennomgått nefrektomi (REK 2014/200) ble anvendt. Det
ble laget homogenater ved hjelp av Precellys 24. Western blot-metoder for CYP3A4,
CYP3A5 og P-gp ble optimalisert med hensyn til både prøveopparbeidelse og prosedyre. Det
ble benyttet spesifikke antistoffer for CYP3A5, CYP3A4 og P-glykoprotein. Intensiteten til
de respektive båndene ble deretter interpolert til en tilhørende standardrekke. Disse
standardrekkene ble laget fra transfekterte insektsmikrosomer.
Resultater
Det ble ikke funnet kryssbinding mellom primærantistoffene for CYP3A5 eller CYP3A5.
Intensiteten til standardrekkene viste et sigmoidalt kurveforløp for P-gp, CYP3A5
ogCYP3A4. Standardrekkene for CYP3A4 og CYP3A5 ble validert for innen-serie presisjon
og viste lav variasjon. Innledende forsøk viser kvantifiserbart, men variabelt proteinuttrykk
av CYP3A4, CYP3A5 og Pgp i homogenater fra små nyrebiopsier. Endelige resultater vil bli
presentert på møtet.
Veien videre
Den optimaliserte Western blot-metoden skal anvendes til kvantifisering av CYP3A4,
CYP3A5 og P-gp i nyrebiopsier fra pasienter som benytter takrolimus, for å få økt forståelse
for mulige mekanismer bak nefrotoksisitet. En nedre deteksjonsgrense for metoden bør
avklares før anvendelse på små nyrebiopsier fra nyretransplanterte pasienter.
[101]
FP8
Betydning av kjønn og alder for nivåer av CYP3A4-biomarkøren 4β-
hydroksykolesterol hos pasienter behandlet med enzyminduserbarende antiepileptika
Camilla Nguyen1,2
, Birgit Malene Tovik Wollmann1,2
, Kristine Hole1, Tore Haslemo
2, Espen
Molden1,2
1Senter for Psykofarmakologi, Diakonhjemmet sykehus, Oslo
2Avdeling for farmasøytisk biovitenskap, Farmasøytisk institutt, Universitet i Oslo
Problemstilling
CYP3A4 er involvert i metabolismen av mer enn 50 % av alle markedsførte legemidler. Det
er stor individuell variasjon i CYP3A4-fenotype, og bruk av enzymindusere er en av flere
faktorer som bidrar til dette. Grad av enzyminduksjon varierer også mye, og hensikten med
denne studien var å undersøke betydning av kjønn og alder for variasjon i CYP3A4-fenotype,
malt som 4β-hydroksykolesterol (4β-HK; en endogen markør), hos pasienter behandlet med
enzyminduserende antiepileptika.
Metode
Studien ble gjennomført ved a analysere 4β-HK-konsentrasjon i lagrede serumprøver fra 415
pasienter der det tidligere hadde blitt analysert enzyminduserende antiepileptika
(fenobarbital, fenytoin eller/og karbamazapin). Prøvene var tatt i forbindelse med
rutinemessig legemiddelmonitorering, og i tillegg til målt serumkonsentrasjon av respektive
induser ble det hentet ut informasjon om alder, kjønn og dose. 4β-HK-konsentrasjon i
resterende serum fra monitoreringsanalysene ble bestemt ved UPLC-MS/MS, og 4β-HK-
nivåer ble sammenlignet mellom kvinner og menn i følgende aldersgrupper: 18-35, 36-45,
46-55, 56-65, 66-75 og >75 år.
Resultater
I materialet var det et overskudd med karbamazepin-brukere (65%), mens fordelingen
mellom kvinner og menn var relativ lik (48% kvinner mot 52% menn). Det ble observert en
signifikant høyere 4β-HK-konsentrasjon hos kvinner og menn, uavhengig av indusertype og
alder (P<0,0001). 4β-HK-konsentrasjon var gjennomgående høyere hos kvinner enn menn i
alle aldersgrupper, bortsett fra den yngste gruppen. Den største kjønnsforskjellen ble
observert i aldersgruppen 36-45 år, der kvinner hadde 145% høyere median 4β-HK-
konsentrasjon enn menn (P<0,0001). I den eldste aldersgruppen var til sammenligning
median 4β-HK-konsentrasjon 20% høyere hos kvinner enn menn (P=0,3). Mellom kvinner i
de ulike aldersgrupper var det en signifikant forskjell 4β-HK-konsentrasjon (P=0,03), mens
tilsvarende aldersforskjell ikke var signfikant blant menn (P=0,08).
Konklusjon
Resultater fra denne studien tyder på at kvinner gjennomgående har høyere CYP3A4-
fenotype enn menn ved bruk av enzyminduserende antiepileptika. Ulik grad av
kjønnsforskjell på tvers av aldersgrupper virker å reflektere aldersendringer blant kvinner, og
kan indikere at hormonstatus er av betydning for induksjonsgrad og regulering av CYP3A4-
metabolisme. Denne hypotesen vil bli fulgt opp med tilsvarende kjønnssammenligninger
blant pasienter behandlet med ikke-induserende antiepileptika.
[102]
FP9
Måling av takrolimus i immunceller i løpet av det første året etter nyretransplantasjon
Lina Daleq1,4
, Rolf Klaasen1, Nils Tore Vethe
1, Sara Bremer
2, Morten Skauby
3, Karsten
Midtvedt3, Stein Bergan
1,4
1Avdeling for farmakologi, Oslo universitetssykehus,
2Avdeling for medisinsk biokjemi, Oslo
universitetssykehus, 3Avdeling for transplantasjonsmedisin, Oslo universitetssykehus,
4Farmasøytisk institutt, Universitetet i Oslo
Problemstilling
Immundempende legemidler som takrolimus har vist stor farmakokinetisk variasjon hos
nyretransplanterte pasienter. For å forhindre avstøtningsepisoder og redusere forekomsten av
bivirkninger, er det nødvendig å tilpasse doseringen ut ifra takrolimus-konsentrasjoner målt i
fullblod. Takrolimus utøver sin effekt i lymfocyttene, men foreløpige resultater tyder på at
det ikke er så klar sammenheng mellom konsentrasjon av takrolimus i fullblod og
lymfocytter. Direkte konsentrasjonsmålinger av takrolimus i lymfocytter kan derfor være
bedre egnet til å monitorere effekten av legemidlet. Hensikten med dette prosjektet er å
beskrive nivåene av takrolimus i lymfocytter fra nyretransplanterte pasienter det første året
etter transplantasjon, samt vise hvordan dette er relatert til takrolimus i fullblod og
farmakologiske effekter.
Metode
Totalt 29 nyretransplanterte pasienter ble inkludert og fullførte studien. Blodprøver ble tatt
før (t0) og 1,5 timer etter (t1,5) dose ved 6-9 dager, 5-7 uker og ved 1 år etter transplantasjon.
Isolering av mononukleære celler fra perifert blod (PBMC) ble gjort ved hjelp av
gradientsentrifugering (Leucosep®). Fullblodkonsentrasjon ble målt med antistoff-basert
assay (CMIA). Intracellulær takrolimus ble ekstrahert fra PBMC med metanol og analysert
ved kromatografi koblet til massespektrometri.
Resultater
Median konsentrasjon for takrolimus i PBMC før og etter dose var 22,5 og 43,9 pg/106 celler
(p<0,001) ved 6-9 dager, 33,0 og 29,9 pg/106celler (p=0,48) ved 5-7 uker og 27,4 og 27,2
pg/106 celler (p=0,55) ved 1 år. Median konsentrasjon i fullblod før og etter dose var 5,0 og
10,5 μg/L (p<0,001) ved 6-9 dager, 6,0 og 8,3 μg/L (p<0,001) ved 5-7 uker og 5,4 og
9,1μg/L(p<0,001) ved 1 ar. Variasjonskoeffisienten (CV) for takrolimus i PBMC før og etter
dose var 68 % og 53 % ved 6-9 dager, 72 % og 51 % ved 5-7 uker, og 40 % og 63 % ved 1
år. Variasjonskoeffisienten (CV) for takrolimus i fullblod før og etter dose var 30 % og 57 %
ved 6-9 dager, 24 % og 37 % ved 5-7 uker, og 28 % og 38 % ved 1 år. Takrolimus i PBMC
korrelerte signifikant (p<0,01) med fullblod ved 6-9 dager før og etter dose.
Signifikansverdiene var 0,002 og <0,001, og korrelasjonsverdiene var 0,558 og 0,803.
Takrolimus i PBMC korrelerte ikke signifikant med fullblod ved 5-7 uker før og etter dose.
Signifikansverdiene var 0,264 og 0,112, og korrelasjonsverdiene var -0,214 og 0,112.
Takrolimus i PBMC korrelerte signifikant (p<0,01) med fullblod ved 1 år før og etter dose.
Signifikansverdiene var 0,001 og <0,001, og korrelasjonsverdiene var 0,602 og 0,829.
Konklusjon
Resultatene viser at metoden egner seg for måling av intracellulær takrolimus-konsentrasjon
hos nyretransplanterte pasienter. Nivået av korrelasjon med fullblod varierer ut ifra om
blodprøver ble tatt før og etter dose, og for tidspunkt etter nyretransplantasjon.
[103]
FP10
The Proton Pump Inhibitor Lansoprazole Inhibits Protease Activity of Legumain
Paya Diana Hemati1, Tatjana Bosnjak
1, Hilde Nilsen
1, Ngoc Nguyen Lunde
1, Harald
Thidemann Johansen1, Rigmor Solberg
1
1Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
Introduction
Proton pump inhibitors (PPIs) are used against peptic ulcer disorders by inhibition of the
parietal H+-pump. PPIs are prodrugs requiring activation by acidic pH to active forms that
react covalently with SH-groups. The specificity of PPI toward the proton pump is mainly
due to the very low pH at the parietal cell canalicular membrane. However, active PPI forms
could also be generated in other acidic microenvironments e.g. in lysosomes or in
extracellularly environment of osteoclasts or tumor cells. Increased proton secretion in
tumors is assumed to contribute to cancer cell proliferation and invasion, and PPIs have
recently been considered in cancer treatment. Legumain is an asparaginyl endopeptidase
primarily localized to acidic lysosomes. It is expressed as a proform (56 kDa), which is auto-
activated to an intermediate active form (46 kDa) at acidic pH, and further processed to the
mature active form of 36 kDa. Highest expressions of legumain are found in kidney, placenta,
spleen, liver and testis, whereas increased legumain is found in malignant tumors and
correlated with poor prognosis. As the protease is dependent on acidic pH and a reduced SH-
group in the active site for enzymatic activity, its actions in tumorous environments could be
inhibited by PPIs. This study examines both direct effects of lansoprazole on pure legumain
and effects in various cell types.
Methods
Four different cell lines were used: HEK 293 (human embryonic kidney), M38L (HEK293
over-expressing legumain), RAW264.7 (macrophages) and HCT 116 (colorectal carcinoma).
The cells were incubated with increased concentrations of lansoprazole (0-10 µM) for 48 h.
Purified bovine legumain was exposed to different concentrations of lansoprazole at different
pH values (pH 3-7.5). Methods used to measure legumain were enzyme activity
measurements, immunoblotting and ELISA measurements, and in addition total protein
measurements were performed.
Results
Preliminary data have shown a significant direct inhibition of purified bovine legumain
activity by 10 µM lansoprazole at acidic pH. At pH 5.8, where legumain is both active and
stable, lansoprazole gave a dose-dependent inhibition of legumain activity. Also, cells
incubated with lansoprazole showed decreased legumain activity. Furthermore, decreased
amounts of both the pro– and active form of legumain were observed in cells after treatment
with increasing lansoprazole concentrations.
Conclusion
The active form of lansoprazole functions directly as a covalent inhibitor of cysteine
proteases like legumain, by a reaction with the SH-group in the active site of the enzyme. A
similar legumain inhibition is present in cellular models and suggests a mechanism for off-
target effects of PPIs.
[104]
FP11
Validering av en antistoffbasert metode for analyse av belatacept i serum
Rolf Anton Klaasen1,2
, Stein Bergan2,3
, Nils Bolstad1, David Warren
1
1 Medisinsk Biokjemi Radiumhospitalet, Oslo universitetssykehus
2 Avdeling for Farmakologi Rikshospitalet, Oslo universitetssykehus
3 Farmasøytisk institutt, Universitetet i Oslo
Problemstilling
Belatacept (Nulojix®, Bristol-Myers Squibb, USA) er et first-in-class immundempende
legemiddel brukt etter nyretransplantasjon som et alternativ til kalsineurinhemmerne
takrolimus og ciklosporin. Legemiddelet er et fusjonsprotein bestående av CTLA-4-reseptor
og Fc-fragmentet til IgG1. Belatacept bindes til CD80 og CD86 på antigenpresenterende
celler og hindrer signal 2 i å aktivere T-cellen. Dette hemmer proliferering av T-cellene og
immunsystemet dempes. Belatacept doseres hver fjerde uke som infusjon. For å kunne utføre
farmakokinetiske studier og optimalisere bruken av belatacept, er det nødvendig å utvikle
analysemetoder for konsentrasjonsmålinger i serum. Antistoffbaserte målemetoder som
dissociation-enhanced lanthanide fluorescence immunoassay kan være et egnet
analyseprinsipp for måling av belatacept. Ved å bruke en automatisert pipetteringsrobot kan
et stort antall prøver analyseres raskt, som er aktuelt ved bruk av biobanker. Hensikten med
dette arbeidet er å utvikle og validere en antistoffbasert analysemetode automatisert på robot
for måling av belatacept i humant serum.
Metode
Serum fra nyretransplanterte pasienter ble isolert med serum-seperasjonsglass og belatacept
ble målt med en time resolved fluorescens antistoffbasert metode automatisert med robot
(AutoDELFIA®, Perkin Elmer, USA). Biotinylert CD80 ble festet til brønner på 96-brønns
streptavidin-plate. Ubundet biotinylert CD80 ble fjernet. Prøver ble fortynnet (1000x hvis tatt
mindre enn en uke etter infusjon, 100 x om senere) og tilsatt til brønnene. Protein A merket
med Europium ble tilsatt og ubundet protein A ble fjernet. Europium ble eksitert (340 nm) og
emisjon (650 nm) ble målt. For å validere metoden ble variasjon og presisjon, både innad og
mellom kjøringer undersøkt. Stabilitet ved frysing/tining og lagring i kjøleskap samt
påvirkning av pre-fortynning ble også undersøkt.
Resultater
Analysen viste et lineært konsentrasjon-signal forhold mellom 0.1 og 30 mg/L. Variasjonen
(CV %) innad en kjøring var <5.4 % og <6.9 % mellom kjøringer. Unøyaktighet var i snitt 16
% (4-23 %). Det var ingen nedgang i målt konsentrasjon etter lagring i ti dager ved 4 ˚C.
Frysing og tining gav en reduksjon på <12 %. Effekten av fortynning var lineær ved 100x,
1000x (< 5,1 % feil ift 100 x) og 2000x-fortynning (<4,4 % feil ift 100x).
Konklusjon
Vi har utviklet og validert en automatisert målemetode for belatacept i serum.
[105]
FP12
Identification and characterization of small molecular NPR-A agonists
Henriette Andresen1,2
, Lise Román Moltzau2, Alessandro Cataliotti
1, Finn Olav Levy
2
1Institute of experimental medical research, University of Oslo
2Department of Pharmacology, University of Oslo and Oslo University Hospital
Introduction
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). Resistant hypertension and uncontrolled
hypertension are conditions increasing in prevalence and are associated with increased
cardiovascular and renal events. There are currently no good treatment options available.
Administration of recombinant BNP has shown effective blood pressure reduction in
uncontrolled hypertension, suggesting BNP as a potential treatment of uncontrolled
hypertension (Cataliotti et al. 2012). However, due to poor drugability of peptides, BNP
needs to be administrated subcutaneously at least twice daily. As a potential antihypertensive
drug, small molecular compounds could offer better pharmaceutical properties, such as oral
administration and longer half-life than peptides. Our aim was therefor to identify small
molecular NPR-A agonists and characterize their pharmacological properties.
Method
High throughput screening using AlphaScreen® technology (PerkinElmer, USA) was
performed to identify NPR-A agonists by measuring cGMP increase in NPR-A expressing
HEK293 cells. Hit compounds were counter screened and rescreened, and later tested for
selectivity towards NPR-B expressing HEK293 cells. Compound analogues were found in
silico using similarity and substructure search in databases from MolPort and eMolecule.
Results and conclusion
About 30,000 compounds from two chemical libraries (Enamine and PPI) were screened for
activity towards NPR-A. The cut-off was set to >30% stimulation compared to maximum
BNP response. 113 compounds were identified as hits, and were counter screened and
rescreened. Only one of these compounds was finally verified as a hit, and later characterized
as a positive allosteric modulator of NPR-A. In the presence of a very small concentration of
BNP, this hit compound had a low potency, but was able to stimulate the cGMP production
almost to the same level as BNP. This compound showed selectivity towards NPR-A with
little or no effect towards NPR-B. After testing about 70 analogues, we identified compounds
with increased potency, but reduced efficacy compared to our hit compound. Information
about structure and activity relationship will be used in an optimization process.
References
Cataliotti A, Costello-Boerrigter LC, Chen HH, Textor SC, Burnett JC, 2012, Mayo Clin
Proc 87, 413-5
[106]
FP13
CYP3A4 phenotype and inflammatory state in patients with rheumatoid arthritis
Birgit M. Wollmann1, Silje W. Syversen
2, Elisabeth Lie
2, Lise L. Mehus
3, Tore K. Kvien
2,
Espen Molden1,4
1
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo 2
Department of Rheumatology, Diakonhjemmet Hospital, Oslo 3Department of Medical Biochemistry, Diakonhjemmet Hospital, Oslo
4 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo
Background
Individual variability in CYP3A4 phenotype is extensive, and systemic inflammation has
recently attracted great interest as a factor associated with downregulated expression of
CYP3A4. Thus, we investigated the association between the endogenous CYP3A4 biomarker
4-hydroxycholesterol (4OHC) and inflammatory state in patients with rheumatoid arthritis
(RA).
Methods
Measurements of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were
correlated with 4OHC levels in 41 RA patients before and 2-5 months after initiation of
treatment with biological disease-modifying antirheumatic drugs (bDMARDs), with the
majority starting on TNF inhibitors (75.6 %). Correlation analyses between CRP/ESR and
4OHC levels were performed at both time points by Spearman’s rank correlation test.
Results
There were no correlations between CRP or ESR and 4OHC before bDMARD treatment
(P>0.5), but highly significant correlations were observed between inflammatory markers and
CYP3A4 phenotype following initiation of bDMARD treatment (CRP = Spearman r -0.40; P
< 0.01; ESR = r -0.34; P = 0.028).
Conclusion
The present study supports that systemic inflammation in RA may reduce CYP3A4
metabolism, but inflammatory markers seem to reflect drug-metabolizing phenotype only
during effective anti-inflammatory treatment. Use of bDMARDs mainly seems to reduce
non-CYP3A4-suppressive cytokines. A likely mechanistic explanation behind this latter
finding is that bDMARD therapy – at least with TNF inhibitors – enrich interleukins
affecting CYP3A4 expression.
[107]
Deltakerliste vintermøtet 2017 Geir Øystein Andersen Hjertemedisinsk avdeling, OUS, Ullevål
Tommy B Andersson AstraZeneca R&D Gothenburg
Henriette Andresen Farmakologisk institutt, UiO
Kjetil Andressen Farmakologisk institutt, UiO
Libe Aranguren UiB
Guro Arnekleiv Universitetet i Oslo
Nicolai Bach Oslo universitetssykehus HF
Stein Bergan OUS, Avd for farmakologi
Aksel Bernhoft Veterinærinstituttet
Audun Bersaas Vaccibody AS
Ketil Berstad Norsk legemiddelhåndbok
Kåre Birkeland Universitetet i Oslo
Trine Bjørner Avd. for allmennmedisin HELSAM
Hans Fredrik Braaten Norsk Institutt for Vannforskning
Sara Bremer Oslo universitetssykehus
Kari Marie Børtveit NMBU Veterinærhøgskolen
Martina Galatea Castelli Universitetet i Bergen
Hege Christensen Farmasøytisk institutt, UiO
Jon E. Dahl NIOM
Karina Dale Universitetet i Bergen
Ola Dale NTNU/St. Olavs Hospital
Lina Daleq Universitetet i Oslo
Hubert Dirven Folkehelseinstituttet
Erlend Johannessen Egeland Seksjon for Farmasøytisk Biovitenskap, Farmasøytisk Institutt, UiO
Gunnar Sundstøl Eriksen Veterinærinstituttet
Thomas Fraser NMBU
Anders Goksøyr Universitetet i Bergen
Siri Øfsthus Goksøyr Universitet i Bergen
Merete Grung NIVA
Marte Theie Gustavsen Seksjon for nyresykdommer, Avdeling for transplantasjonsmedisin, OUS, Rikshospitalet
Kristine B. Gutzkow FHI
Thea A. S. Halden Oslo Universitetssykehus Rikshospitalet
Bent Hellum NTNU / St. Olavs Hospital
Paya Diana Hemati Farmasøytisk institutt, Universitetet i Oslo
Anna Herland Karolinska Institutet
Monica Hermann Høgskolen på Vestlandet
Tim Hofer Folkehelseinstituttet, Oslo
Kristine Hole Diakonhjemmet sykehus
Jørn A. Holme Folkehelseinstituttet
Ketil Hylland IBV, Universitetet i Oslo
[108]
Harald Thidemann Johansen Farmasøytisk institutt, UiO
Odd Andre Karlsen Universitetet i Bergen
Abdolrahman Khezri NMBU
Rolf Anton Klaasen Avdeling for Farmakologi, OUS
Mari Kolås Universitetet i Bergen
Veronica Krogstad Universitetet i Oslo
Kine Eide Kvitne Universitetet i Oslo
Finn Olav Levy Farmakologisk institutt, UiO
Amalie Sofie Liane Universitetet i Oslo
Yan Lin NIVA
Philipp Lobmaier SERAF, UiO
Eleonora Longhin University of Milano-Bicocca
Birgitte Lyrån Mattilsynet
Nils Gunnar Løvsletten Universitet i Oslo, Farmasøytisk institutt
Vladimir Martinov Medical Faculty, Inst. of Clinical Medicine, Department of Pharmacology
Jason Matthews Universitetet i Oslo
Espen Molden Senter for Psykofarmakologi, Diakonhjemmet Sykehus
Lise Román Moltzau Farmakologisk Institutt
Oddvar Myhre Folkehelseinstituttet
Camilla Nguyen Senter for Psykofarmakologi
Laila Sortvik Nilssen Statens legemiddelverk
Hedvig Nordeng Farmasøytisk institutt, Universitetet i Oslo
Ole Jakob Nøstbakken NIFES
Bergitte Pearl Olderbø NIOM
Mimi Stokke Opdal OUS, Avdeling for farmakologi
Anne-Marthe Due Ose Universitetet i Oslo
Jan-Bjørn Osnes Farmakologisk institutt, Institutt for klinisk medisin, UiO
Elise Rundén Pran NILU - Norsk institutt for luftforskning
Kirsten Eline Rakkestad Nordisk institutt for odontologiske materialer
Josef Daniel Rasinger NIFES
Kjetil Retterstøl Lipidklinikken OUS og Avdeling for ernæring UiO
Ida Robertsen Farmasøytisk institutt, UiO
Erik Ropstad NMBU
Anders Ruus NIVA/UiO
Jérôme Ruzzin UiB
Joëlle Rüegg Senior Scientist
Jan T. Samuelsen NIOM
Geir Simonsen Dnepharma
Torkild Skjelmerud Norsk legemiddelhåndbok
Tor Skomedal Farmakologisk institutt, UiO.
Arne Skulberg NTNU
Robert Smith Senter for Psykofarmakologi, Diakonhjemmet Sykehus
[109]
Eirik Steindal Miljødirektoratet
Oline Marie Steinkopf UiB
Kjell Torgeir Stokke Fürst Medisinsk Laboratorium
John Strang King’s College London
Elisabet Størset Oslo universitetssykehus Rikshospitalet
Sofie Söderström Universitetet i Bergen
Vibeke Telle-Hansen Høgskolen i Oslo og Akershus
Alexandra Isabel Sveinsen Treimo Universitetet i Oslo
Ida Tylleskär NTNU
Dag Tønnesen NILU
Solveig Uvsløkk Nordisk institutt for odontologiske materialer
Renate Valand Høgskolen i Oslo og Akershus
Helene L. N Vu Farmasøytisk Institutt, UiO
Martin Vu Farmasøytisk institutt UiO
Birgit M. T. Wollmann Senter for Psykofarmakologi, Diakonhjemmet Sykehus
Fekadu Yadetie Institutt for biologi, UiB
Shan Zienolddiny STAMI
Åse Marit Leere Øiestad Oslo Universitetssykehus, Klinikk for laboratoriemedisin, Rettsmedisinske fag
Johan Øvrevik Folkehelseinstituttet
Elisabeth Øya Folkehelseinstituttet
Vigdis Aas Høgskolen i Oslo og Akershus
Anders Åsberg OUS-Rikshospitalet / Farmasøytisk institutt UiO
[110]
Stipendmottakere 2017
Alexandra Isabel Sveinsen Treimo Universitetet i Oslo
Amalie Sofie Liane Universitetet i Oslo
Anne-Marthe Due Ose Universitetet i Oslo
Camilla Nguyen Senter for Psykofarmakologi
Guro Arnekleiv Universitetet i Oslo
Helene L. N Vu Farmasøytisk Institutt, UiO
Kine Eide Kvitne Universitetet i Oslo
Lina Daleq Universitetet i Oslo
Mari Kolås Universitetet i Bergen
Martin Vu Farmasøytisk institutt UiO
Oline Marie Steinkopf Universitetet i Bergen
Paya Diana Hemati Farmasøytisk institutt, Universitetet i Oslo
Renate Valand Høgskolen i Oslo og Akershus
Sofie Söderström Universitetet i Bergen
Solveig Uvsløkk Nordisk institutt for odontologiske materialer
Mottakere av stipend må sende kontonummer og adresse til [email protected] innen 15. februar 2017.
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