In vitro to in vivo extrapolation (IVIVE) - A case study for rotenone and NAFLD

Diplôme Master d'études avancées In vitro to in vivo extrapolation (IVIVE) - A case study for rotenone and NAFLD eng 2020-09-25 author Trudel David 868255 director Sturla Shana 955237 Non-alcoholic fatty liver disease (NAFLD) is a disease that affects a large portion of the western society (it is estimated that about 30% of Americans have NAFLD). To better understand the etiology of NAFLD and the risk of food related chemicals to cause NAFLD a PhD project has been set up at the chair of Prof. Shana Sturla at ETHZ. In this project human in vitro models are used to assess the concentration-response relationship for various substances and endpoints (mitochondrial dysfunction, lipid accumulation, oxidative stress, and cell number). Based on the data of the in vitro assays in vitro to in vivo extrapolation (IVIVE) is performed to estimate an oral human dose. As part of the PhD project this MAS thesis was conducted with rotenone as model compound for mitochondrial dysfunction. Based on the in vitro data from the PhD project four different tools to estimate a benchmark concentration (BMC) and the corresponding lower bound (BMCL) were tested and evaluated. The comparison of the tools reveals that for screening purposes the R-function calc_bmd is recommended and for in-depth analysis the BMDS tool from the US EPA. In the current case calc_bmd provides the most reliable BMCL estimate amounting to 460 nM for mitochondrial dysfunction. Based on this BMCL IVIVE was performed using the R package httk and an oral dose estimate of 0.16 mg/kgBW/d could be derived. When compared to the relevant NOEAL and LOAEL, respectively, the dose estimate is about a factor of two lower than the NOAEL and factor of 12 lower than the LOAEL. This evaluation reveals that the above described procedure can produce conservative dose estimates that are within one order of magnitude of the relevant animal data and, hence, gives support for the use of IVIVE for risk assessment purposes. IVIVE BMD BMDS BMC PBTK Rotenone NAFLD Liver Systems toxicology Httk R Drc Calc_bmd Dewey 610 Dewey 615 Master of Advanced Studies in Toxicology 31 Section des sciences pharmaceutiques 17 3 Faculté de médecine 2 false bd469289-ba93-45df-a5d9-9bdb1d526397 Master thesis Restricted MT_200930_Trudel.pdf 3396285 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine

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In vitro to in vivo extrapolation (IVIVE) - A case study for rotenone and NAFLD				2020	73	3

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Trudel, David