posted on 2020-12-15, 19:41authored bySebastian Lungu-Mitea, Carolina Vogs, Gunnar Carlsson, Maximiliane Montag, Kim Frieberg, Agneta Oskarsson, Johan Lundqvist
Linking
cellular toxicity to low-tier animal toxicity and beyond
is crucial within the adverse outcome pathway concept and the 3R framework.
This study aimed to determine and compare the bioavailable effect
concentrations in zebrafish cell lines and embryos. Acute, short-term
toxicity (48 h) of eight veterinary pharmaceuticals was measured in
two zebrafish cell lines (hepatocytes, fibroblasts) and zebrafish
embryos. Seven endpoints of cytotoxicity were recorded. The fish embryo
acute toxicity test was modified by adding sublethal endpoints. Chemical
distribution modeling (mass balance) was applied to compute the bioavailable
compound concentrations in cells (Cfree) and embryos (Cint;aq) based on nominal
effect concentrations (Cnom). Effect concentration
ratios were calculated (cell effects/embryo effects). A low correlation
was observed between cytotoxicity and embryo toxicity when nominal
concentrations were used. Modeled bioavailable effect concentrations
strongly increased correlations and placed regression lines close
to the line of unity and axis origin. Cytotoxicity endpoints showed
differences in sensitivity and predictability. The hepatocyte cell
line depicted closer proximity to the embryo data. Conclusively, the
high positive correlation between the cell- and embryo-based test
systems emphasizes the appropriate modulation of toxicity when linked
to bioavailable concentrations. Furthermore, it highlights the potential
of fish cell lines to be utilized in integrated testing strategies.