Licentiatseminarium: "An analysis of potential limitations of in vitro cell lines and in silico models in current chemical risk assessments for mixtures - A case study on azole mixtures in Sweden"

Fokus för Charlottes doktorandprojekt har varit interaktionen mellan olika  giftiga kemikalier  och hur man kan skapa modeller för att beskriva och förutsäga vad som ska hända, se nedan. Handledare har varit Elisabeth Jönsson-Bergman och Mikael Gustavsson, med Mats Olsson som examinator, samtliga från institutionen för biologi och miljövetenskap. Opponent vid lic-seminariet är Steffen Keiter från Örebro universitet.

Kort sammanfattning:

During my studies, I have explored the correlation between in vitro and in vivo test types, where we used azoles as a case study. We studied the toxicokinetic interaction on the detoxification pathway when a fish liver cell-line (PLHC-1) was exposed to the mixture of an azole and a polycyclic aromatic hydrocarbon (PAH) and created an in silico model to demonstrate the toxicokinetics using the detoxification enzyme cytochrome P450 1 A (CYP1A).

• In study I (unpublished), we used clotrimazole and benzo[a]pyrene) in our chemical mixture. This resulted in a 7.3-fold increase in CYP1A activity after a 24-hour exposure with mixture of 5 nM benzo[a]pyrene and 5µM clotrimazole, and a 6.9-fold increase after 36-hour exposure with the mixture of10 nM benzo[a]pyrene and 5µM clotrimazole. This indicates a toxicokinetic interaction and inhibition of clotrimazole on the biotransformation of benzo[a]pyrene.
• In study 2 (Paper I), we created a mathematical bottom-up model for a synergistic mixture effect, with CYP1A activity data of the mixture of the azole nocodazole and the PAH β-naphthoflavone. The model uses ordinary differential equations (ODEs) to describe the toxicokinetic pathway, and interaction.
• In study 3 (Paper II), we show a moderate correlation between embryonic in vitro and in vivo LC50 values and that although detected azole concentrations indicate a risk in sewage treatment plant  effluent and surface water, their concentrations are well below the concentrations seen to have synergistic effects seen in fish cell-line in vitro studies