Fozia Noor
Biochemical Engineering Institute, Saarland University, Germany
Title: Advanced human cell cultures for repeated dose exposure in toxicity prediction and adverse outcome pathways studies
Biography
Biography: Fozia Noor
Abstract
Currently long term repeated dose toxicity is tested in vivo on animals in the safety assessment of chemicals and drugs. This is mainly due to unavailability of suitable human in vitro models. Another problem is the extrapolation of in vitro results to human in vivo. Most in vitro methods rely on apical endpoints that do not necessarily provide mechanistic information. In addition to toxicological studies, application of in vitro “omics†studies often requires serum-free cultivation. We optimized a serum-free cultivation medium (Mueller et al, 2012) that allows long term maintenance of hepatocytes for their application in repeated dose toxicity (Klein et al, 2013). To improve the longevity and functionality of liver cells, we are using high throughput 3D cultivation techniques. We have shown that these 3D cultures can be maintained for many weeks in culture with functionality better than that in 2D. The effects of several compounds (acetaminophen, aflatoxin B, valproic acid, chlorpromazine, troglitazone and rosiglitazone) were monitored and compared. The organotypic cultures are more sensitive to acetaminophen and aflatoxin toxicity than the 2D cultures (Gunness et al, 2013, Mueller et al, 2013). Using reverse dosimetry and a simple PBPK model, we predicted toxicity for valproic acid and bosentan from in vitro repeated dose toxicity data. Currently we are using such systems for pathway based mechanistic studies on cholestasis and steatosis as adverse outcomes. This high-throughput in vitro technology is suitable for drug screenings for long term repeated dose toxicity for which currently no alternative method to animal testing exists.