Aligning in vitro exposures with in vivo exposures in SLE belugas using chemical activity

James Armitage, Frank Wania

In vitro bioactivity and toxicity assays are increasingly being used to assess the potential effects of organic chemicals in humans and ecological receptors.  For example, in vitro assays can be used to screen for numerous modes of action including endocrine disruption, enzyme induction/inhibition, genotoxicity and general cytotoxicity. In vitro dose-responses are typically reported using initial nominal medium concentrations which for various reasons complicates the extrapolation to and comparison with in vivo exposures (e.g., measured concentrations of contaminants in SLE beluga blubber).  Chemical activity has many applications within the field of environmental toxicology and chemistry.  For the purposes of the current application, chemical activity can be thought of as a method to normalize wet weight concentrations whereby sorption to all relevant phases (e.g., storage lipids, membrane lipids, proteins, water) is accounted for.  Accordingly, the chemical activity approach aligns in vitro and in vivo exposures by expressing the two quantities as directly comparable dose metrics.  To demonstrate this approach, reported tissue concentrations of various organic contaminants in SLE beluga are first converted to chemical activities following the standard approach.  We then parameterize and apply an in vitro mass balance model (IV-MBM v2.1) to estimate the initial nominal concentrations in the medium corresponding to the chemical activities estimated for SLE beluga tissues.  Calculations are made for chemicals spanning a wide range of physical-chemical properties and in vitro system parameters (e.g., the volume fraction of fetal bovine serum present).  The results generated following the procedure demonstrated here can be used to design representative dosing regimes for in vitro bioactivity and toxicity testing in the future and therefore help identify and prioritize the organic contaminants in SLE beluga that are of greatest potential toxicological concern.