Quantitative in Vitro to in Vivo Extrapolation (QIVIVE) for Risk Assessment of Persistent Organic Pollutant Mixtures in Cetaceans

Cetaceans accumulate high levels of persistent organic pollutants (POPs), yet their biological effects in the real environment remain unclear. Here, we use a quantitative in vitro to in vivo extrapolation (QIVIVE) model that compares the freely dissolved concentrations of 15 POPs in finless porpoise (<i>Neophocaena asiaeorientalis</i>) blood and blubber with freely dissolved effect concentrations in a fibroblast bioassay for cell viability and apoptosis. To enable QIVIVE based on free concentrations, we developed a mass distribution model for the distribution of POPs, parameterized with the measured protein and lipid contents of finless porpoise blood and blubber, as well as the bioassay medium. The freely dissolved concentrations were 2-3 (medium), 4-6 (blood), and 6-8 (blubber) orders of magnitude lower than their nominal and measured total concentrations. QIVIVE ratios (ratios of in vivo to in vitro freely dissolved concentrations) indicated that, at current exposure levels, the POP mixture was unlikely to pose a risk to cell viability or induce apoptosis in finless porpoise blood and blubber. Mass distribution modeling and QIVIVE ratios provide a realistic basis for chemical risk assessment in cetaceans. We highlight the need to include chronic end points such as endocrine disruption and immunotoxicity in future in vitro test batteries to better capture potential health risks.