S3: Where is the Chemical?: The In Vitro Disposition of Tox21 Chemicals
National Toxicology Program
Understanding the in vitro disposition of chemicals evaluated in alternative models would enable better translation of in vitro bioactivity to the human dose context. In an effort to extrapolate in vitro media concentrations to in vivo exposures, toxicokinetic models can be used to estimate human oral exposures that would result in blood concentrations equivalent to the nominal media concentrations. One assumption in these models is that the ratio of the chemical concentration in media to cells is equivalent to the ratio of blood to tissue. Another assumption is the static nature of the cell culture exposure compared to the kinetic processes occurring in vivo. In contrast, human exposure is a dynamic process in which absorption, distribution, metabolism and elimination influence blood and tissue chemical concentrations. In the Tox21 project most of the assays employ immortalized cell lines cultured in monolayers in plastic wells. It is known that chemicals can distribute between the plastic, media, and the cells, but it is unknown for what fraction of the Tox21 chemical space and to what extent this differential partitioning between in vitro compartments occurs. These initial studies evaluate the in vitro distribution of chemicals over a period of 24 hours, the length of many of the Tox21/ToxCast assays. This pilot study involves the use of MCF-7 cells exposed to a diverse set of ten chemicals. The development of a data set that quantifies the concentration of chemicals in the media, plastic, and cells provides quantitative insight into the magnitude and directionality of the uncertainty in the assumption that media to cells and blood to tissue partitioning are equivalent, and may inform revised modeling assumptions to better approximate human doses from in vitro concentrations. This abstract does not reflect EPA policy.