In Vitro Translational Studies
Cell cultures can be used to evaluate a number of cellular processes and responses, from physiological to pathological. Simultaneous measurements of multiple toxic responses are also possible with high-content imaging and other techniques. Furthermore, cell cultures can be scaled to a high-throughput format and can be derived from genetically diverse populations. Thus variability in response to chemical exposure due to genetic differences can be studied.
In addition to cell-based assays, advances in engineered three-dimensional (3D) models of tissues led to the development of many organotypic and organ-on-a-chip models. Although promising, these models are not yet ready for inclusion in risk assessment. Despite their limitations, the importance of these models in environmental health research, risk assessment, and public health decisions could be significant. TiCER scientists are discovering ways to overcome these limitations and challenges and develop effective in vitro models for environmental health research, as illustrated in the examples given below.
Check out some examples of how the in vitro translational research area of the IHSFC core has been used by TiCER scientists below.
While risk assessment research has shifted towards greater reliance on in vitro data, no assays in Tox21/ToxCast are designed to address inter-individual variability. The lack of population variability is one impediment to research translation and integration of these data into human health evaluations. Genetic polymorphisms have a profound effect on differences between individuals who may develop disease after exposure to toxicants, yet they are difficult to evaluate using current approaches.
However, the availability of genetically diverse/defined renewable sources of human cells, such as lymphoblasts from the HapMap and 1000 Genomes projects, enables in vitro toxicity testing at the population scale. The utility of an in vitro population-based toxicogenetics approach has been demonstrated by our prior work.
For example, in one recent study, we tested the hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude and molecular causes of inter-individual toxicodynamic variability (Figure 7). We used 1,100 lymphoblastoid cell lines representing nine populations from five continents to assess variation in toxicity of ~180 chemicals. We observed that for about half the tested compounds, cytotoxic response in the 1% most “sensitive” individual occurred at concentrations within a factor of 101⁄2 (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was much greater than 10.
Also important for translation of these in vitro results to humans, we showed that the cumulative distribution of in vitro toxicodynamic variability factors across screened chemicals was nearly identical to in vivo human toxicodynamic variability of 34 drugs.