Assessing the Predictive Ability of In Vitro High-Throughput Screening (HTS) Assays
Open AccessThis dissertation includes a literature review and two studies conducted in partial fulfilment of the requirements for the degree of Doctor of Public Health in Environmental and Occupational Health. The goal of this dissertation was to summarize current studies investigating the paradigm shift in toxicity testing and assess whether chemical toxicity rankings derived from in vitro high-throughput screening (HTS) assays can predict in vivo chemical toxicity rankings. In consideration of this paradigm shift, the literature review conducted as a part of this dissertation provides an overview of example applications in which in vitro HTS assays may be leveraged in chemical risk assessments (e.g., as a prioritization tool that ranks chemical toxicities and identifies chemicals for additional in vivo testing). Also discussed are current challenges and solutions associated with increased reliance on in vitro HTS assays, as well as potential focuses for next steps in the use of in vitro HTS assays for chemical risk assessments and regulatory decision-making.Study 1 (Chapter 4) deployed a streamlined method to assess whether chemical toxicity rankings derived from in vitro high-throughput screening (HTS) assays can predict in vivo chemical toxicity rankings. This was assessed by correlating chemical toxicity rankings obtained using Benchmark Doses and Benchmark Dose Lower Limits (BMD(L)s) derived from in vivo and in vitro assays. Specifically, this study assessed whether the ability of in vitro assay data to predict in vivo toxicity rankings was impacted by certain in vitro and in vivo assay characteristics. Minimum best-fit BMD(L)s (i.e., BMD(L)s from the best fitting dose-response models) related to non-cancerous in vitro and in vivo endpoints were calculated for chemicals using Environmental Protection Agency’s (EPA’s) Benchmark Dose Software (BMDS). Previously published in vivo data were leveraged for this study (Kratchman et al. 2018; Kratchman, Wang, and Gray 2018). Relative chemical toxicity rankings were assessed through Kappa statistics, Pearson correlations, and/or Ordinary Least Squares (OLS) regressions. Results illustrated likely ability of in vitro data to predict similar chemical toxicity rankings as short-term in vivo data. Additionally, toxicity rankings derived from in vitro cytotoxicity assays, unlike stress response assays, significantly correlated with toxicity rankings derived from short-term in vivo assays. These results support previous studies that emphasize use of in vitro data as a prioritization tool within toxicity testing (Cote et al. 2016; Huang et al. 2016; Johansson et al. 2019; Piersma et al. 2014; Thomas et al. 2012). In vitro HTS assays assessed could thus potentially be used a prioritization tool within the scope of chemicals included in this study.Study 2 (Chapter 5) further assessed whether chemical toxicity rankings derived from in vitro high-throughput screening (HTS) assays can predict in vivo chemical toxicity rankings. Methods similar to Study 1 were leveraged; however, in vivo assay characteristics assessed included in vivo sex, species, and species-sex combinations. In vitro HTS assay characteristics assessed included cell species and cell type. Results from this study illustrated significant correlations between in vitro HTS assay toxicity rankings and short-term in vivo toxicity rankings from male rats. These results support previous studies that observed potential sensitivities of in vivo male rats when compared to other rodent species-sex combinations (Kratchman, Wang, and Gray 2018).
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