Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework

Abstract

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency.

BMDExpress Data Viewer ‐ a visualization tool to analyze BMDExpress datasets

“…2015; Thomas et al . 2012, 2013a, b). The application of toxicogenomics in risk assessment is still in an early phase of development.…”

“…using a feature called “Functional Classifications.” Global transcriptional BMD modeling using BMDExpress has been used to demonstrate that toxicogenomic BMDs fall within the range of BMDs derived from apical data, and has been useful for investigating the mode of action of several toxicants (Bhat et al ., 2013; Bourdon et al ., 2013; Jackson et al ., 2014; Moffat et al ., 2015). These studies support the notion that transcriptional BMDs can be used to derive points of departure for human health risk assessment, particularly in instances when apical data are not available (Chepelev et al ., 2015; Moffat et al ., 2015; Thomas et al ., 2012, 2013a, b).…”

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

“…This is relevant, since the majority of industrial chemicals are likely to have relatively non-specific modes of action [51]. There is no reason to believe that these chemicals will be missed by the battery, since relevant pathways seem available.…”

Cancer Biology, Toxicology and Alternative Methods Development Go Hand‐in‐Hand

“…A constantly increasing number of chemicals and engineered nanomaterials (ENMs) emphasize the need of applying novel tools and screening technologies outside of the standard, both lengthy and expensive, rodent toxicological tests traditionally used in such work [1][2][3][4][5][6][7][8][9][10][11][12][13]. Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12].…”

“…Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12]. Summarized under a concept termed 'Toxicity Testing in the 21st Century' or 'Tox21', biochemical and cell-based in vitro assays coupled with bioinformatics and modelling-driven in silico assays are now considered key to transforming toxicology from a previously animal-based testing practice into a computational science built on systems biology [2,4,6,[9][10][11]13]. The resulting novel research field is variably termed 'systems toxicology', 'toxicogenomics' or 'computational toxicology' [3,4,8,14,15].…”