Perspectives on validation of high-throughput assays supporting 21st century toxicity testing

Abstract

Summary In vitro, high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals, but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. Here we discuss streamlining the validation process, specifically for prioritization applications in which HTS assays are used to identify a high-concern subset of a collection of chemicals. The high-concern chemicals could then be tested sooner rather than later in standard guideline bioassays. The streamlined validation process would continue to ensure the reliability and relevance of assays for this application. We discuss the following practical guidelines: (1) follow current validation practice to the extent possible and practical; (2) make increased use of reference compounds to better demonstrate assay reliability and relevance; (3) deemphasize the need for cross-laboratory testing, and; (4) implement a web-based, transparent and expedited peer review process.

Evidence-based toxicology for the 21st century: Opportunities and challenges

“…The text (comprising the balance of Section 3.3.) provides recommendations focused on the paper prepared by Judson et al (2013) and is a summary of a longer document, "ACC Perspectives on Validation of High-Throughput Assays Supporting 21 st Century toxicity evaluation," prepared by the American Chemistry Council (ACC) Computational Profiling Workgroup, which she co-chairs with Richard Becker of the American Chemistry Council.…”

“…First, the EBTC is seeking to apply evidence-based methods to assessing the performance of emerging pathway-based methods consistent with the National Research Council (NRC) report on "Toxicity Testing in the 21 st Century" (NRC, 2007). In keeping with this priority, workshop Session 1 featured a presentation by Richard Judson on the validation of high-throughput pathwaybased assays (Judson et al, 2013) and Session 3 featured a presentation by Suzanne Fitzpatrick on a potential role for EBT in 21 st century validation strategies (see Section 5.1). Similarly, two of the three presentations in Session 2 addressed fundamental questions relevant to establishing the scientific basis of pathway-based assays -one by Daland Juberg on the challenge of distinguishing adverse responses in these assays from those that are adaptive or compensatory (see Keller et al, 2012), and one by Patricia Harlow on the process of confirming that biomarkers used in these and related assays truly reflect the biology of interest (see Section 4.1).…”

“…the papers associated with the formal presentations in each of the four workshop sessions either appear elsewhere in this issue of ALTEX (Judson, 2013;Silbergeld and Scherer, 2013) or are summarized below, except the one associated with Daland Juberg's presentation, which was already in press at the time of the EBTC workshop (Keller et al, 2012). A science writer was contracted to take the lead in summarizing the invited commentaries and open discussions for the proceedings, except where noted otherwise below.…”

Building associations between markers of environmental stressors and adverse human health impacts using frequent itemset mining

“…There is a critical need for cost-effective identification and prioritization of those compounds most likely contributing to adverse health outcomes, spawning several initiatives [20,24,36]. High throughput in vitro assays offer one tool for addressing these data gaps [3,18,24]. While these approaches show some promise, they necessarily focus on early molecular and cellular effects, making it hard to directly extrapolate to adverse outcomes in a whole organism [33].…”

Moving from rats to cellular omics in regulatory toxicology: great challenge toward sustainability or “up-shit-creek without a paddle”?

“…This leads to another unresolved issue, that is, assay validation. The multitude of assays and the pace of assay development make it unrealistic to subject them to validation as practiced currently (Judson et al 2013). With many cellular test systems being based on human cells, it also has to be questioned if the current practice of defining animal tests as the "gold standard" really is the best way to go.…”