Abstract
In the past 10 years, the public, private, and non-profit sectors have found agreement that hazard identification and risk assessment should capitalize on the explosion of knowledge in the biological sciences, moving away from in life animal testing toward more human-relevant in vitro and in silico methods, collectively referred to as new approach methodologies (NAMs). The goals for implementation of NAMs are to efficiently identify possible chemical hazards and to gather dose-response data to inform more human-relevant safety assessment. While work proceeds to develop NAMs, there has been less emphasis on creating decision criteria or showing how risk context should guide selection and use of NAMs. Here, we outline application scenarios for NAMs in different risk contexts and place different NAMs and conventional testing approaches into four broad levels. Level 1 relies solely on computational screening; Level 2 consists of high throughput in vitro screening with human cells intended to provide broad coverage of possible responses; Level 3 focuses on fit-for-purpose assays selected based on presumptive modes of action (MOA) and designed to provide more quantitative estimates of relevant dose responses; Level 4 has a variety of more complex multi-dimensional or multi-cellular assays and might include targeted in vivo studies to further define MOA. Each level also includes decision-appropriate exposure assessment tools. Our aims here are to (1) foster discussion about context-dependent applications of NAMs in relation to risk assessment needs and (2) describe a functional roadmap to identify where NAMs are expected to be adequate for chemical safety decision-making.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 523-534 |
| Number of pages | 12 |
| Journal | Altex |
| Volume | 36 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2019 |
Funding
The National Academy of Sciences (NAS) report in 2007, “Toxicity Testing in the 21st Century: A Vision and A Strategy,” proposed fundamental changes in chemical risk assessment, including moving to human cells, tissues, or cell lines, developing high-throughput methods for evaluating large numbers of chemicals more efficiently, and using various computational chemistry and bioinformatic tools for data analysis and prediction of risk (NRC, 2007). The National Center for Computational Toxicology (NCCT) at the US EPA had previously developed a plan to incorporate many of these approaches in toxicity testing, as described in “A Framework for a Computational Toxicology Research Strategy” (Kavlock et al., 2003) and after publication of the NAS report, moved forward to outline a broadly collaborative program (Collins et al., 2008) with other United States federal agencies to implement recommendations from the NAS report. A multi-stakeholder program, SEURAT (Safety Evaluation Ultimately Replacing Animal Testing)1 that focused on implementation of non-animal methods also began in Europe. Following SEURAT, EU-ToxRisk, a large-scale project funded by the European Commission’s Horizon 2020 program2, is now driving the European research efforts on alternative testing methods. Many of our efforts to develop coherent approaches for decision-context appropriate testing with non-animal methods, including computational methods, IVIVE techniques and bespoke assay development, have received multi-year support at the Hamner Institutes and now ScitoVation from the Long Range Research Initiative of the American Chemistry Council (ACC-LRI). In addition, another program – TT21C: Toxicity Pathways and Network Biology – pursued three case studies to develop an understanding of the use of in vitro fit-for-purpose assays in human cells as the basis for risk assessment. This broad TT21C program received support from Dow Chemical, ExxonMobil Foundation, Dow Corning, Unilever, Agilent, Crop Life America and 3M Company. We are grateful for the support from all these organizations over the life of this research effort and the opportunity to integrate these efforts to pursue context dependent strategies for toxicity evaluation and risk assessments. Many of our efforts to develop coherent approaches for decision-context appropriate testing with non-animal methods, including computational methods, IVIVE techniques and bespoke assay development, have received multi-year support at the Hamner Institutes and now ScitoVation from the Long Range Research Initiative of the American Chemistry Council (ACC-LRI). In addition, another program - TT21C: Toxicity Pathways and Network Biology - pursued three case studies to develop an understanding of the use of in vitro fit-for-purpose assays in human cells as the basis for risk assessment. This broad TT21C program received support from Dow Chemical, ExxonMobil Foundation, Dow Corning, Unilever, Agilent, Crop Life America and 3M Company. We are grateful for the support from all these organizations over the life of this research effort and the opportunity to integrate these efforts to pursue context dependent strategies for toxicity evaluation and risk assessments.
ASJC Scopus subject areas
- Pharmacology
- Medical Laboratory Technology