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.
Highlights
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)
Quantitative IVIVE (QIVIVE), accounting for human relevant metabolism coupled with dose-response relationships from the FFP assays, would provide more confidence in estimated MOEs and determination of regions of safety, i.e., exposure concentrations at which no increased risk is expected in a human
With the explosion of available new approach methodologies (NAMs) in the past decade and changes in the regulatory environment afforded by various initiatives such as the Frank R
Summary
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). These in vitro and computational technologies, together with application of existing tools to new data streams (e.g., readacross), are collectively referred to as new approach methodologies – NAMs (US EPA, 2018b). The primary testing initiatives following the release of the 2007 NAS report focused on screening large numbers of compounds with existing high-throughput assays (e.g., ToxCast, Tox21), many of which were repurposed from pharmaceutical applications (Judson et al, 2010; Reif et al, 2010) These efforts developed the infrastructure necessary for collection and analysis of large-scale data and determining the utility of existing methods for supporting chemical safety decisions. A variety of considerations, such as the magnitude of the MOE and the accuracy, regulatory acceptance and biological coverage of the assays populating the level, would have to be considered in deciding if higher-level testing would be necessary
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