Accelerating the Pace of Chemical Risk Assessment

Abstract

Changes in chemical regulations worldwide have increased the demand for new data on chemical safety. New approach methodologies (NAMs) are defined broadly here as including in silico approaches and in chemico and in vitro assays, as well as the inclusion of information from the exposure of chemicals in the context of hazard [European Chemicals Agency, " New Approach Methodologies in Regulatory Science ", 2016]. NAMs for toxicity testing, including alternatives to animal testing approaches, have shown promise to provide a large amount of data to fill information gaps in both hazard and exposure. In order to increase experience with the new data and to advance the applications of NAM data to evaluate the safety of data-poor chemicals, demonstration case studies have to be developed to build confidence in their usability. Case studies can be used to explore the domains of applicability of the NAM data and identify areas that would benefit from further research, development, and application. To ensure that this science evolves with direct input from and engagement by risk managers and regulatory decision makers, a workshop was convened among senior leaders from international regulatory agencies to identify common barriers for using NAMs and to propose next steps to address them. Central to the workshop were a series of collaborative case studies designed to explore areas where the benefits of NAM data could be demonstrated. These included use of in vitro bioassays data in combination with exposure estimates to derive a quantitative assessment of risk, use of NAMs for updating chemical categorizations, and use of NAMs to increase understanding of exposure and human health toxicity of various chemicals. The case study approach proved effective in building collaborations and engagement with regulatory decision makers and to promote the importance of data and knowledge sharing among international regulatory agencies. The case studies will be continued to explore new ways of describing hazard (i.e., pathway perturbations as a measure of adversity) and new ways of describing risk (i.e., using NAMs to identify protective levels without necessarily being predictive of a specific hazard). Importantly, the case studies also highlighted the need for increased training and communication across the various communities including the risk assessors, regulators, stakeholders (e.g., industry, non-governmental organizations), and the general public. The development and application of NAMs will play an increasing role in filling important data gaps on the safety of chemicals, but confidence in NAMs will only come with learning by doing and sharing in the experience.

Factors Affecting the Perception of New Approach Methodologies (NAMs) in the Ecotoxicology Community

“…Following the outcome of a European Chemicals Agency (ECHA) international scientific workshop, NAMs are defined broadly as “in silico approaches, in chemico and in vitro assays including high‐throughput and high‐content techniques, omics with a focus on metabolomics” (ECHA 2016a, p 47). Although international initiatives to “modernize” toxicity testing are multiplying and gathering momentum (Arnold 2015; ECHA 2016a; ICCVAM 2018; Kavlock et al 2018), the formal adoption and deployment of NAMs in chemical risk assessment generally remains limited. This situation represents an increasing source of frustration and topic of debate among different actors within the community of practice engaged in chemical risk assessment (Vachon et al 2017; Zaunbrecher et al 2017).…”

“…Given current legislative mandates in North America (Chemicals Management Plan [Government of Canada 2016] in Canada, and Toxic Substances Control Act [Bergeson et al 1976] in the United States) and Europe (Registration, Evaluation, Authorisation and Restriction of Chemicals) (Smith 2006) and the slow pace at which conventional testing proceeds, there is a need to accelerate the pace of chemical risk assessment (Kavlock et al 2018). The gap between these legislative mandates and the number of chemical substances in need of toxicity data is large and widening (Basu et al 2019).…”

T1000: A reduced toxicogenomics gene set for improved decision making

“…In addition, our approach in selecting T1000 genes was purely datadriven without considering input from scientific experts as was done by the NTP to derive the S1500 gene set (Mav et al 2018). It is unclear how such gene sets (e.g., T1000, S1500) will be used by the community and under which domains of applicability, and thus there is a need to perform case studies in which new approach methods are compared to traditional methods (Kavlock et al 2018).…”

EcoToxChip: A next‐generation toxicogenomics tool for chemical prioritization and environmental management

“…The ultimate goal of these efforts is to transform conventional testing approaches, which are based on apical and largely qualitative measures (e.g., survival, growth, development), to a model founded on contemporary scientific understanding, new technologies (e.g., toxicogenomics, high‐throughput screening), and alternatives to animal testing strategies (i.e., in silico, in vitro, and embryo‐based approaches that incorporate Russell and Burch's [] “3 Rs” principle [reduce, refine, replace]). The big data that emerge from these new approaches, when integrated using systems biology frameworks, promise to predict apical outcomes, and thus, significantly improve the ability of scientists and regulators to prioritize chemicals more effectively based on their mode of action (Kavlock et al ). In addition to clear scientific, ethical, and regulatory benefits, there are important economic drivers for this shift in testing strategies.…”