A framework for chemical safety assessment incorporating new approach methodologies within REACH

Abstract

The long-term investment in new approach methodologies (NAMs) within the EU and other parts of the world is beginning to result in an emerging consensus of how to use information from in silico, in vitro and targeted in vivo sources to assess the safety of chemicals. However, this methodology is being adopted very slowly for regulatory purposes. Here, we have developed a framework incorporating in silico, in vitro and in vivo methods designed to meet the requirements of REACH in which both hazard and exposure can be assessed using a tiered approach. The outputs from each tier are classification categories, safe doses, and risk assessments, and progress through the tiers depends on the output from previous tiers. We have exemplified the use of the framework with three examples. The outputs were the same or more conservative than parallel assessments based on conventional studies. The framework allows a transparent and phased introduction of NAMs in chemical safety assessment and enables science-based safety decisions which provide the same level of public health protection using fewer animals, taking less time, and using less financial and expert resource. Furthermore, it would also allow new methods to be incorporated as they develop through continuous selective evolution rather than periodic revolution.

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

“…To overcome these challenges, the introduction of new methodologies to conduct "smart" in vivo studies with the same level of risk confidence has been proposed. 7 Consistent with this paradigm, in this communication we propose the incorporation of toxic stress reporter mice into such smart in vivo studies (Table 1). We describe how stress reporter mice can overcome some of the issues surrounding traditional in vivo toxicity studies, accelerate toxicity testing and aid in risk assessment while simultaneously reducing animal use.…”

Application of AOPs to assist regulatory assessment of chemical risks – Case studies, needs and recommendations

“…Knowledge stored in the AOP-Wiki and other data sources, such as the CompTox database ( https://comptox.epa.gov/dashboard/ ), was used to link scattered (toxicological) data at different levels of biological organization. It also facilitated the identification of potential molecular targets and key mechanistic nodes, which could assist in the design of the tiered approaches in the NGRA ( Ball et al, 2022 ).…”

Cell-Based Chemical Safety Assessment and Therapeutic Discovery Using Array-Based Sensors

“…Synthetic chemicals are widely used in agriculture [ 68 ], food [ 69 ] and medicine [ 70 ], raising concerns and fears regarding potential risks to human health. Current chemical safety assessment approaches generally focus on acute health outcomes as the endpoints for assessing the risks posed by chemical agents [ 71 ]. This focus limits their application in the detection of early cellular responses following chemical exposure.…”