Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing

Abstract

Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants.

Keywords: 3Rs; Acute systemic toxicity; Alternatives; Dermal; In silico; In vitro; Inhalation; LD(50); Oral.

Figure 1

Proposed prioritization strategy for testing of chemicals for acute toxicity adapted from (National Research Council 2015)

Figure 2

Schematic representing the use of alternatives to move away from animal tests. Putting the pieces together involves multiple approaches and requires increased harmonization and cooperation among regulatory agencies and industry.

Figure 3

A: Sandalore; B: 3-cylopentene-l-butanol, beta,2,2,3-tetramethyl-

Figure 4

Overview of the AOP framework (adapted from (Oki, Nelms et al. 2016).

Figure 5

Tox21 involved the testing of more than 10.000 substances using the automated robotic screening system housed at NCATS. During Phase II of testing, the assay is optimized, validated, and miniaturized into a 1536-well plate format, followed by the robotic validation Robotic qHTS against the Tox21 10K library is then run, followed by data processing The screening results are first shared by government partners, and then are made publicly accessible. Figure reproduced from (Attene-Ramos, Miller et al. 2013).