Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA)

Abstract

Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. Current approaches are too resource intensive in terms of time, money and animal use to evaluate all chemicals under development or already on the market. The need for timely and robust decision making demands that regulatory toxicity testing becomes more cost-effective and efficient. One way to realize this goal is by being more strategic in directing testing resources; focusing on chemicals of highest concern, limiting testing to the most probable hazards, or targeting the most vulnerable species. Hypothesis driven Integrated Approaches to Testing and Assessment (IATA) have been proposed as practical solutions to such strategic testing. In parallel, the development of the Adverse Outcome Pathway (AOP) framework, which provides information on the causal links between a molecular initiating event (MIE), intermediate key events (KEs) and an adverse outcome (AO) of regulatory concern, offers the biological context to facilitate development of IATA for regulatory decision making. This manuscript summarizes discussions at the Workshop entitled "Advancing AOPs for Integrated Toxicology and Regulatory Applications" with particular focus on the role AOPs play in informing the development of IATA for different regulatory purposes.

Breath biomarkers in toxicology

“…The general idea is that the toxicological impact of an exogenous chemical exposure is initiated in the human systems biology and then creates a cascade of subsequent events (typically at the molecular or cellular level) that ultimately lead to an adverse preclinical or clinical outcome (Adeleye et al 2015;Pleil et al 2015;Tollefsen et al 2014). Once an AOP is established from in vivo laboratory study, one small section of the chemical reaction chain is reproduced in vitro to represent the full pathway.…”

An economic approach to non-animal toxicity testing for skin sensitisation

“…The integration of information is characterised as a dynamic process which progresses along with development of non-animal testing methods and the mechanistic understanding of endpoints (Tollefsen et al, 2014;Jaworska, 2016). In the scientific toxicological literature of the past decade a number of criteria have been suggested, seeking to explain "what the ITSs should be" (Jaworska and Hoffmann, 2010), "what the ITS should contain" (Rovida et al, 2015), "what the DAs should be associated with" (OECD, 2016b).…”

“…Publications discussing criteria for developing optimal testing strategies often refer to ITS, however, sets of criteria have also been proposed and discussed for IATA, see e.g. (Tollefsen et al, 2014), and for DA, see e.g. (OECD, 2016b).…”

“…During the past decade, non-animal testing strategies have been developed for several toxicological endpoints. In addition to developing individual methods such as in vitro methods, in silico and in chemico methods, experts in science, industry and regulatory agencies have put a lot of effort in combining non-animal testing methods into toxicity testing strategies (Tollefsen et al, 2014).…”

“…Integrating information from various sources for human health endpoints (ECHA, 2014a;Gocht et al, 2015;Worth and Patlewicz, 2016) such as skin sensitisation and eye irritation (Sauer et al, 2016), repeated dose toxicity and toxicity to reproduction (Gocht et al, 2015) as well as environmental endpoints such as fish toxicity (Nendza et al, 2014) (Tollefsen et al, 2014). Furthermore, the WoE approach has been closely related to the concept of ITS or DA, with the difference being that "...the WoE approach is usually based on existing data while ITS should prospectively address which assays need to be performed ..." (Rovida et al, 2015).…”