New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis

Abstract

The World Health Organization/International Programme on Chemical Safety mode of action/human relevance framework has been updated to reflect the experience acquired in its application and extend its utility to emerging areas in toxicity testing and non-testing methods. The underlying principles have not changed, but the framework's scope has been extended to enable integration of information at different levels of biological organization and reflect evolving experience in a much broader range of potential applications. Mode of action/species concordance analysis can also inform hypothesis-based data generation and research priorities in support of risk assessment. The modified framework is incorporated within a roadmap, with feedback loops encouraging continuous refinement of fit-for-purpose testing strategies and risk assessment. Important in this construct is consideration of dose-response relationships and species concordance analysis in weight of evidence. The modified Bradford Hill considerations have been updated and additionally articulated to reflect increasing experience in application for cases where the toxicological outcome of chemical exposure is known. The modified framework can be used as originally intended, where the toxicological effects of chemical exposure are known, or in hypothesizing effects resulting from chemical exposure, using information on putative key events in established modes of action from appropriate in vitro or in silico systems and other lines of evidence. This modified mode of action framework and accompanying roadmap and case examples are expected to contribute to improving transparency in explicitly addressing weight of evidence considerations in mode of action/species concordance analysis based on both conventional data sources and evolving methods.

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

“…Over the past 15 years, the MOA framework has provided an important scaffold for organizing pathway-based toxicity data (Boobis et al 2006;Meek et al 2014). To the extent possible, MOA knowledge should be taken into account in a WOE of adversity.…”

Risk assessment in the 21st century: Roadmap and matrix

“…Tier 3 consists of the derivation of the key events that lead to an adverse outcome, described as a mode of action (MOA) or adverse outcome pathway (AOP) (Meek et al 2013). This tier is typically more resource intensive in estimating toxicity, unless the MOA is already known for a group of chemicals.…”

International regulatory needs for development ofan IATA for non-genotoxic carcinogenic chemical substances

“…Therefore systematic analysis of the GHS category 1 criteria for multi-species carcinogenicity will be needed to adequately identify NGTxC (Gray et al, 1995), whilst also some uncertainties of this test method in terms of reliability and relevance are recognized (Gottmann et al, 2001;Alden et al, 2011). Additionally, critical MoA information providing insights into the human relevance may be missing (Meek et al, 2014;WHO, 2007), and this is discussed further below.…”