IPCS Framework for Analyzing the Relevance of a Noncancer Mode of Action for Humans

Section of Experimental Medicine and Toxicology, Division of Medicine, Imperial College London, London, UK.
Critical Reviews in Toxicology (Impact Factor: 5.1). 02/2008; 38(2):87-96. DOI: 10.1080/10408440701749421
Source: PubMed


Structured frameworks are extremely useful in promoting transparent, harmonized approaches to the risk assessment of chemicals. One area where this has been particularly successful is in the analysis of modes of action (MOAs) for chemical carcinogens in experimental animals and their relevance to humans. The International Programme on Chemical Safety (IPCS) recently published an updated version of its MOA framework in animals to address human relevance (cancer human relevance framework, or HRF). This work has now been extended to noncancer effects, with the eventual objective of harmonizing framework approaches to both cancer and noncancer endpoints. As in the cancer HRF, the first step is to determine whether the weight of evidence based on experimental observations is sufficient to establish a hypothesized MOA. This comprises a series of key events causally related to the toxic effect, identified using an approach based on the Bradford Hill criteria. These events are then compared qualitatively and, next, quantitatively between experimental animals and humans. The output of the analysis is a clear statement of conclusions, together with the confidence, analysis, and implications of the findings. This framework provides a means of ensuring a transparent evaluation of the data, identification of key data gaps and of information that would be of value in the further risk assessment of the compound, such as on dose-response relationships, and recognition of potentially susceptible subgroups, for example, based on life-stage considerations.

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Available from: Bette Meek,
    • "Initially, the focus was on assembling, evaluating, and determining the human relevance of toxicological data for cancer (Sonich-Mullin et al., 2001; Meek et al., 2003; EPA, 2005; Boobis et al., 2006). This framework was then extended to include non-cancer outcomes (Seed et al., 2005; Boobis et al., 2008). The MOA framework has many similarities with the AOP framework. "
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    ABSTRACT: The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high throughput toxicity testing (HTT) and other results to potential impacts on humans and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways in order to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables Integrated Approaches to Testing and Assessment (IATA), which incorporate results of assays at various levels of biological organization including in silico, HTT, chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME), and an AOP describing the biological basis of toxicity. It's envisaged, then, that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research where a higher precision is needed based on the decision context.
    Journal of Pharmacology and Experimental Therapeutics 11/2015; DOI:10.1124/jpet.115.228239 · 3.97 Impact Factor
    • "The first focuses on the logic and scientific evidence underpinning an AOP. An adaption of Bradford-Hill criteria for assessing causality , first used in assessing the value of MOA pathways (Boobis et al., 2008; Meek et al., 2014), has been developed to transparently evaluate the plausibility and scientific support for elements of an AOP (Becker et al., 2015; Hill, 1965; OECD, 2013b). Here, confidence is based on expert judgment of the amount and quality of data supporting (1) Biological plausibility of KE relationships; (2) Essentiality of KEs in context of the entire AOP; and (3) Empirical support for dose-response, temporality, and consistency of KE relationships. "
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    ABSTRACT: Adverse outcome pathways (AOPs) offer a pathway-based toxicological framework to support hazard assessment and regulatory decision-making. However, little has been discussed about the scientific confidence needed, or how complete a pathway should be, before use in a specific regulatory application. Here we review four case studies to explore the degree of scientific confidence and extent of completeness (in terms of causal events) that is required for an AOP to be useful for a specific purpose in a regulatory application: (i) Membrane disruption (Narcosis) leading to respiratory failure (low confidence), (ii) Hepatocellular proliferation leading to cancer (partial pathway, moderate confidence), (iii) Covalent binding to proteins leading to skin sensitization (high confidence), and (iv) Aromatase inhibition leading to reproductive dysfunction in fish (high confidence). Partially complete AOPs with unknown molecular initiating events, such as 'Hepatocellular proliferation leading to cancer', were found to be valuable. We demonstrate that scientific confidence in these pathways can be increased though the use of unconventional information (eg, computational identification of potential initiators). AOPs at all levels of confidence can contribute to specific uses. A significant statistical or quantitative relationship between events and/or the adverse outcome relationships is a common characteristic of AOPs, both incomplete and complete, that have specific regulatory uses. For AOPs to be useful in a regulatory context they must be at least as useful as the tools that regulators currently possess, or the techniques currently employed by regulators.
    Toxicological Sciences 10/2015; 148(1):14-25. DOI:10.1093/toxsci/kfv181 · 3.85 Impact Factor
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    • "Advance Publication: Not Copyedited 6 methods with a clearly defined toxicity prediction goal, and (3) applying existing information (e.g., physical chemical properties, in vivo animal data, human data) and with selected data generated from alternative methods, achieve a regulatory accepted safety assessment, based on MoA knowledge of the compound. MoA describes a biological response to a specific chemical challenge, while an Adverse Outcome Pathway is a conceptual construct describing biological activities, beginning with a molecular initial event (MIE), and progressing through different biological levels to an observable adverse effect in a population (Ankley et al. 2010; Boobis et al. 2008). AOP constructs primarily related to hepatotoxicity were developed within SEURAT-1 (Landesmann and Vinken 2013), and included in the inventories of the AOP Development Programme (OECD 2013b) and the AOP Wiki (OECD 2014a), initiatives of the Organisation for Economic Cooperation and Development (OECD). "

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