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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    • "Critical effects warranting a higher confidence result in risk management decisions that have a firmer foundation. References (Boobis et al., 2006; Boobis et al., 2008; United States Environmental Protection Agency, 2002) If the figures and tables are developed using a consistent approach, comparisons of uncertainty across different chemical toxicity values could be made more easily. For example, this approach facilitates rapid visual comparison of the confidence scoring inFig. "
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    ABSTRACT: Single point estimates of human health hazard/toxicity values such as a reference dose (RfD) are generally used in chemical hazard and risk assessment programs for assessing potential risks associated with site- or use-specific exposures. The resulting point estimates are often used by risk managers for regulatory decision-making, including standard setting, determination of emission controls, and mitigation of exposures to chemical substances. Risk managers, as well as stakeholders (interested and affected parties), often have limited information regarding assumptions and uncertainty factors in numerical estimates of both hazards and risks. Further, the use of different approaches for addressing uncertainty, which vary in transparency, can lead to a lack of confidence in the scientific underpinning of regulatory decision-making. The overarching goal of this paper, which was developed from an invited participant workshop, is to offer five approaches for presenting toxicity values in a transparent manner in order to improve the understanding, consideration, and informed use of uncertainty by risk assessors, risk managers, and stakeholders. The five approaches for improving the presentation and communication of uncertainty are described using U.S. Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) as a case study. These approaches will ensure transparency in the documentation, development, and use of toxicity values at EPA, the Agency for Toxic Substances and Disease Registry (ATSDR), and other similar assessment programs in the public and private sector. Further empirical testing will help to inform the approaches that will work best for specific audiences and situations.
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    • "This motivation has resulted in MOA case studies that are primarily defined by the chemical(s) used to elicit the organismal response. Since MOA analysis has focused on the application of mechanistic data in the assessment of specific chemicals, it addresses both toxicokinetics (in species concordance analysis) and metabolism (as a KE) (Boobis et al., 2006Boobis et al., , 2008 Meek, 2008; Meek et al., 2014a,b). Indeed, several highly cited MOA case studies include metabolic activation of the chemical (Meek et al., 2003; Seed et al., 2005) as a KE in the MOA. "
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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.
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    • "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.
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