Article

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

ABSTRACT

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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    • "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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