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

Abstract

The use of structured frameworks can be invaluable in promoting harmonization in the assessment of chemical risk. IPCS has therefore updated and extended its mode of action (MOA) framework for cancer to address the issue of human relevance of a carcinogenic response observed in an experimental study. The first stage is to determine whether it is possible to establish an MOA. This comprises a series of key events along the causal pathway to cancer, identified using a weight-of-evidence approach based on the Bradford Hill criteria. The key events are then compared first qualitatively and then quantitatively between the experimental animals and humans. Finally, a clear statement of confidence, analysis, and implications is produced. The IPCS human relevance framework for cancer provides an analytical tool to enable the transparent evaluation of the data, identification of key data gaps, and structured presentation of information that would be of value in the further risk assessment of the compound, even if relevancy cannot be excluded. This might include data on the shape of the dose-response curve, identification of any thresholds and recognition of potentially susceptible subgroups, for example, the basis of genetic or life-stage differences.

Hypothesis-based weight of evidence: A tool for evaluating and communicating uncertainties and inconsistencies in the large body of evidence in proposing a carcinogenic mode of action—naphthalene as an example

“…arises� Although it is often not explicit, the basic rationale for these schemes is based on the "universality" idea discussed at the outset of this paper-that observations in one setting suggest that similar results would be obtained in other settings, including the setting of the human population being protected� MoA does come in, but usually as a secondary factor and not in a particularly formal way� That is, existence of multiple positive studies is taken as evidence that effect is not specific to one species/system/study and may therefore be general� The justifying arguments for this assertion usually flow from policy, precedent, analogy with other cases, etc�, rather than from case-specific inferences� In WoE, judgment is necessary, but what the rationale and reasoning for conclusions may be is rarely explicit� This leads to disputation of the judgments based largely on ad hominem considerations-who is judging (and whether they are "unbiased") rather than on the soundness of their judgments per se� Our approach is aimed at making the connection between judgments and case-specific evidence more explicit� In this way, the discussion can focus on the scientific interpretation of specific observations and the degree to which that interpretation is supported by those observations, rather than on who is making the interpretation� It should foster a more scientific and objective evaluation of WoE� To the degree that the issues come down to evaluation of MoA, the soundness of the MoA conclusions for the animal studies and the question of whether humans have the same MoA elements, the HBWoE method is complementary to the Human Relevance/MoA framework (Boobis et al�, 2006;Cohen et al�, 2003;Meek et al�, 2003;Sonich-Mullin et al�, 2001)� Our approach makes more explicit how one should evaluate the MoA information, and it shows the value of looking beyond just the single-animal model in which the response is seen to consider what happens (and what does not happen) in other nontarget species and tissues� It calls attention to the role of inconsistent information, not just to the plausibility of the proposed MoA elements in setting where they produced the endpoint of interest� It emphasizes the role of wider scientific understanding in judging what reasonable inferences are, and it points out the pitfalls of post hoc reasoning about the potential role of MoA elements (remembering the example of direct air contact explaining the location of tumors)� HBWoE comes down to evaluation of alternative "accounts� " An account (which we put forth in this context as a technical term) is a proposed set of explanations for the set of observed phenomena across the body of relevant observations� The essence of the accounts is that they constitute being explicit about Bradford Hill's "ways of explaining the set of facts before us� " They are not conclusions or findings, but rather provisional proposals for the reasons behind the set of observations we have at hand, set out in a way that makes clear where assumptions, interpretations, and tentative inferences have been drawn� It is by comparing alternative accounts-alternative hypotheses about what causal effects actually exist-and assessing: their comparative success at explaining phenomena; their comparative need for assumptions to fill in gaps (and the comparative reasonableness of those assumptions); and their comparative invocation of ad hoc suppositions that are necessary to accommodate what might otherwise be inexplicable results, that we can judge how compelling each alternative should be deemed, and hence with what degree of confidence we can judge the hypothesized causal processes (and their consequences for human risk estimation) to be supported by the factual r...…”

Statement of EFSA on the scientific evaluation of two studies related to the safety of artificial sweeteners

“…Biological significance of the findings EFSA noted that there is a general consensus in the scientific community backed up by a considerable body of evidence that hepatic tumours in mice when induced by non-genotoxic compounds can be considered as irrelevant for human risk assessment (Gold and Slone, 1995;Carmichael et al, 1997;Boobis et al, 2006;Holsapple et al, 2006;Billington et al, 2010). The lack of genotoxicity of aspartame has been demonstrated in several standard in vivo genotoxicity studies and moreover it was not carcinogenic in several models of transgenic mice, particularly sensitive to genotoxic agents.…”

Key scientific issues relevant to the identification and characterisation of endocrine disrupting substances—Report of the Endocrine Disrupters Expert Advisory Group

“…It was agreed that it was often difficult to demonstrate convincingly the non-relevance to humans of adverse effects observed in the animal models and that the usual approach was to assume relevance unless non-relevance to humans could be convincingly demonstrated by, for example, applying the guidance provided by the IPCS mode of action and human relevancy framework (Boobis et al, 2008).Thus relevance to humans should be assumed by default in the absence of appropriate scientific data demonstrating non relevance.…”

“…A substance may be shown to be endocrinally active usually through in vitro mechanistic assays demonstrating for example receptor binding/(in)activation or interference with hormone production, however, such activity may not be expressed in vivo and the link to an adverse outcome is not provided by evidence of such endocrine activity alone. In the context of the IPCS mode of action and human relevancy framework (Boobis et al, 2008(Boobis et al, & 2009 whereby mode of action is defined as "The biologically plausible sequence of key events, starting with the interaction of an agent with a cell, through functional and anatomical changes leading to an observed effect supported by robust experimental observations and mechanistic data" the causal link is embedded in the definition.…”