IPCS Conceptual Framework for Evaluating a Mode of Action for Chemical Carcinogenesis

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...…”

Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

“…Generally, these initiatives have been aimed at reducing the unnecessary toxicity testing; however, it is also becoming more common for PPPs to be tested beyond the " standard " requirements and incorporate investigative studies such as MoA to facilitate better characterization of the underlying hazard characteristics to inform the risk assessment and risk management decisions. The MoA/Human Relevance Framework (HRF) developed by the International Programme on Chemical Safety of the World Health Organization , Sonich-Mullin et al 2001 and ILSI , Seed et al 2005 can be used as a template upon which to elucidate the human relevance of eff ects observed in animals. This paper, along with the companion papers , discusses the application of the MoA/HRF approach to a recently registered active substance, sulfoxafl or (CAS# 946578-00-3;XDE-208, X11422208, XR-208, [1-(6-Trifl uormethylpyridin-3-yl)ethyl)](methyl)-oxido-l 4 -sulfanylidenecyanamide).…”

“…This HRF evaluation for sulfoxafl or-induced hepatocellular tumors in mice and rats follows the guideline established for this process (Sonich-Mullin et al 2001, USEPA 2005, Holsapple et al 2006). The extensive toxicological database for sulfoxafl or, including several focused MoA studies in both mice and rats, as well as a study in genetically engineered (knockout and humanized) mice provide the necessary data to establish the CAR-mediated MoA for sulfoxafl or-induced rodent liver tumors.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…When sufficient data are available, use of the benchmark dose (BMD) or benchmark concentration (BMC) approach is preferable to the traditional health-based guidance value approaches (IPCS, 1999a(IPCS, , 2005USEPA, 2000;Sonich-Mullin et al, 2001). The BMDL (or BMCL) is the lower confidence limit on a dose (the BMD) (or concentration, BMC) that produces a particular level of response or change from the control mean (e.g.…”