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

Abstract

(2010) 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, Critical Reviews in Toxicology, 40:8, 671-696, DOI: 10.3109/10408444.2010 R E V I E W A R T I C L EHypothesis-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 exampleLorenz R� Rhomberg, Lisa A� Bailey, and Julie E� Goodman Gradient, Cambridge, Massachusetts, USA AbstractHuman health risk assessment consists of bringing to bear a large body of in vitro, animal, and epidemiologic studies on the question of whether environmental exposures to a substance are a potential risk to humans. The body of scientific information is typically less than definitive and often contains apparent contradictions. Often various possible conclusions about potential human risks may be drawn from the data and these may vary from very strong to tenuous. The task, therefore, is to communicate the uncertainties in the inferences from the data effectively, giving proper consideration to contrary data and alternative scientifically plausible interpretations. We propose an approach, Hypothesis-Based Weight of Evidence (HBWoE), to organize, evaluate, and communicate the large body of available relevant data on a given chemical, using naphthalene as an example. The goal for our use of the term "weight of evidence" (WoE) is broad in that we express the relative degrees of credence that should be placed in alternative possible interpretations of the naphthalene data and hypothesized carcinogenic modes of action (MoAs), expressed in a way that shows how such credence is tied to specific scientific interpretations, considering consistencies, inconsistencies, and contradictions within the data set.

Characterization of the toxicological hazards of hydrocarbon solvents

“…Based on an evaluation of mode of action, Cruzan et al (2009) concluded that these tumors arose as a secondary consequence of the generation of cytotoxic metabolites of CYP2F2 in nasal and lung tissue in mice and CYP2F4 in nasal tissues in rats. Rhomberg and colleagues (2010) explored the hypothesis-based weight of evidence analysis of the naphthalene data in more detail and essentially reached the same conclusions as Cruzan et al (2009), although they could not definitively rule out the involvement of other CYPs such as CYP2E1 and/or other biochemical events such as GSH depletion (Rhomberg et al 2010). Overall, the underlying cancer mechanism, particularly with regard to the proposed involvement of CYP2F enzymes for cumene, naphthalene, styrene, and other similar chemicals remains under investigation, and its relevance to humans is controversial (Cruzan et al 2009, Rhomberg et al 2010).…”

“…Rhomberg et al (2010) concluded that the tumors were most likely the consequence of a cytotoxic (or dual cytotoxic/genotoxic) mode of action although a genotoxic mode of action could not be ruled out. As Rhomberg pointed out, the choice of mode of action is directly related to human relevance as humans…"have insufficient metabolic activation to the naphthalene epoxide to deplete GSH or to create sufficient levels of reactive metabolites so as to produce cytotoxicity, genotoxicity, or both, and without such toxicity, no carcinogenic risk is induced" (Rhomberg et al 2010). Gagnaire et al (1990Gagnaire et al ( , 1991Gagnaire et al ( , 1992 reported that 1,2-diethylbenzene (1,2-DEB) produced a characteristic neurological effect in mice, whereas the other two diethylbenzene isomers (1,3-DEB, 1,4-DEB) were not neurotoxic.…”

“…Questions have been raised as to whether the pulmonary effects in rats and mice were species-specific, due in part to differences in pulmonary physiology (Morris and Buckpitt 2009) and metabolic differences (Buckpitt et al 2002), and the underlying mode of action is controversial (Piccirillo et al 2012). Rhomberg et al (2010) concluded that the tumors were most likely the consequence of a cytotoxic (or dual cytotoxic/genotoxic) mode of action although a genotoxic mode of action could not be ruled out. As Rhomberg pointed out, the choice of mode of action is directly related to human relevance as humans…"have insufficient metabolic activation to the naphthalene epoxide to deplete GSH or to create sufficient levels of reactive metabolites so as to produce cytotoxicity, genotoxicity, or both, and without such toxicity, no carcinogenic risk is induced" (Rhomberg et al 2010).…”

Incorporating Low-Dose Epidemiology Data in a Chlorpyrifos Risk Assessment

“…To determine which study is most appropriate and most consistent with the weight of evidence (WoE), a WoE analysis should be conducted. There are many WoE frameworks available (e.g., Krimsky 2005;ECETOC 2009;Linkov et al 2009;Rhomberg et al 2010;USEPA 2010;Rhomberg et al 2011). The HBWoE framework we used in the Prueitt et al (2011) analysis incorporates several aspects of many of the others and can be summarized in seven steps:…”

Response to Kortenkamp et al. Rebuttal

“…We agree that widely endorsed weight-of-evidence methods are not readily available; indeed, several of us have publicly addressed this very lack and have proposed approaches that might be appropriate for endocrine disruption evaluation (e.g. Borgert et al, 2011;Rhomberg et al, 2010). We cited the WHO/IPCS (2002) approach to this question because, first, it seemed a reasonable approach that would be appropriate to the present case and, second, the SOTA ED itself suggested it was following this approach.…”