Application of Key Events Analysis to Chemical Carcinogens and Noncarcinogens

Abstract

The existence of thresholds for toxicants is a matter of debate in chemical risk assessment and regulation. Current risk assessment methods are based on the assumption that, in the absence of sufficient data, carcinogenesis does not have a threshold, while noncarcinogenic endpoints are assumed to be thresholded. Advances in our fundamental understanding of the events that underlie toxicity are providing opportunities to address these assumptions about thresholds. A key events dose-response analytic framework was used to evaluate three aspects of toxicity. The first section illustrates how a fundamental understanding of the mode of action for the hepatic toxicity and the hepatocarcinogenicity of chloroform in rodents can replace the assumption of low-dose linearity. The second section describes how advances in our understanding of the molecular aspects of carcinogenesis allow us to consider the critical steps in genotoxic carcinogenesis in a key events framework. The third section deals with the case of endocrine disrupters, where the most significant question regarding thresholds is the possible additivity to an endogenous background of hormonal activity. Each of the examples suggests that current assumptions about thresholds can be refined. Understanding inter-individual variability in the events involved in toxicological effects may enable a true population threshold(s) to be identified.

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

“…"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" (Boobis et al, 2009). In addition "Mode of action differs from mechanism in that the latter implies a more detailed understanding of the molecular basis of the toxic effect" (Seed at al, 2005).…”

“…Whilst acknowledging that absolute proof of causation might be too high a requirement in establishing a substance as an endocrine disrupter, a biologically plausible linkage between the activity of the chemical in producing the alteration of the endocrine system and an observed adverse effect would need to be accepted as the most likely underlying explanation. Such a causal chain of events from initial interaction of a substance with its target site in the organism through to the adverse outcome was seen to be encapsulated in the definition of mode of action (Boobis et al, 2009) and are key in the development of Adverse Outcome Pathways (Ankley et al, 2010). During the discussion it became obvious, that the type and amount of information needed to demonstrate a biologically plausible linkage depend on the mode of action and the type of effects observed (see discussion under 3.1.2, 3.1.3 and 4).…”

“…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.…”

DNA Reactivity as a Mode of Action and Its Relevance to Cancer Risk Assessment

“…41, No. 2, 2013 DNA REACTIVITY AND CANCER RISK ASSESSMENTcurve, quite possibly having an initial threshold for response (Boobis et al 2009). …”

Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrichet al.

“…They do not, however, provide scientific support for this position. Instead, they list several references (Boobis et al, 2009;Piersma et al, 2011;Rhomberg et al, 2011;Borgert et al, 2012;Rhomberg & Goodman, 2012) that, upon examination, do not contain data supporting their assumption but rather simply assert that the assumption is true. They also fail to address the considerable literature that speaks against that assumption (e.g., Sheehan & vom Saal, 1997;vom Saal & Sheehan, 1998;Sheehan et al, 1999;Welshons et al, 2003;Sheehan, 2006).…”