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Framework Analysis for Determining Mode of Action & Human Relevance
Citation:
PRESTON, J. Framework Analysis for Determining Mode of Action & Human Relevance. Chapter 13, Gene Hsu, and Todd Stedeford (ed.), Cancer Risk Assessment: Chemical Carcinogenesis, Hazard Evaluation, and Risk Quantification. John Wiley & Sons, Inc, Hoboken, NJ, , 363-376, (2010).
Impact/Purpose:
Book Chapter - framework based on the mode of action of a chemical, the key events that define a particular mode of action, and a human arelevance framework for assessing the plausibility of an animal mode of action to humans.
Description:
The overall aim of a cancer risk assessment is to characterize the risk to humans from environmental exposures. This risk characterization includes a qualitative and quantitative risk characterization that relies on the development of separate hazard, dose- response and exposure assessments. The specific approach currently used by the U.S. Environmental Protection Agency (U.S. EPA) can be found in its Guidelines for Carcinogen Risk Assessment (EPA, 2005). A similar approach is applied by other national and international organizations. In general terms, the risk characterization summarizes, in a narrative form, the analyses of hazard, dose-response and exposure assessment. These three assessment are summarized in light of “the extent and weight of evidence, major points of interpretation and rationale for their selection, strengths and weaknesses of the evidence and the analysis, and [a discussion] of alterative conclusions and uncertainties that deserve serious consideration” (EPA, 2000). This summary serves as the starting materials for the overall risk characterization process that completes the risk assessment. This chapter will concentrate on a specific feature of this risk characterization process, namely the importance of developing approaches for incorporating mechanistic data into the hazard, dose-response and exposure assessments to reduce uncertainties in the process and thereby reduce the reliance on default factors that are used in the absence of reliable data. Given that the risk characterization is for the estimation of risks to humans from low, environmental exposures, then the issues that cover the necessary defaults are: • Is the presence or absence of effects observed in a human population predictive of effects in another exposed human population? • Is the presence or absence of effects observed in an animal population predictive of effects in exposed humans? • How do metabolic pathways relate across species and among different age groups and between sexes in humans? • How do toxicokinetic processes relate across species and among different age groups and between sexes in humans? • What is the relationship between the observed dose-response relationship to the relationship at lower doses? These issues are ones of extrapolation and as noted by Preston (2005) such extrapolations are “the Achilles heel of risk assessment”. The U.S. EPA, The International Program on Chemical Safety (IPCS) and The International Life Sciences Institute (ILSI), for example, have proposed a framework based on the mode of action of a chemical, the key events that define a particular mode of action, and a human relevance framework for assessing the plausibility of an animal mode of action to humans. It is this approach that will be described and discussed in this chapter.