Hazard characterization mechanistic data

Overall, cancer risk assessment involves the four steps of hazard identification, dose-response, exposure assessment, and risk characterization. The dose-response curve established for cancer potency derivation for a chemical is based on evaluation of data on the carcinogenicity and dose-response characteristics of the chemical. The pharmacokinetics and mechanistic data evaluation (e.g., genotoxic or nongenotoxic) and a dose-response review of all adequate bioassays are conducted to determine, if target dose estimates or a dose-response model different from the default may be suggested. 

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, enviromnental exposures, then the issues that cover the necessary defaults are as follows (see Rart I, this volume) ... 

Mechanistic data for cancer are considered in hazard characterization in the context of mode of induction of toxic effects. A postulated mode of action is a biologically plausible sequence of key events leading to an observed effect supported by robust experimental observations and mechanistic data. It describes key cytologi-cal, genetic, and biochemical events— that is, those that are both measurable and necessary to the observed effect. Mode of action is contrasted with mechanism of action, which generally involves a much greater understanding of the molecular basis for an effect. 

Chapter 21 achieves this collective human health hazard characterization for lead via a ranking of the component human adverse health effects with respect to thoroughness and quality of the data, the relative sensitivity or ranges of sensitivities of the toxic responses with reference to typical ambient or occupational Pb exposures, the relative gravity of the toxic response in terms of both injury and persistence/irreversibiUty, and reliable supporting evidence from experimental and mechanistic data. 

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