Adverse Outcome Pathways, Key Events and Radiation Risk Assessment.

PURPOSE The overall aim of this contribution to the "Second Bill Morgan Memorial Special Issue" is to provide a high-level review of a recent report developed by a Committee for the National Council on Radiation Protection and Measurements (NCRP) titled "Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment". It derives from previous NCRP Reports and Commentaries that provide the case for integrating data from radiation biology studies (available and proposed) with epidemiological studies (also available and proposed) to develop Biologically-Based Dose- Response (BBDR) Models. In the present review it is proposed for such models to leverage the Adverse Outcome Pathways (AOP) and Key Events (KE) approach for better characterizing radiation-induced cancers and circulatory disease (as the example for a noncancer outcome). The review discusses the current state of knowledge of mechanisms of carcinogenesis, with an emphasis on radiation-induced cancers, and a similar discussion for circulatory disease. The types of the various informative BBDR models are presented along with a proposed generalized BBDR model for cancer and a more speculative one for circulatory disease. The way forward is presented in a comprehensive discussion of the research needs to address the goal of enhancing health risk assessment of exposures to low doses of radiation. CONCLUSION The use of an AOP/KE approach for developing a mechanistic framework for BBDR models of radiation-induced cancer and circulatory disease is considered to be a viable one based upon current knowledge of the mechanisms of formation of these adverse health outcomes and the available technical capabilities and computational advances. The way forward for enhancing low-dose radiation risk estimates will require there to be a tight integration of epidemiology data and radiation biology information to meet the goals of relevance and sensitivity of the adverse health outcomes required for overall health risk assessment at low doses and dose rates.