What do Risk Modelers Want? What Can Biologists Provide?

Speaker
Michael M. Weil

Description
Biologically based dose-response (BBDR) models are used frequently for assessing radiation associated health risks, particularly for exposure scenarios with limited epidemiological data. This presentation, which draws heavily on NCRP Report No. 186, Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment, will delve into what biological data are needed to provide parameters for BBDR models for cancer risks and the technologies and experimental approaches available to generate these types of data. BBDR model inputs can include the kinetics of clonal expansion and cell loss amongst cells comprising nascent tumors and the rates at which critical mutations and epigenetic alterations are acquired at key steps in the carcinogenic process. The crucial empirical data needed are those that describe how radiation induces or modifies these factors. A major challenge in deciding which particular biologic data are relevant for incorporation into a BBDR model is that the molecular and cytogenetic signatures of most radiogenic cancers are largely unknown. There are multiple pathways to cancer, but radiation acts only through a subset of them. Knowing which carcinogenic pathway is employed by a particular radiogenic tumor type is requisite to knowing which cells, beginning with the cell of origin, are at risk at key points along the pathway, which mutations must accrue, and how these mutations accelerate or impede subsequent events. Thus, experimental approaches are needed to sort out which pathways are likely to be exploited by radiogenic tumors and which are not. Having molecular and cytogenetic data from tumors arising in irradiated animals can guide this effort. Another challenge will be in the actual data collection. This will require the use of newly emerging technologies including methodological advances for accurately detecting very rare somatic mutations, single cell sequencing, engineered human tissues and cells, and humanized experimental animals. As noted in NCRP Report 186, these technologies are advancing rapidly. Since technological advancements are often driven by necessity, it is important to clearly define what data are needed. There is an obvious need for methods that can quantify processes such as proliferation and loss in vivo in the very few target cells that may eventually give rise to a tumor but are otherwise indistinguishable from other more numerous cells of the same lineage and differentiation stage. Finally, this presentation will ask what model radiogenic tumors in animals can be used to test how well BBDR models predict risk. Appropriate models will allow exposure conditions, background genetic susceptibility and other factors to be modified resulting in a range of outcomes.

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