Reflections on Basic Science Studies Involving Low Doses of Ionizing Radiation

Abstract

Investigation of health effects of low doses of radiation as a field of study has been riddled with difficulties since its inception. In this document we will use 100 mGy as the cutoff upper limit for low-dose radiation, borrowing this definition from the U.S. Department of Energy, although other agencies and researchers sometimes include up to five-fold higher doses under the same title. Difficulties in this area of research are most often ascribed to the fact that effects of low doses of radiation are subtle and difficult to distinguish from the plethora of other low-grade stresses. Thus, for example, most epidemiological studies include hundreds of thousands of samples and generate risk estimates that are statistically meaningful only when they are considered on a scale of hundreds or thousands of people. A logical approach to remedy the situation for low-dose research was to conduct well-controlled animal studies with hundreds of animals; nevertheless, even after many such studies were completed, our understanding of the biological basis for risk from low-dose radiation exposure is still not conclusive. In this paper we argue that the problem lies in the fact that our approach to animal studies is not comprehensive but conceptually binary. While some researchers apply epidemiological models to animal data, others look into molecular and cellular biology only. Very few studies are conducted to bridge this gap and consider how a realistic model of DNA damage could be integrated into a realistic model of radiation carcinogenesis.

Figure 1.

Many issues need to be considered in basic science exploration of low dose radiation effects and we propose that it should be possible to model them as well. This illustration is far from a complete view of the situation, nevertheless it conceptualizes some of the most important questions that require additional basic science research. A set of gauges at the left side of the image represent different aspects of radiation exposure such as radiation quality, dose and dose rate, fractionation and protraction, and other physical aspects of radiation exposure such as entire or partial volume of the cell, organ or organism exposed. Images in yellow plane represent cellular communications, physiological and molecular environment of an irradiated cell. Each cell is in constant communication with its environment as a part of a whole organism – with its immediate cell neighbors to which it is connected by tight junctions, with mobile cells such as red blood cells as well as “foreign” cells and agents such as bacteria. Cellular environment also includes extracellular matrix, exosomes, protein ligands, multitude of cytokines, chemokines, hormones, free ions etc. Images in orange plane represent different structural components of cellular organization, from organelles and their sub-parts to their component macromolecules and different structural aspects of their organization. In this context, DNA would be examined at all levels of organization - from its sequence to its 3D organization within chromatin and numerous structural and chemical modifications. White panel on the right side of the figure is depicting six kingdoms of living organisms [adapted from (Cavalier-Smith 1998)] and the fact that organisms from all kingdoms of life cohabit same space and respond to stresses in a complex manner and in so doing affect one another. In the beige colored plane are many clocks. This drawing conceptually represents the importance of time and timing for all aspects of biological responses to radiation exposures. The time that the cell has for repair of radiation damage before it encounters another stress or responds to a physiological stimulus is critical for maintenance of cellular homeostasis. Equally important are “age” of a cell, age of the organism as a whole, etc. With the development of new computational approaches, we are nearing the situation where we may be able to integrate all of these different data (especially if we are using prospective “wet bench” and animal experiments) into multi-dimensional models.