Basic radiobiology

Experimental studies of the biological effects of radiation were started soon after the discoveries of x-rays in 1895, but there is still much that is not known. This article includes some research objectives that are essentially pragmatic in nature, intended to support and improve the current practice of radiotherapy, but the central thrust is the understanding of the mechanisms involved in the biological effects of radiation at the cellular and molecular levels. The article was written by a consortium of scientists and suffers inevitably from the drawback that writing styles are inconsistent, and coverage is not uniform. However, it benefits from the enormous advantage that it reflects the accumulated wisdom and judgment of more than a dozen scientists who, in their own areas of expertise, are recognized as being at the cutting edge of radiation research. The niceties of style and syntax are sacrificed in favor of the quality of the science and the maturity of judgment. The study of DNA damage as a mechanism for cell injury in early- and late-responding tissues, as well as a comparison of DNA damage that leads to lethality, as opposed to transformation and mutagenesis, are key items. The study of cell lethality with cells in culture led to the identification of repair, both sublethal and potentially lethal, as well as the dose-rate effect, and has had a considerable impact on radiotherapy. Future studies should focus on understanding the factors that determine radiosensitivity/radioresistance. A variety of approaches are available, including the study of genetically deficient cell lines from cancer-prone individuals. A parallel approach is the application of the techniques of molecular biology to clone the repair genes in mammalian cells, and to understand genetic defects that alter gene regulation, or to regulate biochemical factors in the cell. Substantial progress has been made in developing in vitro assays for mutagenesis, particularly using hybrids of rodent and human cells. Better methods are needed to study the effects of mutation on gene expression, and sensitive systems are needed that can detect low doses of radiation. Assays of oncogenic transformation, the in vitro counterpart of carcinogenesis, have been used to investigate the oncogenic potential of various types of radiation and chemotherapy agents. Key topics in future will include the investigation of supra-additivity between different agents, the identification and characterization of oncogenes that may be activated by radiation, the development of quantitative assays based on human cells, and further studies involving cell-to-cell communication. Chromosome aberrations represent the earliest observable biological effects of exposure to radiation. Future research should be designed to identify the molecular lesions involved in aberration production, and to elucidate the details of chromatin structure, control of gene expression, and the interaction of chromatin with the nuclear matrix. It will also be important to know the relative importance of different chromosome rearrangements in radiation-induced mutagenesis and oncogenesis. Cytogenetics must be considered to have an important place in the assessment of health hazards from radiation exposure, and in predictive assays of radiation response in individual patients receiving radiotherapy. Carcinogenesis experiments in laboratory animals must focus on questions that cannot be addressed adequately in the Petri dish. Dose-response relationships for radiations of different quality and for tumors of different types are still needed, with the interaction between radiation and other potential carcinogens becoming of increasing concern. Studies of factors that modify carcinogenesis, whether exogenous, endogenous, or a result of genetic background, are vital to understand the mechanisms of carcinogenesis, which may in turn suggest ways of prevention. Models of radiation have played their part in the developments of concepts concerning cell lethality and the production of chromosome aberrations. What is needed in the future are models of carcinogenesis in whole organisms, taking into account as many as possible of the complex variables involved.