Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

The radiation space environment includes particles such as protons and mult iple species of heavy ions, with much of the exposure to these radiations o ccurring at extremely low average dose-rates. Limitations in databases need ed to predict cancer hazards in human beings from such radiations are signi ficant and currently do not provide confidence that such predictions are ac ceptably precise or accurate. In this article, we outline the need for anim al carcinogenesis data based on a more sophisticated understanding of the d ose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a mode l that can interrelate human and animal carcinogenesis data with cellular m echanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model'', we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more pr ecisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We ha ve measured induction of complex chromosome aberrations in multiple cell ty pes by two space radiations, Fe-ions and protons, and compared these to pho tons delivered at high dose-rate or low dose-rate. Our data demonstrate tha t at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose- rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6 - and 3-fold variability. These data demonstrate the need to understand bet ter the role of intrinsic radiosensitivity and dose-rate effects in mammali an cell response to ionizing radiation. Such understanding is critical in e xtrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool f or such extrapolation. (C) 1999 Elsevier Science B.V. All rights reserved.