Scaling Human Cancer Risks from Low LET to High LET when Dose-Effect Relationships are Complex

Health risks from space radiations, particularly from densely ionizing radiations, represent an important challenge for long-ranged manned space missions. Reliable methods are needed for scaling low-LET to high-LET radiation risks for humans, based on animal or in vitro studies comparing these radiations. The current standard metric, relative biological effectiveness (RBE) compares iso-effect doses of two radiations. By contrast, a proposed new metric, radiation effects ratio (RER), compares effects of two radiations at the same dose. This definition of RER allows direct scaling of low-LET to high-LET radiation risks in humans at the dose or doses of interest. By contrast to RBE, RER can be used without need for detailed information about dose response shapes for compared radiations. This property of RER allows animal carcinogenesis experiments to be simplified by reducing the number of tested radiation doses. For simple linear dose-effect relationships, RBE = RER. However, for more complex dose-effect relationships, such as those with nontargeted effects at low doses, RER can be lower than RBE. We estimated RBE and RER values and uncertainties using heavy ion (¹²C, ²⁸Si, ⁵⁶Fe) and gamma-ray-induced tumors in a mouse model for intestinal cancer (APC^1638N/+), and used both RBE and RER to estimate low-LET to high-LET risk scaling factors. The data showed clear evidence of nontargeted effects at low doses. In situations, such as the ones discussed here where nontargeted effects dominate at low doses, RER was lower than RBE by factors around 2.8-3.5 at 0.03 Gy and 1.3-1.4 at 0.3 Gy. It follows that low-dose high-LET human cancer risks scaled from low-LET human risks using RBE may be correspondingly overestimated.