title: Mixed Beam Murine Harderian Gland Tumorigenesis: Predicted Dose-Effect Relationships if neither Synergism nor Antagonism Occurs.
abstract: Complex mixed radiation fields exist in interplanetary space, and little is known about their late effects on space travelers. In silico synergy analysis default predictions are useful when planning relevant mixed-ion-beam experiments and interpreting their results. These predictions are based on individual dose-effect relationships (IDER) for each component of the mixed-ion beam, assuming no synergy or antagonism. For example, a default hypothesis of simple effect additivity has often been used throughout the study of biology. However, for more than a century pharmacologists interested in mixtures of therapeutic drugs have analyzed conceptual, mathematical and practical questions similar to those that arise when analyzing mixed radiation fields, and have shown that simple effect additivity often gives unreasonable predictions when the IDER are curvilinear. Various alternatives to simple effect additivity proposed in radiobiology, pharmacometrics, toxicology and other fields are also known to have important limitations. In this work, we analyze upcoming murine Harderian gland (HG) tumor prevalence mixed-beam experiments, using customized open-source software and published IDER from past single-ion experiments. The upcoming experiments will use acute irradiation and the mixed beam will include components of high atomic number and energy (HZE). We introduce a new alternative to simple effect additivity, "incremental effect additivity", which is more suitable for the HG analysis and perhaps for other end points. We use incremental effect additivity to calculate default predictions for mixture dose-effect relationships, including 95% confidence intervals. We have drawn three main conclusions from this work. 1. It is important to supplement mixed-beam experiments with single-ion experiments, with matching end point(s), shielding and dose timing. 2. For HG tumorigenesis due to a mixed beam, simple effect additivity and incremental effect additivity sometimes give default predictions that are numerically close. However, if nontargeted effects are important and the mixed beam includes a number of different HZE components, simple effect additivity becomes unusable and another method is needed such as incremental effect additivity. 3. Eventually, synergy analysis default predictions of the effects of mixed radiation fields will be replaced by more mechanistic, biophysically-based predictions. However, optimizing synergy analyses is an important first step. If mixed-beam experiments indicate little synergy or antagonism, plans by NASA for further experiments and possible missions beyond low earth orbit will be substantially simplified.
authors.affiliation: a Department of Mathematics, University of California at Berkeley, Berkeley, California.
authors.forename: Nopphon
authors.initials: N
authors.lastname: Siranart
authors.affiliation: b Biosciences Area, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Eleanor A
authors.initials: EA
authors.lastname: Blakely
authors.affiliation: a Department of Mathematics, University of California at Berkeley, Berkeley, California.
authors.forename: Alden
authors.initials: A
authors.lastname: Cheng
authors.affiliation: a Department of Mathematics, University of California at Berkeley, Berkeley, California.
authors.forename: Naval
authors.initials: N
authors.lastname: Handa
authors.affiliation: a Department of Mathematics, University of California at Berkeley, Berkeley, California.
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Sachs
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000528:radiation effects*; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D019295:Computational Biology / Q000379:methods*; D004307:Dose-Response Relationship, Radiation; D006243:Harderian Gland / Q000473:pathology* / Q000528:radiation effects*; D012984:Software