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.

Everything you wanted to know about space radiation but were afraid to ask

“…Limitations in the ability to translate study outcomes into equivalent health consequences in humans also result from critical disparities, usually disease-specific, between the animal models and the human subject in clinical trials and space missions, for example the development of harderian gland tumors which only appear in mice. 10,11,29 Additionally, because nonhuman mammals are genetically different from humans, they may yield results that are difficult to interpret. A growing list of genes is known to affect radiation sensitivity phenotypes for numerous radiation effects, such as molecular, chromosomal, signal transduction associated growth-regulating changes, cell killing, tumor acute and late effects, and animal carcinogens.…”

How certain are we? Development of an ensemble based framework for assessing astronaut cancer risks from space radiation

“…Likewise, it is assumed that the biological response from a mixed-field irradiation (in particle type and energy), as would be found in space, can be determined by simple additivity or by directly adding responses from individual ions and energies. However, results for Harderian gland tumorigenesis [Siranart et al 2016] and lung cancer tumorigenesis [Luitel et al 2020] in murine models suggest that synergies between particles may exist and that more complex additivity models need to be considered. Emerging models for non-targeted effects (NTE), which have a significant influence on low-dose extrapolations expressed through RBEs, are being developed and have been shown to significantly impact radiation quality factors Cacao 2017, Matsuya et al 2018].…”

Synergy theory for murine Harderian gland tumours after irradiation by mixtures of high-energy ionized atomic nuclei

“…When the SEA synergy theory is inappropriate, an IEA baseline NSNA mixture DER I(d) has a number of conceptual and practical advantages over other replacements for S(d) (Siranart et al 2016). This subsection defines the elementary version of IEA synergy theory, which suffices for the present paper; an advanced version (Ham et al 2018) is in general preferred; this advanced IEA version is described in Online Resources 1, parts W3 and W4.…”

“…The present paper will use a replacement for SEA theory called incremental effect additivity (IEA). IEA theory was introduced in two recent papers (Siranart et al 2016;Ham et al 2018). "Incremental" refers to the fact that one-ion DER slopes play an essential role in the theory.…”

“…The two recent references (Siranart et al 2016;Ham et al 2018) that introduced IEA, after reviewing many other synergy theories, gave evidence that IEA synergy theory is probably the optimal substitute for SEA synergy theory.…”