“…12, 13 and Chang et al . 14 , respectively for the dose response for Harderian gland tumor prevalence. Error bars represent standard errors in the experiments.Figure 2Comparison of targeted effects (TE) and non-targeted effects (NTE) models for proton and helium beams to the experiment of Alpen et al .…”
Section: Resultsmentioning
confidence: 99%
“…Results are compared to a recently published study using a LET dependent model fit to the same data 14 , and then applied to predictions of GCR exposures. In the remainder of this paper, we first discuss a Hazard function for TP using a track structure model consistent with either TE and NTE models.…”
Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-set for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth’s geomagnetic sphere.
“…12, 13 and Chang et al . 14 , respectively for the dose response for Harderian gland tumor prevalence. Error bars represent standard errors in the experiments.Figure 2Comparison of targeted effects (TE) and non-targeted effects (NTE) models for proton and helium beams to the experiment of Alpen et al .…”
Section: Resultsmentioning
confidence: 99%
“…Results are compared to a recently published study using a LET dependent model fit to the same data 14 , and then applied to predictions of GCR exposures. In the remainder of this paper, we first discuss a Hazard function for TP using a track structure model consistent with either TE and NTE models.…”
Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-set for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth’s geomagnetic sphere.
“…The present study uses new DERs for the one-ion data. These are more parsimonious (i.e., have fewer adjustable parameters) than other recent models (Cucinotta et al 2013b;Chang et al 2016;Cucinotta and Cacao 2017) for the same data. Because of the parsimony, the new models are of possible interest in their own right.…”
Section: Introductionmentioning
confidence: 98%
“…These often have high relative biological effectiveness (RBE) for various kinds of biological damage (reviewed, e.g., in Cucinotta and Cacao 2017;Goodhead 2018). In particular, murine Harderian gland (HG) tumourigenesis induced, in accelerator beam experiments, by individual ions in the GCR spectrum, with some of the HZE having high RBEs, has long been a NASA concern (Fry et al 1985;Curtis et al 1992;Alpen et al 1993Alpen et al , 1994Edwards 2001;Chang et al 2016;Norbury et al 2016). The Chang et al paper concerns experiments at the Brookhaven (NY) NASA Space Radiation Laboratory (NSRL).…”
Section: Introductionmentioning
confidence: 99%
“…At sufficiently small radiation doses and high LETs, only a small fraction of all cell nuclei suffer a direct hit by a radiation track (Curtis et al 1992;Hanin and Zaider 2014). Non-targeted effects (NTE) are then sometimes important (Cucinotta and Chappell 2010;Cucinotta et al 2013a;Hada et al 2014;Cacao et al 2016;Chang et al 2016;Cucinotta and Cacao 2017;Shuryak 2017), with cells directly hit by an ion influencing nearby cells through inter-cellular signaling (Hatzi et al 2015). However, the question of whether NTE are significantly carcinogenic at very low HZE doses remains open (Piotrowski et al 2017).…”
Experimental studies reporting murine Harderian gland (HG) tumourigenesis have been a NASA concern for many years. Studies used particle accelerators to produce beams that, on beam entry, consist of a single isotope also present in the galactic cosmic ray (GCR) spectrum. In this paper synergy theory is described, potentially applicable to corresponding mixed-field experiments, in progress, planned, or hypothetical. The "obvious" simple effect additivity (SEA) approach of comparing an observed mixture dose-effect relationship (DER) to the sum of the components' DERs is known from other fields of biology to be unreliable when the components' DERs are highly curvilinear. Such curvilinearity may be present at low fluxes such as those used in the one-ion HG experiments due to non-targeted ('bystander') effects, in which case a replacement for SEA synergy theory is needed. This paper comprises in silico modeling of published experimental data using a recently introduced, arguably optimal, replacement for SEA: incremental effect additivity (IEA). Customized open-source software is used. IEA is based on computer numerical integration of non-linear ordinary differential equations. To illustrate IEA synergy theory, possible rapidly-sequential-beam mixture experiments are discussed, including tight 95% confidence intervals calculated by Monte-Carlo sampling from variance-covariance matrices. The importance of having matched one-ion and mixed-beam experiments is emphasized. Arguments are presented against NASA overemphasizing accelerator experiments with mixed beams whose dosing protocols are standardized rather than being adjustable to take biological variability into account. It is currently unknown whether mixed GCR beams sometimes have statistically significant synergy for the carcinogenesis endpoint. Synergy would increase risks for prolonged astronaut voyages in interplanetary space.
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