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Within this special issue, many eminent investigators report on measurements of oxygen (O2) levels in tissues. Given the complexities of spatial and temporal heterogeneities of O2 in tissues and its many sources, this commentary draws attention to what such measurements do and do not actually assess regarding O2 levels in tissues. Given this limitation, it also discusses how these results can be used most effectively. To provide a convenient mechanism to discuss these issues more fully, this analysis focuses on measurements using EPR oximetry, but these considerations apply to all other techniques. The nature of the delivery of O2 to tissues and the mechanisms by which O2 is consumed necessarily result in very different levels of O2 within the volume of each voxel of a measurement. Better spatial resolution cannot fully resolve the problem because the variations include O2 gradients within each cell. Improved resolution of the time-dependent variation in O2 is also very challenging because O2 levels within tissues can have fluctuations of O2 levels in the range of milliseconds, while most methods require longer times to acquire the data from each voxel. Based on these issues, we argue that the values obtained inevitably are complex aggregates of averages of O2 levels across space and time in the tissue. These complexities arise from the complex physiology of tissues and are compounded by the limitations of the technique and its ability to acquire data. However, one often can obtain very meaningful and useful results if these complexities and limitations are taken into account. We illustrate this, using results obtained with in vivo EPR oximetry, especially utilizing its capacity to make repeated measurements to follow changes in O2 levels that occur with interventions and/or over time. [ABSTRACT FROM AUTHOR]

The development of effective uses of biodosimetry in large-scale events has been hampered by residual, i.e., "legacy" thinking based on strategies that scale up from biodosimetry in small accidents. Consequently, there remain vestiges of unrealistic assumptions about the likely magnitude of victims in "large" radiation events and incomplete analyses of the logistics for making biodosimetry measurements/assessments in the field for primary triage. Elements remain from an unrealistic focus on developing methods to use biodosimetry in the initial stage of triage for a million or more victims. Based on recent events and concomitant increased awareness of the potential for large-scale events as well as increased sophistication in planning and experience in the development of biodosimetry, a more realistic assessment of the most effective roles of biodosimetry in large-scale events is urgently needed. We argue this leads to a conclusion that the most effective utilization of biodosimetry in very large events would occur in a second stage of triage, after initially winnowing the population by identifying those most in need of acute medical attention, based on calculations of geographic sites where significant exposures could have occurred. Understanding the potential roles and limitations of biodosimetry in large-scale events involving significant radiation exposure should lead to development of the most effective and useful biodosimetric techniques for each stage of triage for acute radiation syndrome injuries, i.e., based on more realistic assumptions about the underlying event and the logistics for carrying out biodosimetry for large populations. [ABSTRACT FROM AUTHOR]

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose. [ABSTRACT FROM AUTHOR]

Extremely high dose rate radiation delivery (FLASH) for cancer treatment has been shown to produce less damage to normal tissues while having the same radiotoxic effect on tumor tissue (referred to as the FLASH effect). Research on the FLASH effect has two very pertinent implications for the field of biodosimetry: (1) FLASH is a good model to simulate delivery of prompt radiation from the initial moments after detonating a nuclear weapon and (2) the FLASH effect elucidates how dose rate impacts the biological mechanisms that underlie most types of biological biodosimetry. The impact of dose rate will likely differ for different types of biodosimetry, depending on the specific underlying mechanisms. The greatest impact of FLASH effects is likely to occur for assays based on biological responses to radiation damage, but the consequences of differential effects of dose rates on the accuracy of dose estimates has not been taken into account. [ABSTRACT FROM AUTHOR]

Following large-scale radiation events, an overwhelming number of people will potentially need mitigators or treatment for radiation-induced injuries. This necessitates having methods to triage people based on their dose and its likely distribution, so life-saving treatment is directed only to people who can benefit from such care. Using estimates of victims following an improvised nuclear device striking a major city, we illustrate a two-tier approach to triage. At the second tier, after first removing most who would not benefit from care, biodosimetry should provide accurate dose estimates and determine whether the dose was heterogeneous. We illustrate the value of using in vivo electron paramagnetic resonance nail biodosimetry to rapidly assess dose and determine its heterogeneity using independent measurements of nails from the hands and feet. Having previously established its feasibility, we review the benefits and challenges of potential improvements of this method that would make it particularly suitable for tier 2 triage. Improvements, guided by a user-centered approach to design and development, include expanding its capability to make simultaneous, independent measurements and improving its precision and universality. [ABSTRACT FROM AUTHOR]

This paper briefly examines electron paramagnetic resonance (EPR) techniques to measure dose from exposure to external radiation, assessing their current status, potential future uses and the challenges impacting their progress. We conclude the uses and potential value of different EPR techniques depend on the number of victims and whether they characterize short- or long-term risks from exposure. For large populations, EPR biodosimetry based on in vivo measurements or using co-located inanimate objects offer the greatest promise for assessing acute, life-threatening risk and the magnitude and extent of such risk. To assess long-term risk, ex vivo EPR methods using concentrated enamel from exfoliated teeth are most impactful. For small groups, ex vivo EPR biodosimetry based on available samples of teeth, nails and/or bones are most useful. The most important challenges are common to all approaches: improve the technique's technical capabilities and advance recognition by planning groups of the relative strengths EPR techniques offer for each population size. The most useful applications are likely to be for triage and medical guidance in large events and for radiation epidemiology to evaluate long-term risks. [ABSTRACT FROM AUTHOR]

By implementing these recommendations, international biodosimetry networks can be prepared to address large-scale radiological incidents within the context of a pandemic and ensure the safety of biodosimetry personnel as well as victims in such dual emergencies. Biodosimetry and biodosimetry networks for managing radiation emergency. Experience during the COVID-19 pandemic The following summary of some of the changes and adjustments made by dosimetry laboratories during the COVID-19 pandemic is based on an informal survey by the authors from many individuals and laboratories within the biodosimetry community. For example, during the active stages of the COVID-19 pandemic, the RENEB network organized and conducted a large international biodosimetry exercise. [Extracted from the article]