Non-clinical radiation biology and pharmacology models: appraisal of state-of-the-art and innovation

Significant progress was made with medical counter measure (MCM) development typically involving a combination of animal models and clinical trials. In 2018, the first MCM for smallpox was approved by the U.S. FDA under the Animal Rule (Merchlinsky et al. 2019) further expanding the range of indications that obtained approval under this unique regulation (U.S. FDA 2015). Several successful developments within the radiation countermeasure field have achieved Animal Rule approval with leukocyte growth factors (LGFs) as the leading class. In March 2015, filgrastim (Farese et al. 2013) was the first MCM approved under the Animal Rule to increase survival in patients acutely exposed to myelosuppressive doses of radiation. In November 2015, pegfilgrastim (Hankey et al. 2015), which is administered twice one week apart, was the second MCM approved under the Animal Rule for accidental radiation exposure and the first to include the pediatric population. In March 2018, sargramostim was approved (Singh and Seed 2018) to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation. In all cases, approval was based on clinical trial data and a blinded GLP compliant pivotal efficacy study in Rhesus monkeys. There is currently no approved drug for the treatment of radiation induced thrombocytopenia, an important consequence of accidental acute radiation exposure.

The objective of this special issue is to provide an appraisal of the considerations and strategies necessary for preparedness in the event of a mass casualty scenario involving accidental exposure to ionizing radiation. Issues covered in this issue include our current understanding of casualty estimations based on the radiation dose distribution at the site of the incident, development of biodosimetry devices needed for medical triage and animal models used for MCM testing. All of this information is needed to map logical and systematic approaches in the deployment of efficacious countermeasures for radiation protection. This issue highlights innovative results from a number of studies using two animal species showcasing the efficacy of a promising candidate, Romiplostim for the treatment of radiation-induced thrombocytopenia.

Accurate radiation casualty estimations are critical for adequate medical and emergency management planning. Most current estimates of casualties are population-based without taking into consideration the broad age, sex, and ethnicity diversity of individuals in the affected area. Bellman et al. (2019) refined existing models by factoring the impact of age into the predictions and showed that by doing so, a significantly higher estimates of casualties can result depending on the location and age distribution at the site of the incident. Using advanced modeling approaches, Yeddanapudi et al. (2019) illustrated the impact of timing, dosage, and fractional benefit of cytokine therapy and supportive care treatment after nuclear detonation. The importance of resource allocation was identified as a fundamental success factor in the medical management dedicated to a large population after a nuclear detonation (DiCarlo et al. 2011) and modeling is a pivotal strategy to advance knowledge for scenarios that remain hypothetical. On-line resources such as the Radiation Event Medical Management (REMM) website have been developed for clinicians that would manage patients in a mass casualty scenario (Bader et al. 2008) and broad dissemination of the medical consensus on medical management procedures remains a key component towards emergency treatment harmonization.

Accurate and efficient biodosimetry devices are essential in the event of a detonation of an improvised nuclear device (IND) such that the appropriate care can be provided in a timely manner to support patients in need. Multi-parameter diagnostics tools are typically needed for accurate radiation dose estimation but also involved establishment of the appropriate network of laboratories with assay qualification (Dainiak et al. 2019). Point-of-care tools are needed for rapid triage to identify exposed victims shortly after an incident, while high throughput diagnostic tests are essential for dose stratification such that the appropriate medical support can be provided while taking into account logistical considerations. The utility of using radiation-responsive protein (Balog et al. 2019) and gene expression signatures (Iversen et al. 2019; Jacobs et al. 2019) in diagnostic devices are discussed in this volume.

The FDA Animal Rule generally requires the use of more than one animal species for medical counter measure efficacy assessments. Characterizing animal models with a clear understanding of the natural history of organ-specific radiation injury is critical to the medical inference that Animal Rule enables. In line with Bellman’s article, Sticklin’s study showcased age-dependent differences in radiation sensitivities in five different animal species. Comparative analysis of WAG/RijCmcr rats with non-human primates (NHPs) reveals that rats and NHP manifest similar organ dysfunction after radiation (Fish et al. 2019). Although most of the scientific literature has addressed early hematological and gastrointestinal consequences following acute radiation exposure, delayed manifestations of radiation injury in susceptible organs have remained much less characterized. The impact of metabolism on radiosensitivity and gastrointestinal radiation syndrome is comprehensively investigated by Ewing et al. (2019) using a disease model that involves a NZO/HlLtJ mouse strain prone to spontaneous obesity and diabetes exposed to total body irradiation (TBI).

Radiation exposure to partially shielded individuals is likely to be more relevant in the mass casualty scenario. Unlike total body exposures, the level of bone marrow sparing is known to play not only a role in survival but also in the level of initial radiation-induced myelosuppression and delayed tissue effects. Shielding of the oral cavity to protect the mucosal lining can be beneficial programs that evaluate oral countermeasures and Accardi et al. (2019) demonstrated that this model is a suitable alternative to partial body model with limb shielding in NHPs. Minipigs are known to display classical gastrointestinal acute radiation syndrome following total body irradiation. To understand natural history of radiation-induced intestinal functional impairment, Kaur et al. (2019) presented results from a 30-d study that illustrate temporally regulated dose-dependent changes to intestinal functionality and the utility of minipigs in MCM testing. Models of targeted thoracic irradiation have been developed by clinicians and scientists to understand the etiology of pulmonary toxicity. Beach et al. (2019) provided a thorough review of the literature highlighting the dynamic nature of lung injury and can be used as reference for the development of other bone marrow shielding models for delayed effects.

Treatment for radiation-induced thrombocytopenia is a high priority for preparedness to mass casualty scenarios as there is currently no approved product for this indication. Two articles in this issue present romiplostim as an effective medical countermeasure to improve survival and platelet recovery following TBI. Romiplostim-treated mice showed significant survival improvement after a single dose coupled with more rapid platelet recovery when compared to the sham-treated controls. Irradiated non-human primates treated with romiplostim alone or in combination with pegfilgratim demonstrated significant improvements in hematological parameters when compared to the vehicle-treated animals.

Great strides have been made with radiation research related to medical management logistics and modeling, biodosimetry, animal model characterization, and MCM developments. This special issue on non-clinical radiation biology and pharmacology models provided perspectives and innovation to advance a broad range of themes important to the field. Despite these efforts, there remains certain areas that deserve additional research efforts, especially with in-depth characterization of the pathophysiology following acute radiation exposure, delayed organ system effects (Chua et al. 2019) and translational validation of radiation exposure biomarkers.

Disclosure statement

No potential conflict of interest was reported by the authors.