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There have been reports in the media and claims in the courts that radiofrequency (RF) emissions from mobile phones are a cause of cancer, and there have been numerous public objections to the siting of mobile phone base antennas because of a fear of cancer. This review summarizes the current state of evidence concerning whether the RF energy used for wireless communication might be carcinogenic. Relevant studies were identified by searching MedLine with a combination of exposure and endpoint terms. This was supplemented by a review of the over 1700 citations assembled by the Institute of Electrical and Electronics Engineers (IEEE) International Committee on Electromagnetic Safety as part of their updating of the IEEE C95.1 RF energy safety guidelines. Where there were multiple studies, preference was given to recent reports, to positive reports of effects and to attempts to confirm such positive reports. Biophysical considerations indicate that there is little theoretical basis for anticipating that RF energy would have significant biological effects at the power levels used by modern mobile phones and their base station antennas. The epidemiological evidence for a causal association between cancer and RF energy is weak and limited. Animal studies have provided no consistent evidence that exposure to RF energy at non-thermal intensities causes or promotes cancer. Extensive in vitro studies have found no consistent evidence of genotoxic potential, but in vitro studies assessing the epigenetic potential of RF energy are limited. Overall, a weight-of-evidence evaluation shows that the current evidence for a causal association between cancer and exposure to RF energy is weak and unconvincing. However, the existing epidemiology is limited and the possibility of epigenetic effects has not been thoroughly evaluated, so that additional research in those areas will be required for a more thorough assessment of the possibility of a causal connection between cancer and the RF energy from mobile telecommunications. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme (ACE) inhibitors are effective countermeasures to chronic radiation injuries in rodent models, and there is evidence for similar effects in humans. In rodent models ACE inhibitors are effective mitigators of radiation injury to kidney, lung, central nervous system (CNS) and skin, even when started weeks after irradiation. In humans, the best data for their efficacy as radiation countermeasures comes from retrospective studies of injuries in radiotherapy patients. We propose that ACE inhibitors, at doses approved for human use for other indications, could be used to reduce the risk of chronic radiation injuries from deep-space exploration. Because of the potential interaction of ACE inhibitors and microgravity (due to effects of ACE inhibitors on fluid balance) use might be restricted to post-exposure when/if radiation exposures reached a danger level. A major unresolved issue for this approach is the sparse evidence for the efficacy of ACE inhibitors after low-dose-rate exposure and/or for high-LET radiations (as would occur on long-duration space flights). A second issue is that the lack of a clear mechanism of action of the ACE inhibitors as mitigators makes obtaining an appropriate label under the Food and Drug Administration Animal Rule difficult., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

There are no FDA-approved drugs to mitigate the delayed effects of radiation exposure that may occur after a radiological attack or nuclear accident. To date, angiotensin-converting enzyme inhibitors are one of the most successful candidates for mitigation of hematopoietic, lung, kidney, and brain injuries in rodent models and may mitigate delayed radiation injuries after radiotherapy. Rat models of partial body irradiation sparing part of one hind leg (leg-out PBI) have been developed to simultaneously expose multiple organs to high doses of ionizing radiation and avoid lethal hematological toxicity to study the late effects of radiation. Exposures between 9 and 14 Gy damage the gut and bone marrow (acute radiation syndrome), followed by delayed injuries to the lung, heart, and kidney. The goal of the current study is to compare the pharmacokinetics (PK) of a lead angiotensin converting enzyme (ACE) inhibitor, lisinopril, in irradiated vs. nonirradiated rats, as a step toward licensure by the FDA. Methods: Female WAG/RijCmcr rats were irradiated with 12.5-13 Gy leg-out PBI. At day 35 after irradiation, during a latent period for injury, irradiated and nonirradiated siblings received a single gavage (0.3 mg, 0.6 mg) or intravenous injection (0.06 mg) of lisinopril. Plasma, urine, lung, liver and kidney levels of lisinopril were measured at different times. PK modeling (R package) was performed to track distribution of lisinopril in different compartments. Results: A two-compartment (central plasma and periphery) PK model best fit lisinopril measurements, with two additional components, the gavage and urine. The absorption and renal clearance rates were similar between nonirradiated and irradiated animals (respectively: ratios 0.883, p = 0.527; 0.943, p = 0.605). Inter-compartmental clearance (from plasma to periphery) for the irradiated rats was lower than for the nonirradiated rats (ratio 0.615, p = 0.003), while the bioavailability of the drug was 33% higher (ratio = 1.326, p < 0.001). Interpretation: Since receptors for lisinopril are present in endothelial cells lining blood vessels, and radiation induces vascular regression, it is possible that less lisinopril remains bound in irradiated rats, increasing circulating levels of the drug. However, this study cannot rule out changes in total amount of lisinopril absorbed or excreted long-term, after irradiation in rats., Competing Interests: The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Medhora, Phadnis, Narayanan, Gasperetti, Zielonka, Moulder, Fish and Szabo.)

Purpose: Defined animal models are needed to pursue the FDA Animal Rule for approval of medical countermeasure for radiation injuries. This study compares WAG/RijCmcr rat and nonhuman primate (NHP) models for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). Materials and methods: Irradiation models include total body irradiation, partial body irradiation with bone marrow sparing and whole thorax lung irradiations. Organ-specific sequelae of radiation injuries were compared using dose-response relationships. Results and conclusions: Rats and NHP manifest similar organ dysfunctions after radiation, starting with acute gastrointestinal (GI-ARS) and hematopoietic (H-ARS) syndromes followed by lung, heart and kidney toxicities. Humans also manifest these sequelae. Latencies for injury were earlier in rats than in NHP. After whole thorax lung irradiations (WTLI) up to 13 Gy, there was recovery of lung function from pneumonitis in rats. This has not been evaluated in NHP. The latency, incidence, severity and progression of radiation pneumonitis was not influenced by early multi-organ injury from ARS in rats or NHP. Rats developed more severe radiation nephropathy than NHP, and also progressed more rapidly. Dosimetry, anesthesia, environment, supportive care, euthanasia criteria etc., may account for the alterations in radiation sensitivity observed between species.

Purpose: To review the Journal's coverage of chemical radiosensitizers. Methods: I have reviewed all the possibly-relevant papers that appeared in the Journal prior to 1970 and since 2010, plus the most highly-cited papers from the intervening years. I excluded papers that dealt only with oxygen as a sensitizer, that referred to sensitization of phototoxicity or hyperthermia, or that described interactions with antineoplastic agents unless they clearly distinguish between additive toxicity and radiosensitization. My definition of 'chemical' was very broad, so the coverage includes everything from classical hypoxic cell sensitizers to gold nanoparticles. Results: A literature search identifies ∼600 Journal articles as involving 'radiation sensitizing agents'; these articles are not common in Journals' first years but take off after 1970 with a peak in the late 1980s. Half of the highly-cited radiosensitizer papers were published between 1969 and 1974; the two most-cited radiosensitizer papers were 1969 and 1979 papers on hypoxic cell sensitizers. The third most-cited radiosensitizer paper would not come for two more decades, and it would use a physical rather than a chemical approach to radiosensitization. Conclusion: The development of an agent that would differentially sensitize tumors to irradiation remains a 'holy grail' of clinically-oriented radiobiology. Approaches to this goal have been a major feature of the Journal since its first decade, but we have yet to find such an agent. Perhaps we should be discouraged, but personally, I remain optimistic that we (or our students) will succeed.

It has been speculated that the addition of antioxidants to diet could act as either radioprotectors or as mitigators of radiation injury. In preparation for studies of the mitigation efficacy of antioxidants, rats were placed on a modified version of AIN-76A, the diet typically used in such studies. This AIN-76A diet is refined and has no synthetic antioxidants or isoflavones. Compared to the natural-ingredient Teklad 8904 diet used in previous studies, use of the AIN-76A diet from 1-18 wk after irradiation significantly reduced injury in a radiation nephropathy model. A confirmation study included an additional arm in which the AIN-76A diet was started 2 wk prior to irradiation; again, the switch to AIN-76A postirradiation mitigated radiation nephropathy (p < 0.001), but switching to the AIN-76A diet preirradiation had no effect (p > 0.2). The two diets do not differ in salt content, but the AIN-76A diet is somewhat lower in protein (18% vs. 24%). The protein source (primarily soy in Teklad 8904 vs. casein in AIN-76A) might explain the effects. However, replacing the casein in AIN-76A with soy did not change the mitigation efficacy of the diet (p > 0.2 for comparison of the different AIN-76A diets). A similar study in a rat radiation pneumonitis model also suggested mitigation by postirradiation use of AIN-76A, although the effect was not statistically significant (p = 0.07). In conclusion, base diet alone can have biologically significant effects on organ radiosensitivity, but the mechanistic basis for the effect and its dependence of timing relative to irradiation are unclear.

Purpose: Review the historical basis for the use of fractionated radiation in radiation oncology., Conclusion: The history of dose fractionation in radiation oncology is long and tortuous, and the radiobiologist's understanding of why fractionation worked came decades after radiation oncologists had adopted multi-week daily-dose fractionation as 'standard'. Central to the history is the search for 'isoeffective' formulas that would allow different radiation schedules to be compared. Initially, this meant dealing with different lengths of treatment, leading to the 1944 Strandqvist formulation that dominated thinking for decades. Concerns about the number of fractions, not just the total time, led to the 1967 Ellis NSD formulation that held sway through the 1980s. The development of experimental radiotherapy in 1970s (e.g. Fowler's work at the Gray Laboratory, and Fischer's work at Yale) led to biologically-based approaches that culminated with the Biologically Effective Dose (BED) concept. BED is the current dogma for treatment optimization, but it must be used with caution, as there are multiple formulations, and some parameters have debatable values. There is also a controversy about whether BED is biologically-based or a 'curve-fitting' exercise. These latter issues are beyond the scope of this article, but the history of fractionation models suggests that our current concepts are probably wrong, although when used with caution they are clearly useful.

The brain could be exposed to irradiation as part of a nuclear accident, radiological terrorism (dirty bomb scenario) or a medical radiological procedure. In the context of accidents or terrorism, there is considerable interest in compounds that can mitigate radiation-induced injury when treatment is initiated a day or more after the radiation exposure. As it will be challenging to determine the radiation exposure an individual has received within a relatively short time frame, it is also critical that the mitigating agent does not negatively affect individuals, including emergency workers, who might be treated, but who were not exposed. Alterations in hippocampus-dependent cognition often characterize radiation-induced cognitive injury. The catalytic ROS scavenger EUK-207 is a member of the class of metal-containing salen manganese (Mn) complexes that suppress oxidative stress, including in the mitochondria, and have been shown to mitigate radiation dermatitis, promote wound healing in irradiated skin, and mitigate vascular injuries in irradiated lungs. As the effects of EUK-207 against radiation injury in the brain are not known, we assessed the effects of EUK-207 on sham-irradiated animals and the ability of EUK-207 to mitigate radiation-induced cognitive injury. The day following irradiation or sham-irradiation, the mice started to receive EUK-207 and were cognitively tested 3 months following exposure. Mice irradiated at a dose of 15Gy showed cognitive impairments in the water maze probe trial. EUK-207 mitigated these impairments while not affecting cognitive performance of sham-irradiated mice in the water maze probe trial. Thus, EUK-207 has attractive properties and should be considered an ideal candidate to mitigate radiation-induced cognitive injury., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain, and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study, the authors have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ~24 mg m d started orally in the drinking water at 7 d after irradiation and continued to ≥150 d) mitigated late effects in the lungs and kidneys after 12.5-Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 d after 13-Gy leg-out PBI. Furthermore, lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg d from days 1-14), which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, acute and delayed radiation injuries in multiple organs were mitigated.

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis., Competing Interests: Drs. Imig and Falck have a patent application that covers the composition of matter for EET-A. There are no other conflicts of interest, financial or otherwise, are declared by the authors., (© 2016 Authors; published by Portland Press Limited.)

Angiotensin-converting enzyme inhibitors (ACEi) are effective mitigators of radiation nephropathy. To date, their experimental use has been in fixed-dose regimens. In clinical use, doses of ACEi and other medication may be escalated to achieve greater benefit. We therefore used a rodent model to test the ACEi enalapril as a mitigator of radiation injury in an escalating-dose regimen. Single-fraction partial-body irradiation (PBI) with one hind limb out of the radiation field was used to model accidental or belligerent radiation exposures. PBI doses of 12.5, 12.75 and 13 Gy were used to establish multi-organ injury. One third of the rats underwent PBI alone, and two thirds of the rats had enalapril started five days after PBI at a dose of 30 mg/l in the drinking water. When there was established azotemic renal injury enalapril was escalated to a 60 mg/l dose in half of the animals and then later to a 120 mg/l dose. Irradiated rats on enalapril had significant mitigation of combined pulmonary and renal morbidity and had significantly less azotemia. Dose escalation of enalapril did not significantly improve outcomes compared to fixed-dose enalapril. The current data support use of the ACEi enalapril at a fixed and clinically usable dose to mitigate radiation injury after partial-body radiation exposure.

The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The NIH/NIAID initiated a countermeasure program to develop mitigators for radiation-induced injuries from a radiological attack or nuclear accident. We have previously characterized and demonstrated mitigation of single organ injuries, such as radiation pneumonitis, pulmonary fibrosis or nephropathy by angiotensin converting enzyme (ACE) inhibitors. Our current work extends this research to examine the potential for mitigating multiple organ dysfunctions occurring in the same irradiated rats. Using total body irradiation (TBI) followed by bone marrow transplant, we tested four doses of X radiation (11, 11.25, 11.5 and 12 Gy) to develop lethal late effects. We identified three of these doses (11, 11.25 and 11.5 Gy TBI) that were lethal to all irradiated rats by 160 days to test mitigation by ACE inhibitors of injury to the lungs and kidneys. In this study we tested three ACE inhibitors at doses: captopril (88 and 176 mg/m(2)/day), enalapril (18, 24 and 36 mg/m(2)/day) and fosinopril (60 mg/m(2)/day) for mitigation. Our primary end point was survival or criteria for euthanization of morbid animals. Secondary end points included breathing intervals, other assays for lung structure and function and blood urea nitrogen (BUN) to assess renal damage. We found that captopril at 176 mg/m(2)/day increased survival after 11 or 11.5 Gy TBI. Enalapril at 18-36 mg/m(2)/day improved survival at all three doses (TBI). Fosinopril at 60 mg/m(2)/day enhanced survival at a dose of 11 Gy, although no improvement was observed for pneumonitis. These results demonstrate the use of a single countermeasure to mitigate the lethal late effects in the same animal after TBI.

Purpose: To develop mitigators for combined irradiation to the lung and skin., Methods: Rats were treated with X-rays as follows: (1) 12.5 or 13 Gy whole thorax irradiation (WTI); (2) 30 Gy soft X-rays to 10% area of the skin only; (3) 12.5 or 13 Gy WTI + 30 Gy skin irradiation after 3 hours; (4) 12.5 Gy WTI + skin irradiation and treated with captopril (160 mg/m(2)/day) started after 7 days. Our end points were survival (primary) based on IACUC euthanization criteria and secondary measurements of breathing intervals and skin injury. Lung collagen at 210 days was measured in rats surviving 13 Gy WTI., Results: After 12.5 Gy WTI with or without skin irradiation, one rat (12.5 Gy WTI) was euthanized. Survival was less than 10% in rats receiving 13 Gy WTI, but was enhanced when combined with skin irradiation (p < 0.0001). Collagen content was increased at 210 days after 13 Gy WTI vs. 13 Gy WTI + 30 Gy skin irradiation (p < 0.05). Captopril improved radiation-dermatitis after 12.5 Gy WTI + 30 Gy skin irradiation (p = 0.008)., Conclusions: Radiation to the skin given 3 h after WTI mitigated morbidity during pneumonitis in rats. Captopril enhanced the rate of healing of radiation-dermatitis after combined irradiations to the thorax and skin.

Purpose: We tested five different angiotensin converting enzyme inhibitors (ACEI) as mitigators of experimental radiation nephropathy at drug doses calibrated to the plasma renin activity (PRA). This was done to determine whether all ACEI had the same efficacy as mitigators of radiation nephropathy when used at drug doses that gave equivalent suppression of the renin angiotensin system., Method: 10 Gy total body irradiation with bone marrow transplantation was used to cause radiation nephropathy in barrier-maintained rats. Equivalent ACEI doses were determined based on their effect to inhibit angiotensin converting enzyme (ACE) and raise the PRA in unirradiated animals., Results: PRA-equivalent doses were found for captopril, lisinopril, enalapril, ramipril and fosinopril. These doses overlap the human doses of these drugs on a body surface area basis. All ACE inhibitors, except fosinopril, mitigated radiation nephropathy; captopril was a somewhat better mitigator than lisinopril, enalapril or ramipril., Conclusions: Most, but not all, ACEI mitigate radiation nephropathy at doses that overlap their clinically-used doses (on a body surface area basis). Fosinopril is known to be an ineffective mitigator of radiation pneumonitis, and it also does not mitigate radiation nephropathy. These pre-clinical data are critical in planning human studies of the mitigation of normal tissue radiation injury.

The collection of blood samples from laboratory rats requires the use of bleeding techniques that provide quality samples of sufficient volume for analysis without injury to the animal. Retro-orbital bleeding (ROB) is a phlebotomy technique that can yield high-quality samples of adequate volume, but it has been criticized for its potential to cause injury. To evaluate the injury-causing potential of their refined ROB method using a lateral approach, the authors retrospectively reviewed ROB procedures carried out in their colony during an 18-month period and found that 0.6% of these procedures were associated with ocular injury. The authors also compared the quality of blood samples collected by ROB and by saphenous phlebotomy and found that ROB yielded samples of better quality. The authors conclude that, when done using a lateral approach and by an experienced technician, ROB is humane and safe and provides blood samples of adequate volume and quality for analysis.

This review summarizes the current state of research on possible health effects of Wi-Fi (a commercial name for IEEE 802.11-compliant wireless networking). In response to public concerns about health effects of Wi-Fi and wireless networks and calls by government agencies for research on possible health and safety issues with the technology, a considerable amount of technology-specific research has been completed. A series of high quality engineering studies have provided a good, but not complete, understanding of the levels of radiofrequency (RF) exposure to individuals from Wi-Fi. The limited number of technology-specific bioeffects studies done to date are very mixed in terms of quality and outcome. Unequivocally, the RF exposures from Wi-Fi and wireless networks are far below U.S. and international exposure limits for RF energy. While several studies report biological effects due to Wi-Fi-type exposures, technical limitations prevent drawing conclusions from them about possible health risks of the technology. The review concludes with suggestions for future research on the topic.

Victims of a radiological attack or nuclear accident may receive high-dose, heterogeneous exposures from radiation to the chest that lead to lung damage. Our goal is to develop countermeasures to mitigate such injuries. We used WAG/RijCmcr rats receiving 13 Gy to the whole thorax to induce pulmonary fibrosis within 210 days. The angiotensin converting enzyme (ACE) inhibitor enalapril was evaluated as a mitigator of these injuries at two doses (18 and 36 mg/m(2)/day) and 8 schedules: starting at 7, 35, 70, 105 and 140 days and continuing to 210 days or starting at 7 days and stopping at 30, 60 or 90 days after whole-thorax irradiation. The earliest start date at 7 days after irradiation would provide an adequate window of time for triage and dosimetry. Survival after 35 days, as permitted by our Institutional Animal Care and Use Committee (IACUC) was also recorded as a primary end point of pneumonitis. Pulmonary fibrosis was evaluated using the Sircol biochemical assay to measure lung collagen. Our results indicated that a short course of either dose of enalapril from 7-90 days improved survival. However, pulmonary fibrosis was only mitigated by the higher dose of enalapril (36 mg/m(2)/day). The latest effective start date for the drug was 35 days after irradiation. These results indicate that ACE inhibitors can be started at least a month after irradiation for mitigation of pneumonitis and/or pulmonary fibrosis.

The objective of this study was to determine whether radiation-induced injury to the heart after 10 Gy total body irradiation (TBI) is direct or indirect. Young male WAG/RijCmcr rats received a 10 Gy single dose using TBI, upper hemi-body (UHB) irradiation, lower hemi-body (LHB) irradiation, TBI with the kidneys shielded or LHB irradiation with the intestines shielded. Age-matched, sham-irradiated rats served as controls. The lipid profile, kidney injury, heart and liver morphology and cardiac function were determined up to 120 days after irradiation. LHB, but not UHB irradiation, increased the risk factors for cardiac disease as well as the occurrence of cardiac and kidney injury in a way that was quantitatively and qualitatively similar to that observed after TBI. Shielding of the kidneys prevented the increases in risk factors for cardiac disease. Shielding of the intestines did not prevent the increases in risk factors for cardiac disease. There was no histological evidence of liver injury 120 days after irradiation. Injury to the heart from irradiation appears to be indirect, supporting the notion that injury to abdominal organs, principally the kidneys, is responsible for the increased risk factors for and the occurrence of cardiac disease after TBI and LHB irradiation.

Unlabelled: High-dose ionizing irradiation can cause extensive injuries in susceptible tissues. A noninvasive imaging technique that detects a surrogate marker of apoptosis may help characterize the dynamics of radiation-induced tissue damage. The goal of this study was to prove the concept of imaging the temporal and spatial distribution of damage in susceptible tissues after high-dose radiation exposure, using (99m)Tc-duramycin as a phosphatidylethanolamine-binding radiopharmaceutical., Methods: Rats were subjected to 15 Gy of total-body irradiation with x-rays. Planar whole-body (99m)Tc-duramycin scanning (n = 4 per time point) was conducted at 24, 48, and 72 h using a clinical γ-camera. On the basis of findings from planar imaging, preclinical SPECT data were acquired on control rats and on irradiated rats at 6 and 24 h after irradiation (n = 4 per time point). Imaging data were validated by γ-counting and histology, using harvested tissues in parallel groups of animals (n = 4)., Results: Prominent focal uptake was detected in the thymus as early as 6 h after irradiation, followed by a gradual decline in (99m)Tc-duramycin binding accompanied by extensive thymic atrophy. Early (6-24 h) radioactivity uptake in the gastrointestinal region was detected. Significant signal was seen in major bones in a slightly delayed fashion, at 24 h, which persisted for at least 2 d. This finding was paralleled by an elevation in signal intensity in the kidneys, spleen, and liver. The imaging results were consistent with ex vivo γ-counting results and histology. Relatively high levels of apoptosis were detected from histology in the thymus, guts, and bones, with the thymus undergoing substantial atrophy., Conclusion: As a proof of principle, this study demonstrated a noninvasive imaging technique that allows characterization of the temporal and spatial dynamics of injuries in susceptible tissues during the acute phase after high-dose ionizing irradiation. Such an imaging capability will potentially be useful for global, whole-body, assessment of tissue damage after radiation exposure. These data, in turn, will contribute to our general knowledge of tissue susceptibility to ionizing irradiation, as well as the onset and progression of tissue injuries.

In the event of a radionuclear attack or nuclear accident, the skin would be the first barrier exposed to radiation, though skin injury can progress over days to years following exposure. Chronic oxidative stress has been implicated as being a potential contributor to the progression of delayed radiation-induced injury to skin and other organs. To examine the causative role of oxidative stress in delayed radiation-induced skin injury, including impaired wound healing, we tested a synthetic superoxide dismutase (SOD)/catalase mimetic, EUK-207, in a rat model of combined skin irradiation and wound injury. Administered systemically, beginning 48 hours after irradiation, EUK-207 mitigated radiation dermatitis, suppressed indicators of tissue oxidative stress, and enhanced wound healing. Evaluation of gene expression in irradiated skin at 30 days after exposure revealed a significant upregulation of several key genes involved in detoxication of reactive oxygen and nitrogen species. This gene expression pattern was primarily reversed by EUK-207 therapy. These results demonstrate that oxidative stress has a critical role in the progression of radiation-induced skin injury, and that the injury can be mitigated by appropriate antioxidant compounds administered 48 hours after exposure.

The goal of our study was to identify a histological marker for testing countermeasures for mitigation of late radiation injury to the lung. Pulmonary fibrosis is currently the best described "late effect" in survivors of acute radiation pneumonitis. However, robust fibrosis does not develop in some rodent strains for years after a single dose of radiation to the whole thorax. We observed radiation-associated focal alveolar lesions that were rich in giant cells and macrophages containing cholesterol clefts in the lungs of irradiated WAG/RijCmcr rats. These lesions were first observed after pneumonitis, around 21 weeks after receiving a radiation dose of 13 Gy to the thorax but not until 71 weeks in unirradiated rats. The number of cholesterol clefts increased with time after irradiation through 64 weeks of observation, and at 30 weeks after 13 Gy, cholesterol clefts were associated with several indices of deterioration in lung function. The number of cholesterol clefts in irradiated lung sections were reduced by the angiotensin converting enzyme (ACE) inhibitor enalapril (25-42 mg/m²/day) from 18.7 ± 4.2/lung section to 6.8 ± 2.4 (P = 0.029), 5.2 ± 1.9 (P = 0.0051) and 6.7 ± 1.9 (P = 0.029) when the drug was started at 1 week, 5 or 15 weeks after irradiation, respectively, and continued. Similar lesions have been previously observed in the lungs of one strain of irradiated mice and in patients following radiotherapy. We propose that alveolar lesions with cholesterol clefts may be used as a histological marker of the severity of radiation lung injury and to study its mitigation in WAG/RijCmcr rats.

The global rise in terrorism has increased the risk of radiological events aimed at creating chaos and destabilization, although they may cause relatively limited number of immediate casualties. We have proposed that a self-administered test would be valuable for initial triage following terrorist use of nuclear/radiological devices. The urine proteome may be a useful source of the biomarkers required for developing such a test. We have developed and extensively used a rat model to study the acute and late effect of total body (TBI) and partial body irradiation on critical organ systems. This model has proven valuable for correlating the structural and functional effects of radiation with molecular changes. Results show that nephron segments differ with regard to their sensitivity and response to ionizing radiation. The urine proteome was analyzed using LC-MS/MS at 24 h after TBI or local kidney irradiation using a 10 Gy single dose of X rays. LC-MS/MS data were analyzed and grouped under Gene Ontology categories Cellular Localization, Molecular Function and Biological Process. We observed a decrease in urine protein/creatinine ratio that corroborated with decreased spectral counts for urinary albumin and other major serum proteins. Interestingly, TBI caused greater decline in urinary albumin than local kidney irradiation. Analysis of acute-phase response proteins and markers of acute kidney injury showed increased urinary levels of cystatin superfamily proteins and alpha-1-acid glycoprotein. Among proteases and protease inhibitors, levels of Kallikrein 1-related peptidase b24, precursor and products of chymotrypsin-like activity, were noticeably increased. Among the amino acids that are susceptible to oxidation by free radicals, oxidized histidine levels were increased following irradiation. Our results suggest that proteomic analysis of early changes in urinary proteins will identify biomarkers for developing a self-administered test for radiation biodosimetry.

Background: Chronic persistent oxidative stress has been proposed as a mechanism for late radiation injury to normal tissue. Using biochemical, histological, and pharmacological techniques, we have not been able to confirm this hypothesis for late renal radiation injury. Gene expression may be more revealing, especially since the initial effects of radiation are to damage DNA., Methods: Gene array studies were done using kidney tissue from irradiated rats, with particular attention to genes pertinent to oxidative stress. The time points were from 1 to 49 days after irradiation. Cellular RNA and mitochondrial DNA were isolated, for gene expression analysis and common deletion testing, respectively., Results: For the gene expression studies, and from over 30,000 transcripts, only nine related to oxidative stress had 1.4 fold or greater changes in expression. Mitochondrial DNA showed no changes in the common deletion., Conclusion: These studies do not support the hypothesis of chronic oxidative stress as a mechanism for radiation nephropathy.

In the event of a radiological accident or terrorist attack, whole- or partial-body exposure can injure the lungs. To simulate such an incident, we used a single fraction of total-body irradiation (TBI) or whole-thoracic irradiation to induce pneumonitis or pulmonary fibrosis, respectively, in a rat model. The superoxide dismutase and catalase mimetic EUK-207 was given by subcutaneous injection (20 mg/kg/day, 5 days per week, once daily) starting at 7 days after irradiation and stopping before pneumonitis developed. After TBI, morbidity and the increase in breathing rates associated with pneumonitis were significantly improved in rats treated with EUK-207 compared to rats receiving irradiation alone. At 42 days after TBI (the peak of pneumonitis) changes in vascular end points including pulmonary hemodynamics ex vivo and relative arterial density in lungs were also mitigated by EUK-207. At 7 months after whole-thoracic irradiation, EUK-207 reduced synthesis of collagen as assessed by the Sircol collagen assay and Masson's trichrome staining. Our results demonstrate promise for EUK-207 as a mitigator of radiation pneumonitis and fibrosis. We also demonstrate for the first time mitigation of multiple vascular injuries in the irradiated lung in vivo by EUK-207.

Background and Objective: A single dose of 10 Gy radiation to the thorax of rats results in decreased total lung angiotensin-converting enzyme (ACE) activity, pulmonary artery distensibility and distal vascular density while increasing pulmonary vascular resistance (PVR) at 2 months post-exposure. In this study, we evaluate the potential of a renin-angiotensin system (RAS) modulator, the ACE inhibitor captopril, to mitigate this pulmonary vascular damage., Methods: Rats exposed to 10 Gy thorax only irradiation and age-matched controls were studied 2 months after exposure, during the development of radiation pneumonitis. Rats were treated, either immediately or 2 weeks after radiation exposure, with two doses of the ACE inhibitor, captopril, dissolved in their drinking water. To determine pulmonary vascular responses, we measured pulmonary haemodynamics, lung ACE activity, pulmonary arterial distensibility and peripheral vessel density., Results: Captopril, given at a vasoactive, but not a lower dose, mitigated radiation-induced pulmonary vascular injury. More importantly, these beneficial effects were observed even if drug therapy was delayed for up to 2 weeks after exposure., Conclusions: Captopril resulted in a reduction in pulmonary vascular injury that supports its use as a radiomitigator after an unexpected radiological event such as a nuclear accident., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

Our goal is to develop countermeasures for pulmonary injury following unpredictable events such as radiological terrorism or nuclear accidents. We have previously demonstrated that captopril, an angiotensin converting enzyme (ACE) inhibitor, is more effective than losartan, an angiotensin type-1 receptor blocker, in mitigating radiation-pneumopathy in a relevant rodent model. In the current study we determined the dose modifying factors (DMFs) of captopril for mitigation of parameters of radiation pneumonitis. We used a whole animal model, irradiating 9-10-week-old female rats derived from a Wistar strain (WAG/RijCmcr) with a single dose of irradiation to the thorax of 11, 12, 13, 14 or 15 Gy. Our study develops methodology to measure DMFs for morbidity (survival) as well as physiological endpoints such as lung function, taking into account attrition due to lethal radiation-induced pneumonitis. Captopril delivered in drinking water (140-180 mg/m(2)/day, comparable with that given clinically) and started one week after irradiation has a DMF of 1.07-1.17 for morbidity up to 80 days (survival) and 1.21-1.35 for tachypnea at 42 days (at the peak of pneumonitis) after a single dose of ionizing radiation (X-rays). These encouraging results advance our goals, since DMF measurements are essential for drug labeling and comparison with other mitigators.

Considerable public concern has been expressed around the world about the radiation risks posed by the backscatter (ionizing radiation) and millimeter-wave (nonionizing radiation) whole-body scanners that have been deployed at many airports. The backscatter and millimeter-wave scanners currently deployed in the U.S. almost certainly pose negligible radiation risks if used as intended, but their safety is difficult-to-impossible to prove using publicly accessible data. The scanners are widely disliked and often feared, which is a problem made worse by what appears to be a veil of secrecy that covers their specifications and dosimetry. Therefore, for these and future similar technologies to gain wide acceptance, more openness is needed, as is independent review and regulation. Publicly accessible, and preferably peer-reviewed evidence is needed that the deployed units (not just the prototypes) meet widely-accepted safety standards. It is also critical that risk-perception issues be handled more competently.

There is an urgent need for rapid, accurate, and sensitive diagnostic platforms to confirm exposure to radiation and estimate the dose absorbed by individuals subjected to acts of radiological terrorism, nuclear power plant accidents, or nuclear warfare. Clinical symptoms and physical dosimeters, even when available, do not provide adequate diagnostic information to triage and treat life-threatening radiation injuries. We hypothesized that intestinal microbiota act as novel biomarkers of prior radiation exposure. Adult male Wistar rats (n = 5/group) received single or multiple fraction total-body irradiation of 10.0 Gy and 18.0 Gy, respectively. Fresh fecal pellets were obtained from each rat prior to (day 0) and at days 4, 11, and 21 post-irradiation. Fecal microbiota composition was determined using microarray and quantitative PCR (polymerase chain reaction) analyses. The radiation exposure biomarkers consisted of increased 16S rRNA levels of 12 members of the Bacteroidales, Lactobacillaceae, and Streptococcaceae after radiation exposure, unchanged levels of 98 Clostridiaceae and Peptostreptococcaceae, and decreased levels of 47 separate Clostridiaceae members; these biomarkers are present in human and rat feces. As a result of the ubiquity of these biomarkers, this biomarker technique is non-invasive; microbiota provide a sustained level of reporting signals that are increased several-fold following exposure to radiation, and intestinal microbiota that are unaffected by radiation serve as internal controls. We conclude that intestinal microbiota serve as novel biomarkers of prior radiation exposure, and may be able to complement conventional chromosome aberrational analysis to significantly enhance biological dose assessments.

Purpose: To update the results of a clinical trial that assessed whether the angiotensin-converting enzyme inhibitor captopril was effective in mitigating chronic renal failure and pulmonary-related mortality in subjects undergoing total body irradiation (TBI) in preparation for hematopoietic stem cell transplantation (HSCT)., Methods and Materials: Updated records of the 55 subjects who were enrolled in this randomized controlled trial were analyzed. Twenty-eight patients received captopril, and 27 patients received placebo. Definitions of TBI-HSCT-related chronic renal failure (and relapse) were the same as those in the 2007 analysis. Pulmonary-related mortality was based on clinical or autopsy findings of pulmonary failure or infection as the primary cause of death. Follow-up data for overall and pulmonary-related mortality were supplemented by use of the National Death Index., Results: The risk of TBI-HSCT-related chronic renal failure was lower in the captopril group (11% at 4 years) than in the placebo group (17% at 4 years), but this was not statistically significant (p > 0.2). Analysis of mortality was greatly extended by use of the National Death Index, and no patients were lost to follow-up for reasons other than death prior to 67 months. Patient survival was higher in the captopril group than in the placebo group, but this was not statistically significant (p > 0.2). The improvement in survival was influenced more by a decrease in pulmonary mortality (11% risk at 4 years in the captopril group vs. 26% in the placebo group, p = 0.15) than by a decrease in chronic renal failure. There was no adverse effect on relapse risk (p = 0.4)., Conclusions: Captopril therapy produces no detectable adverse effects when given after TBI. Captopril therapy reduces overall and pulmonary-related mortality after radiation-based HSCT, and there is a trend toward mitigation of chronic renal failure., (Published by Elsevier Inc.)

Concern regarding accidental overexposure to radiation has been raised after the devastating Tohuku earthquake and tsunami which initiated the Fukushima Daiichi nuclear disaster in Japan in March 2011. Radiation exposure is toxic and can be fatal depending on the dose received. Injury to the lung is often reported as part of multi-organ failure in victims of accidental exposures. Doses of radiation >8 Gray to the chest can induce pneumonitis with right ventricular hypertrophy starting after ∼2 months. Higher doses may be followed by pulmonary fibrosis that presents months to years after exposure. Though the exact mechanisms of radiation lung damage are not known, experimental animal models have been widely used to study this injury. Rodent models for pneumonitis and fibrosis exhibit vascular, parenchymal and pleural injuries to the lung. Inflammation is a part of the injuries suggesting involvement of the immune system. Researchers worldwide have tested a number of interventions to prevent or mitigate radiation lung injury. One of the first and most successful class of mitigators are inhibitors of angiotensin-converting enzyme (ACE), an enzyme that is abundant in the lung. These results offer hope that lung injury from radiation accidents may be mitigated, since the ACE inhibitor captopril was effective when started up to 1 week after irradiation., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.

Skin exposure to ionizing radiation affects the normal wound healing process and greatly impacts the prognosis of affected individuals. We investigated the effect of ionizing radiation on wound healing in a rat model of combined radiation and wound skin injury. Using a soft X-ray beam, a single dose of ionizing radiation (10-40 Gy) was delivered to the skin without significant exposure to internal organs. At 1 h postirradiation, two skin wounds were made on the back of each rat. Control and experimental animals were euthanized at 3, 7, 14, 21 and 30 days postirradiation. The wound areas were measured, and tissue samples were evaluated for laminin 332 and matrix metalloproteinase (MMP) 2 expression. Our results clearly demonstrate that radiation exposure significantly delayed wound healing in a dose-related manner. Evaluation of irradiated and wounded skin showed decreased deposition of laminin 332 protein in the epidermal basement membrane together with an elevated expression of all three laminin 332 genes within 3 days postirradiation. The elevated laminin 332 gene expression was paralleled by an elevated gene and protein expression of MMP2, suggesting that the reduced amount of laminin 332 in irradiated skin is due to an imbalance between laminin 332 secretion and its accelerated processing by elevated tissue metalloproteinases. Western blot analysis of cultured rat keratinocytes showed decreased laminin 332 deposition by irradiated cells, and incubation of irradiated keratinocytes with MMP inhibitor significantly increased the amount of deposited laminin 332. Furthermore, irradiated keratinocytes exhibited a longer time to close an artificial wound, and this delay was partially corrected by seeding keratinocytes on laminin 332-coated plates. These data strongly suggest that laminin 332 deposition is inhibited by ionizing radiation and, in combination with slower keratinocyte migration, can contribute to the delayed wound healing of irradiated skin.

Abstract population are ubiquitous background radiation and medical exposure of patients. From the early 1980s to 2006, the average dose per individual in the United States for all sources of radiation increased by a factor of 1.7-6.2 mSv, with this increase due to the growth of medical imaging procedures. Radiation can place individuals at an increased risk of developing cardiovascular disease. Excess risk of cardiovascular disease occurs a long time after exposure to lower doses of radiation as demonstrated in Japanese atomic bomb survivors. This review examines sources of radiation (atomic bombs, radiation accidents, radiological terrorism, cancer treatment, space exploration, radiosurgery for cardiac arrhythmia, and computed tomography) and the risk for developing cardiovascular disease. The evidence presented suggests an association between cardiovascular disease and exposure to low-to-moderate levels of radiation, as well as the well-known association at high doses. Studies are needed to define the extent that diagnostic and therapeutic radiation results in increased risk factors for cardiovascular disease, to understand the mechanisms involved, and to develop strategies to mitigate or treat radiation-induced cardiovascular disease.

We recently reported that daily dietary supplementation with 100 µg selenium (a dose exceeding a rat's nutritional requirement by about 33-fold) initiated immediately after total-body irradiation (TBI) and maintained for 21 weeks mitigates radiation nephropathy in a rat model as indicated by blood urea nitrogen (BUN) levels and histopathological criteria (Radiat Res. 2009; 17:368-73). In this follow-up study, we explored the risks and benefits of delaying the onset of supplementation, shortening periods of supplementation, and escalating selenium supplementation beyond 100 µg/day. Supplementation with 200 µg selenium/day (as selenite or seleno-l-methionine) substantially improved the mitigation of radiation nephropathy by lowering BUN levels at 4 months after TBI from 115 to as low as 34 mg/dl and by proportionally lowering the incidence of histopathological abnormalities. Shortening the period of supplementation to 3 or 2 months did not compromise efficacy. Delaying the onset of supplementation for 1 week reduced but did not abrogate the mitigation of radiation nephropathy. Supplementation with 300 µg/day mitigated radiation nephropathy less effectively than 200 µg and was poorly tolerated. Rats that had been given 10 Gy of TBI were less tolerant of high-dose selenium than nonirradiated rats. This reduced tolerance of high-dose selenium would need to be taken into consideration when selenium is used for the mitigation of radiation injury in victims of nuclear accidents or acts of radiological terrorism. The high dose requirements, the pronounced threshold effect, and the superior performance of selenite suggest that the mitigation of radiation nephropathy involves mechanisms that go beyond the induction of selenoproteins.

Salen Mn complexes, including EUK-134, EUK-189 and a newer cyclized analog EUK-207, are synthetic SOD/catalase mimetics that have beneficial effects in many models of oxidative stress. As oxidative stress is implicated in some forms of delayed radiation injury, we are investigating whether these compounds can mitigate injury to normal tissues caused by ionizing radiation. This review describes some of this research, focusing on several tissues of therapeutic interest, namely kidney, lung, skin, and oral mucosa. These studies have demonstrated suppression of delayed radiation injury in animals treated with EUK-189 and/or EUK-207. While an antioxidant mechanism of action is postulated, it is likely that the mechanisms of radiation mitigation by these compounds in vivo are complex and may differ in the various target tissues. Indicators of oxidative stress are increased in lung and skin radiation injury models, and suppressed by salen Mn complexes. The role of oxidative stress in the renal injury model is unclear, though EUK-207 does mitigate. In certain experimental models, salen Mn complexes have shown "mito-protective" properties, that is, attenuating mitochondrial injury. Consistent with this, EUK-134 suppresses effects of ionizing radiation on mitochondrial function in rat astrocyte cultures. In summary, salen Mn complexes could be useful to mitigate delayed radiation injury to normal tissues following radiation therapy, accidental exposure, or radiological terrorism. Optimization of their mode of delivery and other key pharmaceutical properties, and increasing understanding of their mechanism(s) of action as radiation mitigators, are key issues for future study.

From March 2009 to June 2009, a series of drills involving a hypothetical radiological dispersal device (RDD) detonation were conducted in the metropolitan area of Milwaukee, Wisconsin. Named Red Dragon, the drill constituted the largest multi-agency RDD scenario attempted to date in the United States. Froedtert Hospital and the Children's Hospital of Wisconsin comprise the Level One trauma center that served as the site for triage, decontamination, and treatment of approximately 80 victims who participated in the exercise. Examined are hospital resources, plans, interaction with external agencies, communications, and lessons learned.

Recently, many agents have been identified that target molecular pathways that can mitigate radiation toxicity. To date, no drugs have been approved as radiation injury mitigators, which are defined as agents administered after irradiation but before toxicity is manifest. In order to accelerate the application of potential mitigators for cancer patients, a meeting sponsored by the National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID) was held in January 2010. This article presents an algorithm to guide clinical trials for such agents in patients receiving radiotherapy or radiochemotherapy. It reviews the mechanisms of radiation injury, the clinical problem, the preclinical and clinical development of candidate agents, and the design and conduct of clinical trials. The central role of patient reported outcomes is outlined, as well as key lessons learned from prior clinical trials. Ultimately, the goal is to be able to apply such promising agents to improve the quality of life for patients receiving radiotherapy or chemoradiotherapy for cancer., (©2010 AACR.)