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.

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.

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 Animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. The rabbit is an established animal model accepted by the FDA for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as HIV. The purpose of this study was to investigate the New Zealand White (NZW) Rabbit model as a model of acute radiation exposure because of its established similarity to human vascular, immune, and coagulation responses. Materials and methods Two sequential studies were performed in a total of 81 male NZW rabbits, 16-20 weeks of age. All animals underwent clinical observations and peripheral blood analyses following a single dose of 0, 6, 7, 8, 8.5, 9, or 10 Gy of total body irradiation via a 6 MV Linear accelerator photon source on day 0. Animals were treated with timed release fentanyl patch (days 0-30), subcutaneous hydration (day 1, Study 2 only), and oral sulfamethoxazole/trimethoprim 30 mg/kg once daily (days 3-30) and were followed for 30 days or to time of mortality. Results Study 1 revealed the estimated LD30, -50, -70, and -90 with 95% confidence intervals (CI) at 30 days to be 6.7 (CI: 5.9-7.4), 7.3 (CI: 6.7-7.8), 7.9 (CI: 7.3-8.4), and 8.8 (CI: 7.9-9.7) Gy, respectively. In study 2, a survey of blood coagulation and biochemical parameters were performed over time and necropsy. Complete blood counts taken from animals exposed to 7, 8, or 10 Gy, demonstrated dose-dependent depletion of lymphocytes, neutrophils, and platelets. Platelet counts recovered to baseline levels in survivors by day 30, whereas lymphocyte and neutrophil counts did not. Decedent animals demonstrated grade 3 or 4 neutropenia and lymphopenia at time of death; 64% of the decedents experienced a 30% or greater drop in hematocrit. Decedent animals demonstrated more than 100% increases from serum baseline levels of blood urea nitrogen, creatinine, aspartate aminotransferase, and triglyceride levels at the time of death whereas survivors on average demonstrated modest or no elevation. Conclusion This NZW rabbit model demonstrates dose-dependent depletion of hematopoietic parameters. The LD50/30 of 7.8 Gy (95% CI: 6.6-8.4) with supportive care appears to be close to the ranges reported for rhesus macaques (5.25-7.44 Gy) and humans (6-8 Gy) with supportive care. These findings support the utility of the NZW rabbit model for further mechanistic investigation of acute radiation exposure and medical countermeasure testing.

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: 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.

Objectives: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Materials and Methods: Eligible patients included stage II-IIIB non–small cell lung cancer, stage I central non–small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Results: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients’ refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Conclusions: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

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.

In this work we present the personal exposure levels to Radiofrequency Electromagnetic Fields (RF-EMF) from Wireless Fidelity (Wi-Fi) 2.4 GHz and 5.85 GHz bands in a Spanish university, specifically, at the Faculty of Computer Science Engineering at the University of Castilla-La Mancha (Albacete, Spain). We present results from three years, 2017, 2018 and 2019 in the same study place and points; and measurements carried out in 2022 inside a classroom and inside a professor's office, with the aim to compare the measurements and verify compliance with reference levels established by the International Commission on Non-Ionizing Radiation Protection (ICNIRP).The minimum average was 0.0900 μW/m2 in the 2.4 GHz Wi-Fi, in 2019, and the maximum average was 211 μW/m2 in the 5.85 GHz Wi-Fi in 2017, around the building. Comparing the measurements carried out inside the classroom with students and without students, we identified that the maximum value was 278 μW/m2 (classroom with students, in the 5.85 GHz Wi-Fi band) and the minimum value was 37.9 μW/m2 (classroom without students, in the 5.85 GHz Wi-Fi band). Finally, comparing the results of all the measurements (average values) inside the classroom and inside a professor's office, the maximum value was 205 μW/m2 (in the 5.85 GHz Wi-Fi band) inside the classroom with students, and the minimum value was 0.217 μW/m2 inside a professor's office (in the 2.4 GHz Wi-Fi band). These values in no case exceed the limits established by the International Commission on Non-Ionizing Radiation Protection, 10 W/m2 for general public exposure.

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 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.

The accompanying article by Zentai et al. (1) investigates possible effects of radiofrequency (RF) energy from Wi-Fi signals on human brain wave activity. The possible existence of cognitive effects of RF energy has been one of the more contentious discussions in the forevercontentious issue of whether exposure to RF energy at levels that we all commonly encounter in the environment has any health consequences. Are there any physiological effects from such exposures; and if so, do they have any health significance to exposed individuals? To date, more than 100 studies have been published on effects of RF energy on electroencephalograms (EEGs) recorded in sleeping or awake individuals [for reviews see Regel and Achermann (2) and van Rongen et al. (3)]. In addition, many studies have examined other end points related to cognition and brain function. Not unreasonably, most of these studies were directed at uncovering possible biological effects from use of mobile phones or other communications equipment held close to the head. While the results are mixed, a fairly consistent finding is that short (10–20 min) RF energy exposures to the head produce small, but statistically significant, changes in the EEG of resting and sleeping subjects, most commonly a decrease in the amplitude of the EEG signal in the alpha band (8–12 Hz). In some studies, no clear changes were observed from exposures to mobile phone RF [e.g., Loughran et al. (4)], while other studies point to RF-related electrode artifacts as a potential source of error (5). In their reviews of the subject, most health agencies acknowledge these findings, but do not consider them as evidence for adverse health effects. For example, a recent review sponsored by the European Commission (6) concluded that ‘‘relevance of the small physiological changes remains unclear and mechanistic explanation is still lacking’’. Now Zentai and colleagues have waded into this morass, searching for effects of a single hour-long exposure to WiFi signals on resting EEG and other end points related to cognition in humans. This well-designed study has meticulous exposure assessment and careful statistical analysis. Arguably, it is one of the best studies on effects of RF energy on human cognition in the literature; and its results were completely negative. While there is a scattering of articles related to biological effects of Wi-Fi signals (7), there is an almost complete dearth of studies on effects of Wi-Fi signals on human cognition. In 2011, Papageorgiou et al. (8) reported that WiFi exposure (from an access point mounted 1.5 m from the subjects) caused statistically significant reductions in the amplitude of event-related potentials (P300 response) in subjects performing linguistic tasks. However, the Zentai and Papageorgiou studies are quite different and their results are neither mutually supportive nor contradictory. The frequency range of exposure (2.45 GHz) used in Zentai’s study was broadly similar to the operating frequency of cellular telephones (which operate in several bands from 698 to 2,690 MHz) but the exposure levels were far smaller. Mobile phones and Wi-Fi transmitters both emit RF energy in the form of pulses, at (very roughly) similar peak output powers [up to about 0.1 W (Wi-Fi) and 1 W (cell phone)]. Phones typically transmit energy at high duty cycles (i.e., a high fraction of their time is spent transmitting). The duty cycle for Wi-Fi access points (the little boxes in the home that transmit Wi-Fi signals throughout the house) and client cards (the transmitters that are built into laptop computers and smart phones that connect the devices to the wireless network) varies tremendously depending on the user’s activity and network conditions. The average duty cycle may be ,0.1% for a laptop when the user is simply surfing the Internet or reading emails. But peak duty cycles for access points may exceed 50% for brief periods in very heavily loaded networks where a large number of users are uploading or downloading media. When held against the head, a mobile phone will produce a peak specific absorption rate (SAR) in the head of the order of 1 W/kg averaged over 10 g of tissue, with very roughly ten times lower exposure levels in the brain itself. The Wi-Fi access point used in the Zentai study was 1 Address for correspondence: Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226; email: jmoulder@mcw.edu.

Normal tissue radiation injury is a common complication of radiation therapy and is also a major concern after accidental or belligerent radiation exposure, and until recently, it was deemed untreatable. Both experimental and clinical evidence now show that radiation injury can be alleviated by agents started after irradiation but before manifestation of that injury (a therapeutic approach called “mitigation”). Mitigation of normal tissue injuries would improve clinical radiation therapy, and it will be an essential medical countermeasure for accidental or belligerent radiation exposures. In rat radiation nephropathy models over 30 potential mitigators have been tested, some (e.g., angiotensin converting enzyme inhibitors and angiotensin II receptor blockers) have been found to be quite effective, but many others appear ineffective, and a few have actually made injury worse. For the most part, work with the successful agents, and the agents that made radiation injury worse, is in the peer-reviewed literature. However, we have found it difficult to publish information on the agents that were ineffective, although we suspect that others have tried some of the same agents and also found them ineffective. Here, we review all agents we know of that have been tested to date in rat radiation nephropathy models, with the goal of helping to prevent needless duplication of studies.

Kamiya and colleagues (Aug 1, p 469)1 provide a timely report of the late-onset effects of wartime and accidental radiation exposure and briefly mention chronic kidney disease as a potential late-onset effect. Chronic kidney disease is a clinically significant, but underappreciated, late-onset complication of haemopoietic stem-cell transplantation that is often linked to total body irradiation before transplantation.2 Partial or total body exposures to radiation doses as low as 5 Gy in a single fraction are not lethal but can lead to radiation nephropathy.

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 totaland 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.