Biokinetic model analysis with DTPA administration for a case of accidental inhalation of actinides in Japan.

Accidental inhalation intake of plutonium isotopes and 241Am occurred at a Pu research facility in Japan in 2017, and the five workers involved in this accident were treated by the administration of Ca/Zn-diethylenetriaminepentaacetic acid (DTPA). For the worker who was most internally exposed, the therapy was continued over 1 y after the accident. Urinary samples collected before and after each administration were subject to bioassay to evaluate the efficacy of the dose reduction. This study performed numerical analyses using a biokinetic model dealing with 241Am-DTPA with reference to the European Coordinated Network on Radiation Dosimetry approach, which assumes that the complex of actinides and Ca/Zn-DTPA is generated in the designated compartments in the biokinetic model. The results of the model prediction well captured the trend of the observed urinary excretion in the long-term bioassay and would be useful to evaluate the efficacy of the Ca/Zn-DTPA administration for the worker involved in the accident.

No evidence of thyroid consequences in seven nuclear workers at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Plant accident: 10-year follow-up results of thyroid status.

Seven emergency nuclear workers, who had internal exposure due to an intake of radionuclides, mainly I-131, during the emergency response operation in March 2011, after the accident at the Tokyo Electric Power Company (TEPCO) Fukushima Daiichi Nuclear Power Plant (FDNPP), visited the National Institute of Radiological Sciences (NIRS) outpatient clinic for medical evaluation. They were followed up after their first visit for 10 years. The estimated committed equivalent doses to the thyroid were distributed between 3.2 to 1.2 × 10 Sv. This group thought to be received highest exposure at the accident. None of the workers had symptoms related to abnormal thyroid function. The examinations, including thyroid function tests and ultrasound, detected no abnormalities related to radiation exposure. However, there is a need for continuous monitoring of their thyroid status for longer periods in the future.

Effects of the chelating agent DTPA on naturally accumulating metals in the body.

Diethylenetriaminepentaacetate (DTPA) is the most widely used chelating agent for Pu and Am. Volunteers were assigned to receive intravenous injections or aerosol inhalations of 1 g of DTPA on days 1-4; volunteers received once daily injections of CaDTPA or ZnDTPA, CaDTPA inhalation as an aerosol, or CaDTPA injection on day 1 and ZnDTPA on days 2-4. CaDTPA injection or inhalation increased the excretion rates of Zn in urine with concomitantly reduced levels of serum Zn. Injection of CaDTPA reduced activities of serum alkaline phosphatase (AP) in parallel with the kinetics of Zn, whereas CaDTPA and ZnDTPA injection reduced activities of lactate dehydrogenase (LDH), and reduced activities of creatinine kinase (CK) were observed upon CaDTPA injection and its inhalation. Intravenous administration of CaDTPA and ZnDTPA enhanced excretion rates of Mn in urine, whereas transient reduction of Mn levels in serum was detected only via CaDTPA injection. Both CaDTPA and ZnDTPA transiently reduced levels of Mg in serum without affecting the excretion rates. On the other hand, both DTPAs increased excretion rates of toxic metals such as Pb and Cd, and CaDTPA also increased the rates of Hg. These results suggest that DTPA, and especially CaDTPA, removes essential metals and that the activities of these metalloenzymes are good indicators for the imbalance of essential metals during the DTPA administration. Our results also show that CaDTPA injection is more potent for removing these metals than ZnDTPA and inhalation of CaDTPA, and DTPA may be useful for the treatment of acute heavy metal poisoning with Pb, Cd, or Hg.

Numerical Simulation Based on Individual Voxel Phantoms for a Sophisticated Evaluation of Internal Doses Mainly From 131I in Highly Exposed Workers Involved in the TEPCO Fukushima Daiichi NPP Accident.

As a response to the Tokyo Electric Power Company's Fukushima Daiichi nuclear power plant accident in 2011, seven TEPCO workers whose exposure doses were expected to be >250 mSv (a tentative dose limit stipulated by the Japanese central authority) attended Japan's National Institute for Radiological Sciences for additional internal dose measurements. The National Institute for Radiological Sciences examination revealed that these workers' internal doses came mainly from their intake of the radionuclide I during emergency operations. In this study, we performed numerical simulations based on individual volume-pixel (voxel) phantoms of six of the seven workers for a more sophisticated evaluation of their internal doses, taking into account the individual thyroid size and other specific parameters. The voxel phantoms were created from magnetic resonance imaging scan images. As a result, the individual thyroid volumes ranged from 6.5 to 28.2 cm and were considerably smaller than the reference value (~20 cm) adopted in the International Commission on Radiation Protection's dosimetric model for four of the six subjects. Compared to the original estimates of the thyroid absorbed dose, our preliminary evaluation revealed values that were increased by approximately 3-fold or decreased by 30% at maximum. A wide difference in the individual thyroid size would be one of the significant modifiers in the current dose estimation of subjects of the ongoing epidemiological study project. The present simulations also provided evidence that the direct thyroid measurements by the National Institute for Radiological Sciences to determine the workers' I thyroid contents were sufficiently accurate.

AN ACCIDENT OF INTERNAL CONTAMINATION WITH PLUTONIUM AND AMERICIUM AT A NUCLEAR FACILITY IN JAPAN: A PRELIMINARY REPORT AND THE POSSIBILITY OF DTPA ADMINISTRATION ADDING TO THE DIAGNOSIS.

This article introduces the first accident of internal contamination with plutonium (Pu) or americium (Am) in Japan for which treatment was carried out. An accident of internal contamination with Pu and Am occurred at a Pu research facility at Oarai-town of Ibaraki prefecture in Japan. A plastic bag containing these radionuclides ruptured when five workers were inspecting a storage container in a hood. As a consequence, these workers were internally contaminated with Pu and Am. Although contamination on the body surface was observed in all five workers, a positive nasal swab was detected in only three of them. A chelating agent, calcium diethylenetriaminepenta-acetate (CaDTPA), was administered to all of them including the two workers without a positive nasal swab. However, bioassay detected a significant amount of Pu and Am in urine after administration of DTPA in these two workers, whereas the levels of these nuclides were below minimum detectable levels in urine before the administration. Since the prevalence of adverse reactions in DTPAs is low, the present results suggest that administration of DTPA can be used for the diagnosis of internal contamination even when a nasal swab is negative or contamination around body orifices is not detected.

Health effects of radiation and other health problems in the aftermath of nuclear accidents, with an emphasis on Fukushima.

437 nuclear power plants are in operation at present around the world to meet increasing energy demands. Unfortunately, five major nuclear accidents have occurred in the past--ie, at Kyshtym (Russia [then USSR], 1957), Windscale Piles (UK, 1957), Three Mile Island (USA, 1979), Chernobyl (Ukraine [then USSR], 1986), and Fukushima (Japan, 2011). The effects of these accidents on individuals and societies are diverse and enduring. Accumulated evidence about radiation health effects on atomic bomb survivors and other radiation-exposed people has formed the basis for national and international regulations about radiation protection. However, past experiences suggest that common issues were not necessarily physical health problems directly attributable to radiation exposure, but rather psychological and social effects. Additionally, evacuation and long-term displacement created severe health-care problems for the most vulnerable people, such as hospital inpatients and elderly people.

The accident at the Fukushima Daiichi Nuclear Power Plant in 2011.

A huge earthquake struck the northeast coast of the main island of Japan on 11 March 2011, triggering a tsunami with more than 10-m-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake and aftershocks left almost 16,000 people dead and more than 2,800 missing (as of 11 March 2014). The earthquake affected the Fukushima Daiichi Nuclear Power Plant (NPP) of Tokyo Electric Power Company (TEPCO), causing serious damage to the NPP and resulting in large amounts of radioactive materials being released into not only controlled areas but also the environment. Damage was caused to the cooling systems of the NPP, although they automatically shut down after the earthquake. The trouble with the cooling systems led to hydrogen explosions and core meltdown. The major nuclides released on land were ¹³¹I, ¹³4Cs, and ¹³7Cs. The release of these radioactive materials resulted in contamination of first responders and workers and also a high ambient dose of radiation around the NPP. The local hospital system, including that for radiation emergency medicine, was dysfunctional. Hospitals that had been designated as radiation emergency facilities were not able to function because the earthquake and tsunami had caused damage to their facilities; some of these were located within a 20-km radius of the NPP and in the evacuation areas. Local fire department personnel were also ordered to evacuate. Fukushima prefecture changed the screening level required for decontamination from 13,000 to 100,000 cpm, with decontamination by wiping being performed for over 13,000 cpm. However, as hospitals and fire departments had to abide by lower levels than that of the prefecture for receiving or transporting contaminated patients, these personnel could not accept or transport contaminated people from the NPPs. In addition, hospitals not designated as radiation emergency facilities would not receive patients from the NPPs because of concerns about the health effects of radiation. From this disaster, it was learned that basic knowledge of radiation and its effects is extremely important for health care providers.

Medical management of the consequences of the Fukushima nuclear power plant incident.

A huge earthquake struck the northeast coast of the main island of Japan on March 11, 2011, triggering a tsunami with 14-15 meter-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake affected the nuclear power plant (NPP) in Fukushima prefecture, resulting in large amounts of radioactive materials being released into the environment. The major nuclides released on land were ¹³¹I, ¹³4Cs, and ¹³7Cs. Therefore, almost 170,000 people had to be evacuated or stay indoors. Besides the NPP and the telecommunications system, the earthquake also affected infrastructures such as the supplies of water and electricity as well as the radiation monitoring system. The local hospital system was dysfunctional; hospitals designated as radiation-emergency facilities were not able to function because of damage from the earthquake and tsunami, and some of them were located within a 20 km radius of the NPP, the designated evacuation zone. Local fire department personnel were also asked to evacuate. Furthermore, the affected hospitals had not established their evacuation plans at that time. We have learned from this "combined disaster" that the potential for damage to lifelines as well as the monitoring systems for radiation in case of an earthquake requires our intense focus and vigilance, and that hospitals need comprehensive plans for evacuation, including patients requiring life support equipment during and after a nuclear disaster. There is an urgent need for a "combined disaster" strategy, and this should be emphasized in current disaster planning and response.

Screening of Residents Following the Tokyo Electric Fukushima Daiichi Nuclear Power Plant Accident.

ABSTRACT: On 11 March 2011, the Great Eastern Japan Earthquake occurred, causing the accident at the Fukushima Daiichi Nuclear Power Plant of Tokyo Electric Power Co. Residents were surveyed for contamination, and hospitalized patients within a 30-km area were transferred. In this report, the authors review the results of the survey and the effects. The screening teams measured total body contamination of each person using a Geiger-Mueller survey meter. Decontamination level was set at 100 kcpm (100,000 cpm). For levels of 13 to <100 kcpm, decontamination by wiping was planned and took place. Contamination screening during 11-21 March 2011, was carried out for 72,660 people at 200 sites. From 12 March 2011 until 10 February 2012, a total of 244,281 people were screened. As a result, there were 110 cases exceeding 100 kcpm, and 901 cases with contamination levels of 13-100 kcpm. The number of contaminated individuals screened reached a peak from 16-18 March. In the accident, contamination screening of victims and residents was performed to deal with anxiety and discrimination toward the residents. Although there was some early delay, almost all of the evacuees were relatively promptly screened. There was no external contamination at levels thought to affect the health of residents. In addition, the detection of contamination levels over 13 kcpm peaked between 15-22 March. Considering factors such as the evacuation period, this suggests that even if iodine tablets had been administered during this time, they would not have been effective.

[Radiation emergency medical preparedness in Japan--lessons learned from the Fukushima accident].

Although radiation exposure accidents fortunately occur only rarely, potential sources for exposure accidents can be found anywhere. When persons are accidentally exposed to radiation, physicians may be involved in their assessment and care; of course, their early diagnosis and dose assessment are crucial. After the criticality accident at Tokaimura in 1999, the system of radiation emergency medical preparedness has been further strengthened for nuclear facilities in Japan. In the revised system, hospitals involved were classified into three levels, depending on their locations and capabilities. The Great East Japan Earthquake attacked the Pacific coast area of eastern Japan on 11 March 2011. This earthquake and tsunami caused serious damage to the nuclear power plants of Tokyo Electric Power Co.(TEPCO) in Fukushima Prefecture; a large amount of radionuclides such as iodine and cesium were released into the environment. Since the revised system was focused on treatment of heavily exposed patients and knowledge on radiation was not enough for medical staff, many problems were raised at hospitals and fire departments in this disaster.

Exogenously-added copper/zinc superoxide dismutase rescues damage of endothelial cells from lethal irradiation.

The vascular endothelium is important for the early and late effects observed in lethally irradiated tissue and organs. We examined the effects of exogenously added superoxide dismutase on cell survival and angiogenesis in lethally irradiated human primary umbilical vein endothelial cells. Cell survival was significantly improved in superoxide dismutase-treated cells; the addition of superoxide dismutase to cells after irradiation was also effective for increased survival, as it was before irradiation. Moreover, treatment of cells with superoxide dismutase enhanced the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases 1 and 2 in human primary umbilical vein endothelial cells. The addition of superoxide dismutase to cells after irradiation attenuated the reduction of angiogenesis by irradiation, and inhibition of the mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases signaling pathway abrogated the rescue effect of superoxide dismutase. Our results suggest that superoxide dismutase rescues human primary umbilical vein endothelial cells from endothelial dysfunction caused by irradiation via a pathway requiring activation of mitogen-activated protein/extracellular signal-regulated kinase/extracellular signal regulated kinases 1 and 2.

Structure-activity relationships of estrogen derivatives as aromatase inhibitors. Effects of heterocyclic substituents.

Aromatase, which is responsible for the conversion of androgens to estrogens, is a potential therapeutic target for the selective lowering estrogen level in patients with estrogen-dependent breast cancer. We prepared and tested series of the pyridine- and other heterocyclic ring-containing derivatives of 2- and 4-aminoestrones, estrone, and estradiol, compounds 5, 10, 12 and 15. The isonicotinyl derivatives of 2- and 4-aminoestrone, compounds 5c and 10c, were fairly potent competitive inhibitors of aromatase (K(i), 2.1+/-0.14 and 1.53+/-0.08 microM for 5c and 10c, respectively) and other compounds did not show, to a significant extent, the aromatase inhibitory activity. This result suggests that the isonicotinyl-substituted derivatives 5c and 10c would be accessible to the active site of aromatase.

Inhibition of estrone sulfatase by aromatase inhibitor-based estrogen 3-sulfamates.

Our rationale is based on the finding that estrone 3-sulfamate (EMATE, 2d), a typical estrone sulfatase (ES) inhibitor, can be hydrolyzed and the pharmacological effect of the free estrogen contributes to the bioactivity of the sulfamate. A number of 3-sulfamoylated derivatives of the good aromatase inhibitors, 2- and 4-halogeno (F, Cl, and Br) estrones and their estradiol analogs as well as 6beta-methyl and phenyl estrones, were synthesized and evaluated as inhibitors of ES in human placental microsomes in comparison with the lead compound EMATE. Among them, 2-chloro- and 2-bromoestrone 3-sulfamates (2b and 2c), along with their estradiol analogs 3b and 3c, were powerful competitive inhibitors with K(i)'s ranging between 4.0 and 11.3 nM (K(i) for EMATE, 73 nM). These four sulfamates as well as the 2-fluoro analogs 2a and 3a inactivated ES in a time-dependent manner more efficiently than EMATE, and 2-halogeno estrone sulfamates 2 also caused a concentration-dependent loss of ES activity. The results may be useful for developing a new class of drugs having a dual function, ES inhibition and aromatase inhibition, for the treatment of breast cancer.

Structure-activity relationships of 2-, 4-, or 6-substituted estrogens as aromatase inhibitors.

Aromatase, which is responsible for the conversion of androgens to estrogens, is a potential therapeutic target for the selective lowering of estrogen levels in patients with estrogen-dependent breast cancer. To develop a novel class of aromatase inhibitors, we tested series of 2- and 4-substituted (halogeno, methyl, formyl, methoxy, nitro, and amino) estrones (7 and 9), as well as series of 6alpha- and 6beta-substituted (alkyl, phenalkyl, and alkoxy) estrones (13 and 14), and their estradiol analogs (8, 10, 11, and 12) as aromatase inhibitors. All of the inhibitors examined blocked the androstenedione aromatization in a competitive manner. Introduction of halogeno and methyl functions at C-2 of estrone as well as that of a phenalkyl or methyl function at the C-6alpha or C-6beta position markedly increased affinity to aromatase (apparent K(i) value=0.10-0.66 microM for the inhibitors versus 2.5 microM for estrone). 6alpha-Phenylestrone (13c) was the most powerful inhibitor among the estrogens studied, and its affinity was comparable to that of the androgen substrate androstenedione. Estradiol analogs were much weaker inhibitors than the corresponding estrone compounds in each series, indicating that the 17-carbonyl group plays a critical role in the formation of a thermodynamically stable enzyme-inhibitor complex.