Sep 15, 2014

Nobuyuki HAMADA (Central Research Institute of Electric Power Industry)

In 2011, the International Commission on Radiological Protection issued a statement on tissue reactions (formerly termed non-stochastic or deterministic effects) to recommend lowering the threshold for cataracts and the occupational equivalent dose limit for the crystalline lens of the eye. Furthermore, this statement was the first to list circulatory disease (cardiovascular and cerebrovascular disease) as a health hazard ofradiation exposure and to assign its threshold for the heart and brain. These changes have stimulated various discussions and may have impacts on some radiation workers, such as those in the medical sector. This paper considers emerging issues associated with cataracts and cardiovascular disease. For cataracts, topics dealt with herein include (i) the progressive nature, stochastic nature, target cells and trigger events of lens opacification, (ii) roles of lens protein denaturation, oxidative stress, calcium ions, tumor suppressors and DNA repair factors in cataractogenesis, (iii) dose rate effect, radiation weighting factor, and classification systems for cataracts, and (iv) estimation of the lens dose in clinical settings. Topics for cardiovascular disease include experimental animal models, relevant surrogate markers, latency period, target tissues, and roles of inflammation and cellular senescence. Future research needs are also discussed.

Reference:
Hamada et al. Emerging issues in radiogenic cataracts and cardiovascular disease.
J Radiat Res 55, 831-846 (2014)
http://jrr.oxfordjournals.org/content/55/5/831.long

Sep 14, 2014

Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University) 

We carried out two kinds of studies using naturally occurring radioactive material (NORM). First, effects of application of ultralow volume radionuclides (UVR-cream) on carrageenan-induced inflammatory paw edema were examined. A wide range of health products have been developed using the activation of biological functions by low-dose irradiation. These goods contain ore with naturally occurring radionuclides. Although health products containing ultralow volume radionuclides are available for sale, most goods are not tested for the effectiveness of the claimed effects. Therefore, it is reasonable to regulate goods containing NORM in order to reduce unnecessary exposure to radiation. The purpose of this study was to determine treatment with whether cream containing UVR-cream activates antioxidative functions and protects against carrageenan-induced inflammatory paw edema in mice. Results showed that carrageenan administration induced paw edema; however, application of UVR-cream significantly decreased paw volume at 4 hours. Application of UVR-cream produced slight improvement in carrageenan-induced paw edema compared with sham cream. However, no significant changes were observed in paw edema between sham cream and UVR-cream. Carrageenan administration significantly decreased catalase activity and total glutathione content in paw. No significant changes were observed in the catalase activity or total glutathione content in paw among carrageenan-only, sham cream, and UVR-cream. In conclusion, the effects of UVR-cream differed from the beneficial effects induced by low-dose irradiation, since application of the cream did not activate antioxidative functions [1].
Next, we examined effects of radon inhalation (radon source; DOLL STONE, Ningyotoge Gensiryoku Sangyo, Co., Ltd. Okayama, Japan) on transient global cerebral ischemic injury in gerbils, because our previous study suggested that radon inhalation therapy might mitigate brain disorders. Gerbils were treated with inhaled radon at a concentration of 2000 Bq/m3 for 24 hours. After radon inhalation, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that transient global cerebral ischemia induced neuronal damage in hippocampal CA1, and the number of damaged neurons was significantly increased compared with control. However, radon treatment inhibited ischemic damage. Superoxide dismutase (SOD) activity in radon-treated gerbil brain was significantly higher than in sham-operated gerbils. These findings suggested that radon inhalation activates antioxidative function, especially SOD, thereby inhibiting transient global cerebral ischemic injury in gerbils [2].

References: 
[1]. Kataoka T, Takata Y, Etani R, Nishiyama Y, Kawabe A, et al. (2014) Effects of Cream Containing Ultralow Volume Radionuclides on　Carrageenan-Induced Inflammatory Paw Edema in Mice.
Biochem Physiol 3: 133 doi: 10.4172/2168-9652.1000133
[2]. Kataoka T, Etani R, Takata Y, Nishiyama Y, Kawabe A, Kumashiro M, Taguchi T, Yamaoka K. Radon Inhalation Protects Against Transient Global Cerebral Ischemic Injury in Gerbils. 
Inflammation. 2014 May 3. [Epub ahead of print] PMID: 24792782

Sep 14, 2014

Hironori YOSHINO (Hirosaki University Graduate School of Health Sciences) 

Pattern recognition receptors recognize pathogen-associated molecular patterns. Among these, Toll-like receptors (TLRs) have well-characterized roles in antibacterial and antiviral immunity. In the present study, the effects of ionizing radiation on the expression of TLRs and cellular responses to ligands were investigated in THP1 monocytes (human monocytic leukemia cells) and THP1-derived macrophage cells (macrophage-like cells), which are induced by culturing in the presence of phorbol 12-myristate 13-acetate. TLR2 and TLR4 expression was detected in THP1 and macrophage-like cells, X-irradiation caused increased expression of these TLRs in THP1 and decreased expression in macrophage-like cells. Responses to FSL-1 (TLR2 ligand) and lipopolysaccharide (LPS, TLR4 ligand) were estimated by determining the induction of tumor necrosis factor-α (TNF-α). After FSL-1 or LPS stimulation, TNF-α induction was greater in X-irradiated THP1 monocytes than in non-irradiated cells. However, although TNF-α expression was not affected by X-irradiation in macrophage-like cells, the expression of LPS-inducible interferon-β was lower following X-irradiation of macrophage-like cells. To clarify the mechanisms of TLR2 and TLR4 regulation by X-irradiation, expression of mitogen-activated protein kinase was investigated. These experiments showed that c-Jun N-terminal kinase (JNK) mediated increases in TLR expression in X-irradiated THP1 monocytes, and decreases in TLR expression in X-irradiated macrophage-like cells. This study demonstrates that ionizing radiation modulates ligand-responsive TLR expression through the JNK pathway depending on differentiation state. 

References: 

Yoshino et al. Ionizing radiation affects the expression of Toll-like receptors 2 and 4 in human monocytic cells through c-Jun N-terminal kinase activation.
J Radiat Res. 2014 Jun 13. pii: rru040. [Epub ahead of print] PubMed PMID: 24927726.

Aug 08, 2014

Nobuyuki HAMADA (Central Research Institute of Electric Power Industry)

Radiation exposure causes cancer and non-cancer health effects, each of which differs greatly in the shape of the dose-response curve, latency, persistency, recurrence, curability, fatality and impact on quality of life. In recent decades, for dose limitation purposes, the International Commission on Radiological Protection has divided such diverse effects into tissue reactions (formerly termed non-stochastic and deterministic effects) and stochastic effects. On the one hand, effective dose limits aim to reduce the risks of stochastic effects (cancer/heritable effects) and are based on the detriment-adjusted nominal risk coefficients, assuming a linear-non-threshold dose response and a dose and dose rate effectiveness factor of 2. On the other hand, equivalent dose limits aim to avoid tissue reactions (vision-impairing cataracts and cosmetically unacceptable non-cancer skin changes) and are based on a threshold dose. However, the boundary between these two categories is becoming vague. Thus, we review the changes in radiation effect classification, dose limitation concepts, and the definition of detriment and threshold. Then, the current situation is overviewed focusing on (i) stochastic effects with a threshold, (ii) tissue reactions without a threshold, (iii) target organs/tissues for circulatory disease, (iv) dose levels for limitation of cancer risks vs prevention of non-life-threatening tissue reactions vs prevention of life-threatening tissue reactions, (v) mortality or incidence of thyroid cancer, and (vi) the detriment for tissue reactions. For future discussion, one approach is suggested that classifies radiation effects according to whether effects are life threatening, and radiobiological research needs are also briefly discussed. 

Reference:
Hamada and Fujimichi. Classification of radiation effects for dose limitation purposes: history, current situation and future prospects. 
J Radiat Res 55, 629-640 (2014)
http://http://jrr.oxfordjournals.org/content/55/4/629.full

May 20, 2014

Nobuyuki HAMADA (Central Research Institute of Electric Power Industry) 

Exactly a century after Röntgen's discovery of X rays, I entered a university to major in radiological sciences. At that time, I felt that, despite extensive use and indispensable roles of ionizing radiation in medicine and industry, many fascinating questions have yet to be answered concerning its biological mechanisms of action, and thus I decided to get into the field of radiation research. Fifteen years have passed since I started radiobiological studies in 1998, during which time various basic tenets I initially learned in my late teens and early twenties have been challenged by recent observations. Of these, this brief overview particularly focuses on the following five different albeit non mutually exclusive questions: (i) "Is nuclear DNA the only intracellular target for radiation effects?"; (ii) "What is the significance of delayed cell death in clonogenic survival?"; (iii) "Does an irradiated cell become a cancer cell?"; (iv) "Are cataracts tissue reactions?"; and (v) "Why is high-LET radiation biologically effective?". 

Reference: 
Hamada. What are the intracellular targets and intratissue target cells for radiation effects? 
Radiat Res 181, 9-20 (2014) 
http://www.ncbi.nlm.nih.gov/pubmed/24369848 

May 18, 2014

Yuki FUJIMICHI (Central Research Institute of Electric Power Industry) 

Over the past century, ionizing radiation has been known to induce cataracts in the crystalline lens of the eye, but its mechanistic underpinnings remain incompletely understood. This study is the first to report the clonogenic survival of irradiated primary normal human lens epithelial cells and stimulation of its proliferation. Here we used two primary normal human cell strains: HLEC1 lens epithelial cells and WI-38 lung fibroblasts. Both strains were diploid, and a replicative lifespan was shorter in HLEC1 cells. The colony formation assay demonstrated that the clonogenic survival of both strains decreases similarly with increasing doses of X-rays. A difference in the survival between two strains was actually insignificant, although HLEC1 cells had the lower plating efficiency. This indicates that the same dose inactivates the same fraction of clonogenic cells in both strains. Intriguingly, irradiation enlarged the size of clonogenic colonies arising from HLEC1 cells in marked contrast to those from WI-38 cells. Such enhanced proliferation of clonogenic HLEC1 cells was significant at ?2 Gy, and manifested as increments of ?2.6 population doublings besides sham-irradiated controls. These results suggest that irradiation of HLEC1 cells not only inactivates clonogenic potential but also stimulates proliferation of surviving uniactivated clonogenic cells. Given that the lens is a closed system, the stimulated proliferation of lens epithelial cells may not be a homeostatic mechanism to compensate for their cell loss, but rather should be regarded as abnormal. This is because these findings are consistent with the early /in vivo/ evidence documenting that irradiation induces excessive proliferation of rabbit lens epithelial cells and that suppression of lens epithelial cell divisions inhibits radiation cataractogenesis in frogs and rats. Thus, our /in vitro/ model will be useful to evaluate the excessive proliferation of primary normal human lens epithelial cells that may underlie radiation cataractogenesis, warranting further investigations. 

Reference: 
Fujimichi and Hamada. Ionizing irradiation not only inactivates clonogenic potential in primary normal human diploid lens epithelial cells but also stimulates cell proliferation in a subset of this population. 
PLOS ONE. 9, e98154 (2014) 
http://dx.plos.org/10.1371/journal.pone.0098154