Year : 2020 | Volume
: 11 | Issue : 3 | Page : 73--80
Low-dose radiobiology: Opportunities for new research and technology for anticancer and anti-COVID-19 strategies
Kaushala Prasad Mishra
Ex Bhabha Atomic Research Center; Foundation for Education and Research, Ghatkopar (E), Mumbai, India
Dr. Kaushala Prasad Mishra
Ex Bhabha Atomic Research Center; Foundation for Education and Research, Ghatkopar (E), Mumbai
Biological responses to low-dose and high-dose radiations are markedly different; the former produce beneficial effects and the latter at acute doses cause detrimental health effects such as cancer induction. High-dose radiations (>2 Gy) of low linear energy transfer are widely used in the treatment of cancer, but limitations are imposed due to normal tissue adverse reactions. Low-dose radiations (LDRs), such as X-rays (a few mGy), have been widely used in diagnosis of many diseases without any known adverse health effects. LDR preexposures have been known to suppress cancer induction by acute doses of radiation. This article briefly reviews the possible applications of LDR in cancer therapy and delineates the underlying radiobiological mechanisms in suppressing high-dose-induced cancer. It is further argued to develop LDR technology in preventing and for palliative outcomes in fighting COVID-19 pandemic infection among the populations. Furthermore, it is suggested to examine the average number of people living in high background radiation areas for susceptibility to COVID-19 infection and compare with the average infection rate in the general public for gaining new knowledge on the response of LDR-exposed population.
|How to cite this article:|
Mishra KP. Low-dose radiobiology: Opportunities for new research and technology for anticancer and anti-COVID-19 strategies.J Radiat Cancer Res 2020;11:73-80
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Mishra KP. Low-dose radiobiology: Opportunities for new research and technology for anticancer and anti-COVID-19 strategies. J Radiat Cancer Res [serial online] 2020 [cited 2020 Dec 2 ];11:73-80
Available from: https://www.journalrcr.org/text.asp?2020/11/3/73/296556
Biological effects of ionizing radiation (BEIR) continue to attract the focus of researchers after decades of discoveries of X-rays and radioactivity. The excitements of early years for growing medical and industrial applications of ionizing radiation in scientific community as well as the general public were subdued by the adverse health effects of ionizing radiation reported gradually among researchers. Scientists accepted the challenge and subsequent active radiobiology research threw light on the underlying mechanisms of radiation action and laid the foundation for the public safety. Importantly, the use of X ray revolutionized the field of diagnosis and imaging. Also, computed tomography (CT) and nuclear medicine procedures became important radiation techniques in medical care and these procedures became the sought after radiation techniques in medical care. Extensive studies on biological effects of radiation on cells, tissue, and animal models brought the much-awaited molecular mechanisms of radiation effect, setting the grounds for radioprotection.,, One of the long-term radiation health effects of high-dose radiation turned out the incidents of cancer. The perceived fear of high-dose radiation carcinogenesis profoundly hampered the low-dose radiobiological research and potential exploration of low-dose radiation (LDR) beneficial effects became a low priority research. Studies from the Japanese atomic bomb survival population, however, showed that radiation is a weak carcinogen and LDR did not produce significant excess cancer in the surviving population affected in low-dose range.,,,
A most significant fact that became known from radiobiological and epidemiological studies on a wide range of doses lay in the realization of different effects of low-dose radiation (a few tens of mGy) and of the high doses (>1 Gy or 1000 mGy)., In the 1950s, the hypothesis of the linear no-threshold (LNT) model became the basis for radiation safety regulation which states that every exposure of ionizing radiation, no matter how small, constitutes increased cancer risk. The LNT model (i.e. risk was linear with the dose) was mainly based on the radiation mutation theory of cancer based on the Drosophila fruit fly research, for which Herman Joseph Muller was awarded Nobel Prize in Physiology and Medicine in 1946., Today, the basis for safety regulation is based on the LNT model from high-dose ranges (deterministic effects). On the contrary, the nature of LDR effects (stochastic effects) has remained relatively poorly explored due to low priority accorded and poor funding support availability. In the past decades, mainly from the analysis of data from A-bomb survivors, scientists have frequently questioned LNT model, but the issue of the threshold model or LNT model remains controversial and unsettled.,,,,
Among others, enormous health benefits have been derived from the extensive use of ionizing radiation such as X-ray in diagnosis and imaging of diseases, gamma radiation in cancer treatment, and nuclear medicine procedures. It needs to be noted that applications of LDR using X ray in diagnosis of a variety of diseases and its use for the treatment of certain cancers was considered quite some time ago. Needless to say, radiation and nuclear technologies have been increasingly serving the humankind for power, health, industry, agriculture, and medicine. However, undeniably LNT model has unduly stymied the potential development of LDR therapy (LDRT) technology in medicine.,, Present communication is intended to briefly give an account of the latest LDR research scenario and to arouse renewed research interest for optimization of the LDR window for diagnosis and treatment of cancers. Further, an attempt has been made to extend and apply these principles in tackling other diseases, especially COVID-19 pandemic infection. It is argued that greater efforts are urgently warranted on LDR research to determine beneficial window of doses (within a few to a few tens of mGray) of low LET radiation, which are generally considered safe but are known to elicit stimulatory and anti-inflammatory tissue responses. It is particularly emphasized that enormous new prospect exists for identifying and optimizing window of low doses for therapeutic applications to certain types of cancer. Considering the present context of COVID-19 pandemic, enormous new opportunity seems in sight for exploiting anti-inflammatory and immune activation abilities of LDR in controlling and treatment of COVID-19 pandemic infection. Evidently, the low-dose radiobiology research has become more relevant now than ever in the history of science and is perhaps set to offer appropriate treatment procedure. It opened the door for developing novel technologies for diagnosis and therapy of cancer and virus diseases to meet the present global public health challenges.
High-Dose Radiobiology for Radiotherapy
It is well accepted that high doses of radiation (>500 mGy to tens of Grays) are widely used in the treatment of cancer and other applications. Radiobiological studies have revealed that cellular targets for radiation action are proteins, membrane, and genetic molecule DNA. In fact, for many years, studies on radiation damage to DNA at high doses occupied the attention of researchers yielding a wealth of knowledge on how cells were damaged and repaired by inbuilt defense machinery. However, unrepaired damages caused a mutation that may lead to either cancer or killing of irradiated cells.,, It is now well accepted that the long-term effects of acute radiation doses induce cancer. However, even before understanding the underlying mechanisms, physicians were quick to utilize the ability of radiation to kill cancer cells which allowed establishing cancer radiotherapy departments in hospitals. Of course, radiobiological research on molecular/cellular damage, DNA repair mechanisms, oxygen effects, etc., has been gainfully utilized in optimizing cancer treatment in the clinic.,, Over the years, notable progress has been made in improving radiation cancer treatments, and of course, the research attempts to continue to maximize the treatment outcome for the patients. It is, however, widely recognized that high doses of radiation kill cancer cells but cause unintended injuries to surrounding normal cells and may cause secondary cancer, thus limiting the treatment. Despite the fact that cancer radiotherapy is one of the major treatment modalities for >40% of cancer patients, limitations on treatment are encountered due to unacceptable adverse normal tissue damages. At present, physicians and scientists are faced with the concern of secondary tumor to nontarget surrounding tissues in the radiotherapy procedure. At this point of time, the guideline for the regulation of radiation doses has been based on research findings at high doses of radiation. LNT model has been in practice internationally for radiation protection in radiotherapy procedures. Unfortunately, the fact that cellular damage is repairable due to inbuilt defense machinery has been persistently ignored by LNT proponents. Although the existence of cellular defenses and related research results point to threshold model, the scientific community remains divided on this issue. Notably, research contributions from our group at Bhabha Atomic Research Center (BARC) and other world over researchers are engaged in improving radiotherapy combining radiation with certain herbal drugs which have shown enhanced tumor cell killing with minimal or no effects on normal cells.,,,,, These research results may help to reduce radiation dose to improve therapeutic outcomes in cancer treatment without producing undesirable injuries to normal cells. It is significant to note that new research on targeted and selective radiotoxicity to tumor cells in vitro conditions and their validation in animal models are expected to pave the way for clinical trials.
Need for Renewed Low-Dose Radiation Radiobiological Research
In aeneral, radiation-induced DNA damage is repaired by the built-in cellular defense machinery. The effect of low-dose irradiation can be determined by the balance between the rate of DNA damage (increasing linearly with the dose) and the rate of DNA repair. Interestingly, the DNA repair mechanisms are found functional at low doses, but they become less efficient with the increasing doses. It is to be noted that beneficial effects tend to outweigh the detrimental effects at single doses in low-dose range (<100 mGy). More importantly, irradiations at low doses stimulate protection mechanisms that not only compensate for the initial DNA damage but also mitigate the effects of subsequent high-dose radiation including other damaging events that may potentially lead to the development of cancer. Low-dose irradiation suppresses the induction of high-dose radiation cancer which can potentially be employed in improving cancer radiotherapy.,,
Interestingly, the radioprotective cellular mechanisms are found more efficient in the low-dose ranges., Thus, most dose–effect relationships are nonlinear but either have a finite threshold or produce hermetic effect, i.e., response is biphasic with beneficial effects at low doses and detrimental at high doses. In fact, the dose–response relationships are found affected by a variety of factors such as tissue repair, cell proliferation, growth, adaptive and preconditioning responses, aging processes, and environmental stimulations. It is known that the pathways involved in hormetic responses consist of cell membrane receptor activation, free radical scavenging, and secretion of various growth factors, cytokines, and heat-shock proteins. Experimental results suggest that senescent or injured cells (e.g. precancerous cells) can be removed by immunological surveillance and apoptosis mechanisms. Based on the recent findings of bystander effects, and also by abscopal effects, the nature of dose–response relationships seems to follow a more complicated pattern. Radioadaptive responses are observed when preexposure to small doses of ionizing radiation reduce detrimental effects of subsequent high doses. Thus, radiation effects can be beneficial or detrimental to health depends on the dose and dose rate and are influenced by environmental confounding factors such as chemical contaminants and pesticides.
Studies have suggested that epigenetic reprogramming may provide protection of the cells against higher doses of radiation exposures. The observed nontargeted (bystander) effects of ionizing radiation in the cells that were not directly hit by radiation but received signals from the hit cells appear to involve various effectors.,, Therefore, it seems justified to suggest that bystander effects can be either detrimental (chromosomal aberrations, point mutations, genome instability, and neoplastic transformation) or beneficial (radioadaptive response, apoptosis, etc.) depending on the dose, dose rate, and other conditions during and after the irradiation.
Prospects of Low-Dose Radiation Therapies
In recent years, radiobiology and radiotherapy researches from animal and clinical studies have demonstrated that immune responses were stimulated by LDR, but the same were suppressed by high-dose exposures., More significantly, it has now been known that DNA repair is stimulated by low-dose exposures and is suppressed by high-dose exposures, making stronger case in favor of LDR therapies in the treatment of cancer and other diseases.
Recent radiobiological studies have demonstrated that radiation effects at low doses are far from linear. Moreover, experimental and epidemiological studies have shown that low doses of ionizing radiation can be beneficial to health., Mostly, as a measure of extra precaution and unfounded fear of risk, it is held on that even zero or close to zero doses of radiation may invite health risks, especially the induction of cancer. In 2005, the French Academies of Science and Medicine disputed the LNT hypothesis and cited scientific evidence in support of radiation hormesis. On the contrary, the US National Academies of Sciences, the BEIR VII report, argued that the existing scientific evidence is consistent with LNT model. More recently (2016), the United Nations Scientific Committee on the Effects of Atomic Radiation reported an unambiguous statement saying that solid evidence against “LNT” model is unavailable. Currently, the International Commission for Radiation Protection (ICRP) sets the occupational exposure limit at 20 mSv/y and the limit for the general public at 1 mSv/y (500 times lower than in the 1930s). Taking into consideration the contradictory viewpoint of scientists, while LNT has been accepted as a basis of radiation regulation globally, the ambiguity regarding its validity, especially at low-dose ranges, is mostly acknowledged and is subject to discussion in academic groups.,,
Research has demonstrated that radiation-induced immune changes follow the pattern of low-dose stimulation and high-dose suppression. LDR-induced stimulation of immunity is found in most anticancer parameters such as antibody formation, natural killer activity, secretion of interferon, and other cytokines. A review of the present status of relevant research, especially animal model, supporting the use of LDR in a clinic for cancer prevention and treatment shows that LDR retards tumor growth, decreases cancer metastasis, and inhibits carcinogenesis by high-dose radiation exposure primarily ascribed to LDR-induced stimulation on immunity. These experimental results justify initiating clinical trial of LDR in cancer treatment and COVID-19 infection and studies have been attempted. The LDR-treated patients have consistently shown enhanced anticancer immunity.,, The above-described epidemiological and experimental observations of antineoplastic and immunomodulatory effects of LDR exposures provide grounds for clinical trials with whole-body irradiation (WBI) or half-body irradiation (HBI) of cancer patients. Very promising results of low-level total-body exposures to γ-rays of patients with non-Hodgkin's lymphoma (NHL) were reported. A noteworthy clinical study was reported by Sakamoto of Japan who treated the non-Hodgkin's lymphoma (NHL) patients with low doses of whole body irradiation (HBI) with X rays (0.1–0.15 Gy two times a week for 5 weeks) combined with local radiotherapy (RT) of 2 Gy dose given five times a week for 6 weeks. The outcome was the 5 year survival of 84% of patients in Stage I and II NHL as compared to 65% survival of patients treated solely with local RT.
Today, more than half of all patients with cancer undergo radiotherapy, in which high doses of ionizing radiation are aimed to kill cancer cells. However, radiation therapy treatments are substantially limited since moderate (0.1–2.0 Gy) or high (>2 Gy) radiation doses used in present-day radiotherapy cause damage to normal tissues, inhibit immune functions, and enhance the risk of secondary neoplasms. In contrast, these complications do not occur when low-dose radiation exposures (≤100 mGy for acute exposure or ≤0.1 mGy/min dose rate for chronic exposures) are applied.
Low-dose pretreatment has also been proposed as a promising therapeutic approach in radiation therapy. Such pretreatment may trigger an adaptive response which could provide improved protection when large therapeutic doses are subsequently applied, thereby reducing the resultant damage and the probability of secondary cancer. There is also some preclinical experimental evidence that low-dose radiation can be used in the treatment of several noncancer diseases, such as autoimmune diseases, neurodegenerative diseases, as well as diabetes and perhaps prompts COVID-19 therapy and associated cardiovascular complications.
Low-Dose Radiation Immune Stimulation and Relevance to COVID-19 Treatment
In the viral infection process, viruses trigger immune cells to synthesize pro-inflammatory cytokines and chemokines inciting the immune response., Historical evidence points to the induction of an anti-inflammatory phenotype induced by low doses of radiation as a potential explanation for the observed effects. While doses in the range of 200 cGy tend to exert pro-inflammatory effects, triggering common toxicities observed in radiation therapy, more recent work shows low doses (<100cGy) incite anti-inflammatory responses such as decreasing levels of pro-inflammatory cytokines like interleukin-1 (IL-1) or inhibiting leukocyte recruitment. Therefore, it stands to reason that an LDRT treatment of 30–100 cGy to the lungs of a patient with COVID-19 pneumonia may reduce the inflammation and relieve the life-threatening symptoms. A single fraction of 30–100 cGy treatment could easily be delivered on a conventional radiation therapy unit. Routinely, much higher single fraction doses are delivered in a palliative procedure with fast-tracked patients going through the full workflow process of education, scanning, planning, and treatment delivery in matter of hours.
Admittedly, a large scale of such LDRT treatments would not be without obstacles (e.g. existing strain on radiotherapy resources, separating COVID-19 patients and cancer patients, etc.); it is believed that clinical trials to further investigate the efficacy of whole-lung LDRT would present a very low risk to COVID-19 pneumonia patients and have the potential to reduce mortality and alleviate COVID-19-related strains on health-care systems.
Experimental studies have shown the suppressive effect of LDR on tumor growth, metastasis, and carcinogenesis, the increased anticancer immunity factors including enhanced NK and CTL activity and the increased IFNγ and IL-2 secretion seem involved. These data point to the significance of radiation enhanced immune responses in cancer control., These responses may well be attempted in treating or for palliative purposes in severe COVID-19 patients. Notably, LDR is known to increase cellular antioxidant activities, accelerate DNA damage repair, reduce malignant transformation and mutagenesis, and stimulate the immune system.
It is supposed that the balance between radiation damage and defense mechanisms under this circumstance results in either no increase or even lowering of cancer mortality in spite of the long-term exposure of the inhabitants to the low-level radiation. On the basis of these findings, Cameron concluded that “British radiology data show that moderate doses of radiation are beneficial rather than a risk to health.” It is now generally accepted that radiation exposures in doses of lesser than 100 mSv are too low to detect any statistically significant cancer excess in the presence of naturally occurring malignancies. On the basis of available results, it can be safely assumed that lower doses have no harmful effects whatsoever or may even be beneficial.
Immune Boosting and Anti-Inflammation by Low-Dose Radiation
The epidemiological and experimental observations of antineoplastic and immunomodulatory effects of LDR exposures provide strong grounds for clinical trials with WBI or HBI of cancer patients. A report from Safwat who used low-dose total-body exposures (0.1–0.25 Gy several times a week to the total dose of 1.5–2.0 Gy) obtained complete remissions in 11 out of 35 patients and 2-year progression-free survival in 12 patients with relapsed and/or chemo-resistant NHL.,
It needs to be stressed that more careful clinical trials employing WBI or HBI with LDR are justifiably needed, but they are hampered by radiation safety regulations based on the LNT model of the dose–effect relationship, which states finite increase in cancer risk. Nevertheless, there is a growing consensus that the LNT hypothesis lacks a solid experimental foundation and is based largely on the ideology rather than science. Many recent appeals from radiobiologists, physicians, and health physicists to various regulatory bodies and authorities to base the radiation protection system on scientific data indicate that there are quantitative/qualitative differences between the effects of low doses delivered at low-dose rates and high doses delivered at high-dose rates. Such considerations would compel a revision of current radiation protection regulations.
In general, clinical observations show high-dose radiotherapy mediated inflammation in exposed tissues limiting the continuation of treatment to patients. LDR may be safely employed to suppress inflammation giving an advantage to radiotherapy. It is proposed that observed tissue inflammation in lung tissue and other locations in COVID-19 patients may be treated by optimized LDR doses. The proposed treatment looks promising to provide relief to COVID-19 patients, especially in patients with critical pathological manifestations. The need of the hour is to proceed with the careful clinical trial with trained physicians for radiation technology applications in the hospital settings.
Developing Low-Dose Radiation Technology in COVID-19 Pneumonia Treatment
The new COVID-19 pandemic has already inflicted great damage on a number of nations and on the world at large, resulting not only in many tens of thousands of deaths but also in economic, financial, and social crisis. Rapid escalation in the number of infections has resulted in unprecedented burden on public health-care systems worldwide. Frequently, fatal cases of COVID-19 are characterized by acute respiratory distress syndrome, sepsis, pneumonia, and respiratory disruptions., In view of the high transmission rate in advanced stages of community spread of infection, it is important to find new technology with or without drug therapy options in rapidly growing demands of hospital facilities and desperate situations of a high burden on the public health service system. Therefore, it sounds urgent to explore and develop alternative or complementary treatment procedures involving LDR.,,
Among other treatment protocols, either exclusively or in other therapeutic combinations, LDR may offer a new unique tool for palliative or therapeutic goals to virus-infected patients with evoking beneficial response and ensure to minimize unwanted symptoms of irradiated organ. To succeed, the medical goal of physicians must be focused to derive and maximize known beneficial or therapeutic responses of irradiated tissue for improving patient treatment and care. Unfortunately, present knowledge of low-dose radiobiological mechanisms has not yielded enough confidence to proceed or initiate clinical attempts in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus-infected patients. The prudent course appears to be further experimental studies with carefully planned trials. However, as a caution, even if some positive supportive evidence becomes available, it will be impractical without firming up significant medical justification and adequate patient safety and care requirements.
Radiotherapy professionals seem better equipped to explore and apply the potential for low doses (<100 cGy) of low LET radiation to treat viral pneumonia as a possible therapy for COVID-19 patients. It was not uncommon in the early 20th century to treat pneumonia with X-rays., A review showed that low doses of X-rays reduced pneumonia mortality from roughly 30% to 10% on average. Some reports noted rapid symptom relief in the order of hours. Animal model research suggested that LDRT could reduce the acute phase of pneumonia substantially. In light of the current mortality rates associated with COVID-19 pneumonia, it is therefore reasonable to re-examine this old treatment.
Lessons from Radioepidemiological Studies
From these data, it is assumed that doses currently associated with routine diagnostic X-ray procedures (range from 1 to 100 mGy) fall in the “hormetic” zone for high-energy γ-ray photons and therefore may likely be protective against cancer and several noncancer diseases such as COVID-19. Using their analyzed data, Matanoski et al. suggested that low-level radiation exposure might produce protective effects among radiologist professionals. On the basis of these findings, Cameron concluded that “British radiology data show that moderate doses of radiation are beneficial rather than a risk to health.”
A carefully designed study from multinational nuclear cohorts was recently conducted. Interestingly, in the large international cohort of nuclear plant workers in 15 countries, no excess risk of cancer was found for cumulative doses below 150 mSv. In his research findings accumulated in this research field, Tubiana has concluded that the lowest potentially carcinogenic cumulative dose of radiation is about 500 mSv. Considering the totality of evidence available, it can be suggested that lower radiation doses have no adverse effects whatsoever or may even be beneficial.
It is stressed that entirely new opportunity seems to be in waiting for developing LDR-based protective and therapeutic applications in medical practice. Today, the world is faced with the COVID-19 pandemic posing grave danger to life due to its causative SARS-CoV-2 infection and increasing number of deaths. An unprecedented health risk has imposed an extraordinary challenge to scientific and medical community to save lives in the global society. Despite hectic worldwide efforts, at this point of time, the hope of drug availability is not in sight, and successful vaccine development and treatment options appear too far away. In view of the widespread COVID 19 pandemic, LDR may prove a boon for selected group of patients. It is suggestive to examine the possibility of employing LDR particularly in the range of diagnostic doses employed in X ray, CT and nuclear medicine procedures (1 to 50 mSv). Clinicians in the radiotherapy departments who are trained and have adequate experienced in applying radiation may take part in developing the protocols. It needs to be recalled that no cancer excess has been detected for doses below 100 mSv. In parallel, the potential of LDR may be utilized for anti-inflammatory responses in coronavirus-infected patients and perhaps, skilled radiation therapists can seize the opportunity to optimize conditions to achieve therapeutic goals.
Taking the clue from the protective role of LDR in cancer induction, it sounds highly warranted examining the possibility of optimizing technology for either vulnerable individuals such as elderly patients with low immunity level or patients with compromised immunity medical conditions. Both WBI and half or local lung tissue irradiation may be considered depending on the step-by-step clinical experience. Possible patient categories for clinical trial seem to be the medically confirmed noncorona patients such as complicated diabetes, cardiovascular ailments, liver diseases, and other medical pathologies.
New Research Opportunities in Hbr Area Population
As stated above, many epidemiological studies have examined possible excess cancer risk in nuclear workers, radiation technologists, and atomic bomb survivors. It has been concluded that there is no excess risk of cancer in people exposed to low doses of radiation. Often, the cancer risk data in HBR areas are blurred with the natural incidence rate of cancer in the normal population and issue of confounding factors is emphasized.
Epidemiological studies have shown that neither cancers nor early childhood deaths were positively correlated with radiation dose in the high-level background radiation areas (a few mSv-260 mSv, i.e., 13 times of ICRP-recommended dose for radiation workers. There is no increase in cancer incidence or mortality in a high background radiation in Yangjiang, China, and in Kerala, India. On the contrary, both cancer incidence and mortality rates were found to be substantially lowered in high background radiation areas as compared to low-level areas in several regions in India and China.,
The observed absence of significant excess in cancer from epidemiological studies, suspected contributions from confounding factors and the element of uncertainty in cancer incidence from low level exposures, pose considerable ambiguity in drawing the definite conclusions. In the present scenario, the prevailing spread of COVID-19 pandemic in >200 countries has opened a new opportunity for scientists to learn how chronic low-dose exposures can modify virus infectivity responses of the exposed population. A possible correlation (positive, neutral, or negative) should be examined between susceptibility to coronavirus infection/mortality and low radiation dose exposed population in natural radiation-exposed areas. In addition, it seems warranted that research should be initiated to examine how is the occurrence of virus infection in diagnostic radiation workers in the hospitals and in the populations living in the vicinity of nuclear power plants, say 2–5 km from the nuclear power stations. In view of the fact that average rate of virus infection is known in each country, the new research programs have potential to advance our knowledge on the virus infectivity of humans among chronically exposed LDR populations. Perhaps, it is a unique and exciting opportunity to advance knowledge from new radiobiological and epidemiological research data to examine possible correlations between disease incidence/occurrence and LDR-exposed human population.
The marked differences between low- and high-dose radiation effects in living systems have been re-emphasized. The underlying radiobiological mechanisms of their actions have been outlined. It is suggested that LDR should be re-evaluated for cancer therapy and its capability to empower the human body by eliciting immune responses to be harnessed for anticancer outcomes. More importantly, a new research opportunity seems in sight, which needs to be seized, to find the average susceptibility of people living in the environment of high background radiation areas and compare with the rate among the normal population for the SARS-CoV-2 virus infection. Obviously, results of such studies will advance our knowledge on LDR protective health effects in the context of virus infectivity.
The author apologizes to many esteemed authors whose references could not be included due to space limitations.
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Conflicts of interest
There are no conflicts of interest.
|1||IAEA. Radiation Biology-A Handbook for Teachers and Students. IAEA, Tec-Doc-Publication, Training Series No. 42; 2010.|
|2||Mishra KP, editor. Biological Responses, Monitoring and Protection from Radiation Exposure. NY, USA: Nova Science Publishers; 2015.|
|3||Giaccia A, Hall E. Radiobiology for the radiologist. Philadelphia, PA, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012.|
|4||Azzam EI, Colangelo NW, Domogauer JD, Sharma N, De Toledo SM. Is Ionizing Radiation Harmful at any Exposure? An Echo That Continues to Vibrate. In: Health Physics. Lippincott Williams and Wilkins; 2016. p. 249-51.|
|5||Grant EJ, Brenner A, Sugiyama H, Sakata R, Sadakane A, Utada M, et al. Reply to the comments by Mortazavi and doss on “solid cancer incidence among the life span study of atomic bomb survivors: 1958-2009. Radiat Res 2017;187:513-37.|
|6||Muller HJ. The Production of Mutations by X-Rays. Proc Natl Acad Sci 1928;14:714-26.|
|7||Muller HJ. Artificial Transmutation of the Gene. Science, 1927;66:84-7.|
|8||Calabrese EJ. The threshold vs. LNT showdown: Dose rate findings exposed flaws in the LNT model part 1. In: The Russell Muller Debate: Environmental Research. 2017;154:452-8.|
|9||Calabrese EJ. How the US National Academy of Sciences misled the world community on cancer risk assessment: New findings challenge historical foundations of the linear dose response. Arch Toxicol 2013;87:2063-81.|
|10||Calabrese EJ. Biphasic dose responses in biology, toxicology and medicine: Accounting for their generalizability and quantitative features. Environmental Pollution. 2013;182:452-60.|
|11||Calabrese EJ. The emergence of the dose-response concept in biology and medicine. Int J Mol Sci 2016;17:2034.|
|12||Vaiserman A, Koliada A, Zabuga O, Socol Y. Health Impacts of Low-Dose Ionizing Radiation: Current Scientific Debates and Regulatory Issues. Dose-Response. 2018;16:1-27.|
|13||Feinendegen LE, Pollycove M, Neumann RD. Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology. Exp Hematol 2007;4 Suppl 35:37-46.|
|14||Matanoski GM, Sternberg A, Elliott EA. Does radiation exposure produce a protective effect among radiologists? Health Phys 1987;52:637-43.|
|15||Brooks AL. Commentary on: A history of the United States department of energy (DOE) low dose radiation research program: 1998-2008. Radiat Res 2015;183:375-81.|
|16||Beyea J. Lessons to be learned from a contentious challenge to mainstream radiobiological science (the linear no-threshold theory of genetic mutations). Environ Res 2017;154:362-79.|
|17||Ron E. Cancer Risks from Medical Radiation. Health Physics; 2003;85:47-59.|
|18||Brooks AL. Paradigm shifts in radiation biology: Their impact on intervention for radiation-induced disease. Radiat Res 2005;164:454-61.|
|19||Tubiana M, Feinendegen LE, Yang C, Kaminski JM. The linear no-threshold relationship is inconsistent with radiation biologic and experimental data. Radiology 2009;251:13-22.|
|20||Tiwari P, Mishra KP. Flavonoids sensitize tumor cells to radiation: Molecular mechanisms and relevance to cancer radiotherapy. Int J Radiat Biol 2020;96:360-9.|
|21||Ahire V, Das D, Arora S, Kumar A, Ramakrishna G, Mishra KP. Studying the in silico effect of ellagic acid on HIF-2α to improve efficacy of anticancer therapy. Environ Pathol Toxicol Oncol 2018;37:331-9.|
|22||Ahire V, Mishra K. Ellagic acid radiosensitizes tumor cells by evoking apoptotic pathway. Radiat Cancer Res 2016;7:71.|
|23||Ahire V, Mishra KP. Ellagic acid as a potential anti-cancer drug. Int J Radiol Radiat Ther. 2017;3:234-5.|
|24||Mishra K, Girdhani S, Bhosle S, Thulsidas S, Kumar A. Potential of radiosensitizing agents in cancer chemo-radiotherapy. Cancer Res Ther 2005;1:129.|
|25||Madhukar Bhosle S, Ahire VR, Henry MS, Thakur VS, Huilgol NG, Prasad Mishra K. Augmentation of radiation-induced apoptosis by ellagic acid. Cancer Invest 2010;28:323-30.|
|26||Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L, et al. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 2007;222:122-8.|
|27||MotherSill C, Seymour C. Changing paradigms in radiobiology. Mutat Res 2012;750:85-95.|
|28||Hendry J, Simon S, Wojcik A, Sohrabi M, Burkart W, Cardis E, et al. Human exposure to high natural background radiation: What can it teach Us about radiation risks? J Radiol Prot 2009;29, A29–A42.|
|29||Kadhim M, Salomaa S, Wright E, Hildebrandt G, Belyakov OV, Prise KM, et al. Non-targeted effects of ionising radiation-Implications for low dose risk. Mutat Res 2013;752:84-98.|
|30||Pandey BN, Kumar A, Ali M, Mishra KP. Bystander effect of conditioned medium from low and high doses of gamma-irradiated human leukemic cells on normal lymphocytes and cancer cells. Env Pathol Toxicol Oncol 2011;30:333-40.|
|31||Desai S, Srambikkal N, Yadav HD, Shetake N, Balla MM, Kumar A, et al. Molecular understanding of growth inhibitory effect from irradiated to bystander tumor cells in mouse fibrosarcoma tumor model. Roberts DD, editor. PLoS One 2016;11:e0161662.|
|32||Azzam EI, Little JB. The radiation-induced bystander effect: Evidence and significance. Hum Exp Toxicol 2004;23:61-5.|
|33||Prise KM, O'Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 2009;9:351-60.|
|34||Sakai K, Hoshi Y, Nomura T, Oda T, Iwasaki T, Fujita K, et al. Suppression of carcinogenic processes in mice by chronic low dose rate gamma-irradiation. Int J Low Radiat 2003;1:142-6.|
|35||Feinendegen LE. Evidence for beneficial low level radiation effects and radiation hormesis. Br J Radiol 2005;78:3-7.|
|36||Scott BR, Sanders CL, Mitchel RE, Scott BR, Sanders CL, Mitchel RE, Boreham DR. CT scans may reduce rather than increase the risk of cancer. J Am Phys Surg 2008;13:9-11.|
|37||Tubiana M. The carcinogenic effect of low doses: The validity of the linear no-threshold relationship. Int J Low Radiat 2003;1:1-33.|
|38||Tubiana M, Aurengo A. Dose-effect relationship and estimation of the carcinogenic effects of low doses of ionising radiation: The Joint Report of the Académie des Sciences (Paris) and of the Académie Nationale de Médecine. Int J Low Radiat 2006;2:135-53.|
|39||National Research Council. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: The National Academies Press; 2006. Available from: https://www.nap.edu/catalog/11340/health-risks-from-exposure-to-low-levels-of-ionizing-radiation. [Last accessed 2020 Sept 23].|
|40||UNSCEAR 2017. Sources, Effects and Risks of Ionizing Radiation; 2017. Available from: https://www.unscear.org/unscear/en/publications/2017.html. [Last accessed on 2020 Jul 08].|
|41||Socol Y, Dobrzynski L. Atomic bomb survivors life-span study: Insufficient statistical power to select radiation carcinogenesis model. Dose-Response 2015;13:1-17.|
|42||Streffer C, Shore R, Konermann G, Meadows A, Uma Devi P, Withers J, et al. Biological effects after prenatal irradiation (Embryo and Fetus). Report of the international commission on radiological protection. Ann ICRP 2003;33:5-206.|
|43||Yang G, Li W, Jiang H, Liang X, Zhao Y, Yu D, et al. Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics. Int J Cancer 2016;139:2157-68.|
|44||Pollycove M, Feinendegen LE. Low-dose radioimmuno-therapy of cancer. Hum Exp Toxicol 2008;27:169-75.|
|45||Janiak MK, Wincenciak M, Cheda A, Nowosielska EM, Calabrese EJ. Cancer immunotherapy: How low-level ionizing radiation can play a key role. Cancer Immunol Immunother. 2017;66:819-32.|
|46||Choi N, Timothy A, Kaufman S, Carey R, Aisenberg A. Low dose fractionated whole body irradiation in the treatment of advanced non-Hodgkin's Lymphoma. Cancer 1979;43:1636-42.|
|47||Sakamoto K. Radiobiological basis for cancer therapy by total or half-body irradiation. Nonlinearity Biol Toxicol Med 2004;2:293–316.|
|48||Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: Immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-74.|
|49||Cyranoski D. Profile of a Killer Virus. Nature 2020;581:22-6.|
|50||Rouse BT, Hartley D, Doherty PC. Consequences of exposure to ionizing radiation for effector t cell function In vivo. Viral Immunol 1989;2:69-78.|
|51||Persa E, Szatmári T, Sáfrány G, Lumniczky K.In vivo irradiation of mice induces activation of dendritic cells. Int J Mol Sci 2018; 19:2391.|
|52||Cameron JR. Radiation increased the longevity of British radiologists. Br J Radiol Br Instit Radiol 2002;75:637-9.|
|53||Safwat A. The immunobiology of low-dose total-body irradiation: More questions than answers. Radiat Res 2000;153 (5 Pt 1):599-604.|
|54||Safwat A. The role of low-dose total body irradiation in treatment of non- Hodgkin's lymphoma: A new look at an old method. Radiother Oncol 2000;56:1-8.|
|55||Montero A, Arenas M, Algara M. Low-dose radiation therapy: Could it be a game-changer for COVID-19? Clin Trans Oncol 2020;56:1.|
|56||Kirkby C, Mackenzie M. Is low dose radiation therapy a potential treatment for COVID-19 pneumonia? Radiother Oncol 2020;147:221.|
|57||Tarentino AL, Maley F. A comparison of the substrate specificities of endo-beta-n-acetylglucosaminidases from streptomyces griseus and Diplococcus pneumoniae. Biochem Biophys Res Commun 1975;67:455-62.|
|58||Calabrese EJ, Dhawan G. How radiotherapy was historically used to treat pneumonia: Could it be useful today? Yale J Biol Med 2013;86:555-70.|
|59||Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, et al. The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Estimates of radiation-related cancer risks. Radiat Res 2007;167:396-416.|
|60||Abbasi S, Mortazavi SA, Mortazavi SM. Martian residents: Mass media and ramsar high background radiation areas. Biomed Phys Eng 2019;9:483-6.|
|61||Luxin W, Yongru Z, Zufan T, Weihui H, Deqing C, Yongling Y. Epidemiological investigation of radiological effects in high background radiation areas of Yangjiang, China. J Radiat Res 1990;31:119-36.|
|62||Nair RR, Rajan B, Akiba S, Jayalekshmi P, Nair MK, Gangadharan P, et al. Background radiation and cancer incidence in Kerala, India-Karunagappally cohort study. Health Phys 2009;96:55-66|