Therapy for prevention and treatment of skin ionizing radiation damage: a review

Abstract

Radiologic accidents or terrorist acts involving radioactive material, as well as radiation exposure in medical or industrial procedures are potential sources of risk for human health. All these risks share a common element, exposure to ionizing radiation. The extent of ionizing radiation injury will depend on a number of independent variables such as dose, type of radiation and tissue, etc. As a result of ionizing radiation exposure, biological effects can take place in acute or long-term manner. As in the case of other self-renewing tissues (e.g. hematopoietic system and intestinal epithelium), skin is also extremely sensitive to ionizing radiation. In this way, appropriate management of radiation skin effects might improve the therapeutic benefit of medical radiation therapy, as well as reduce the mortality associated with any radiological incident (e.g. accident or terrorist attack). For this reason, current and potential future treatment approaches for skin radiation injury are reviewed in this work. Unfortunately, there is no sufficient evidence for establishing a standard treatment to prevent or mitigate radiation-induced cutaneous injury. Thus, continued research is necessary to achieve effective therapies to address this important health problem.     

Candidate protein biodosimeters of human exposure to ionizing radiation

PURPOSE: To conduct a literature review of candidate protein biomarkers for individual radiation biodosimetry of exposure to ionizing radiation. MATERIALS AND METHODS: Reviewed approximately 300 publications (1973 - April 2006) that reported protein effects in mammalian systems after either in vivo or in vitro radiation exposure. RESULTS: We found 261 radiation-responsive proteins including 173 human proteins. Most of the studies used high doses of ionizing radiation (>4 Gy) and had no information on dose- or time-responses. The majority of the proteins showed increased amounts or changes in phosphorylation states within 24 h after exposure (range: 1.5- to 10-fold). Of the 47 proteins that are responsive at doses of 1 Gy and below, 6 showed phosphorylation changes at doses below 10 cGy. Proteins were assigned to 9 groups based on consistency of response across species, dose- and time-response information and known role in the radiation damage response. CONCLUSIONS: ATM (Ataxia telengiectasia mutated), H2AX (histone 2AX), CDKN1A (Cyclin-dependent kinase inhibitor 1A), and TP53 (tumor protein 53) are top candidate radiation protein biomarkers. Furthermore, we recommend a panel of protein biomarkers, each with different dose and time optima, to improve individual radiation biodosimetry for discriminating between low-, moderate-, and high-dose exposures. Our findings have applications for early triage and follow-up medical assessments.     

Rationale for using multiple antioxidants in protecting humans against low doses of ionizing radiation

Health risks of low doses of ionizing radiation (10 cGy or less) may not be accurately estimated in humans by epidemiological study or mathematical modelling because of several inherent confounding factors including environmental, dietary and biological variables that cannot be accounted for in any radio-epidemiological study. In addition, the expression of radiation-induced damage in humans not only depends upon total dose, dose rate, linear energy transfer (LET), and fractionation and protraction of total doses, but also on repair mechanisms, bystander effects, and exposure to chemical carcinogens, tumour promoters and other toxins. It also depends upon the levels of anti-carcinogenic and anti-tumour promoting agents. Low doses of ionizing radiation should not be considered insignificant with regard to increasing the incidence of somatic mutations (neoplastic and non-neoplastic diseases) and heritable mutations in humans owing to its interaction with other toxins that can enhance damage produced by irradiation. It is very prudent to continue to support the well-established radiobiological concept that no radiation dose can be considered completely safe, and that all efforts must be made to reduce both the radiation dose and biological damage, no matter how small that damage might be, without sacrificing the benefits of radiation. Based on the results of many scientific experiments, formulations containing multiple antioxidants for biological protection against radiation damage in humans can be developed, and this strategy together with the existing physical concept of radiation protection, should further reduce potential risks of low doses of ionizing radiation in humans.     

Current issues and actions in radiation protection of patients

Medical application of ionizing radiation is a massive and increasing activity globally. While the use of ionizing radiation in medicine brings tremendous benefits to the global population, the associated risks due to stochastic and deterministic effects make it necessary to protect patients from potential harm. Current issues in radiation protection of patients include not only the rapidly increasing collective dose to the global population from medical exposure, but also that a substantial percentage of diagnostic imaging examinations are unnecessary, and the cumulative dose to individuals from medical exposure is growing. In addition to this, continued reports on deterministic injuries from safety related events in the medical use of ionizing radiation are raising awareness on the necessity for accident prevention measures. The International Atomic Energy Agency is engaged in several activities to reverse the negative trends of these current issues, including improvement of the justification process, the tracking of radiation history of individual patients, shared learning of safety significant events, and the use of comprehensive quality audits in the clinical environment.     

Physically-based biodosimetry using in vivo EPR of teeth in patients undergoing total body irradiation

Purpose:?The ability to estimate individual exposures to radiation following a large attack or incident has been identified as a necessity for rational and effective emergency medical response. In vivo electron paramagnetic resonance (EPR) spectroscopy of tooth enamel has been developed to meet this need.

Materials and methods:?A novel transportable EPR spectrometer, developed to facilitate tooth dosimetry in an emergency response setting, was used to measure upper incisors in a model system, in unirradiated subjects, and in patients who had received total body doses of 2 Gy.

Results:?A linear dose response was observed in the model system. A statistically significant increase in the intensity of the radiation-induced EPR signal was observed in irradiated versus unirradiated subjects, with an estimated standard error of dose prediction of 0.9?±?0.3 Gy.

Conclusions:?These results demonstrate the current ability of in vivo EPR tooth dosimetry to distinguish between subjects who have not been irradiated and those who have received exposures that place them at risk for acute radiation syndrome. Procedural and technical developments to further increase the precision of dose estimation and ensure reliable operation in the emergency setting are underway. With these developments EPR tooth dosimetry is likely to be a valuable resource for triage following potential radiation exposure of a large population.     

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures

PURPOSE: Following acute irradiation, excess radiosensitivity is generally seen at doses <1 Gy, a phenomenon termed "low-dose hyper-radiosensitivity" (HRS). A very strong, HRS-like inverse dose-rate effect has also been described following continuous low dose-rate (LDR) irradiation at <30 cGy h(-1). We report on the sequential irradiation of a cell line by such LDR exposures followed by low acute doses, where either treatment individually would elicit a hypersensitive response. The aim was to determine if a prior LDR exposure would remove the HRS normally seen in response to very small acute radiation doses. MATERIALS AND METHODS: T98G human glioma cells were given single continuous LDR exposures of 5-60 cGy h(-1) using a (60)Co gamma-source. At intervals of 0 or 4 h following LDR irradiation, cells were further irradiated with a range of acute doses using 240-kVp X-rays. The response to the combined treatment was assessed using high-precision clonogenic cell survival assays, and the amount of HRS at acute doses <1 Gy was determined. RESULTS: LDR at > or = 60 cGy h(-1) to total doses up to 5 Gy in asynchronously growing cells did not remove HRS in the subsequent acute-dose survival curve. In confluent cultures, subsequent acute-dose HRS was not present after an LDR dose of 5 Gy at either 60 or 30 cGy h(-1), but returned if a 4-h interval was left between LDR and acute-dose irradiation. In confluent cultures, acute-dose HRS remained for LDR treatments at 5 or 10 cGy h(-1) or if the total dose was 2 Gy. Taking all cultures and dose-rates together, the "degree" of acute-dose HRS, as measured by alpha(s), was significantly greater in cells irradiated at LDR to a total dose of 2 than of 5Gy. CONCLUSIONS: Initial LDR exposure can affect a subsequent HRS response. HRS is reduced after LDR exposures at greater dose intensity, but can recover again within 4 h of completion of LDR exposure. This suggests that processes determining increased resistance to small acute doses (removal of HRS) might be governed by the level of repairable DNA lesions.     

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures

Purpose : Following acute irradiation, excess radiosensitivity is generally seen at doses <1 Gy, a phenomenon termed 'low-dose hyper-radiosensitivity' (HRS). A very strong, HRS-like inverse dose-rate effect has also been described following continuous low dose-rate (LDR) irradiation at <30 cGy h -1. We report on the sequential irradiation of a cell line by such LDR exposures followed by low acute doses, where either treatment individually would elicit a hypersensitive response. The aim was to determine if a prior LDR exposure would remove the HRS normally seen in response to very small acute radiation doses. Materials and methods : T98G human glioma cells were given single continuous LDR exposures of 5-60 cGy h -1 using a 60 Co γ-source. At intervals of 0 or 4 h following LDR irradiation, cells were further irradiated with a range of acute doses using 240-kVp X-rays. The response to the combined treatment was assessed using high-precision clonogenic cell survival assays, and the amount of HRS at acute doses <1 Gy was determined. Results : LDR at ≥60 cGy h -1 to total doses up to 5 Gy in asynchronously growing cells did not remove HRS in the subsequent acute-dose survival curve. In confluent cultures, subsequent acute-dose HRS was not present after an LDR dose of 5 Gy at either 60 or 30 cGy h -1, but returned if a 4-h interval was left between LDR and acute-dose irradiation. In confluent cultures, acute-dose HRS remained for LDR treatments at 5 or 10 cGy h -1 or if the total dose was 2 Gy. Taking all cultures and dose-rates together, the 'degree' of acute-dose HRS, as measured by α s, was significantly greater in cells irradiated at LDR to a total dose of 2 than of 5Gy. Conclusions : Initial LDR exposure can affect a subsequent HRS response. HRS is reduced after LDR exposures at greater dose intensity, but can recover again within 4 h of completion of LDR exposure. This suggests that processes determining increased resistance to small acute doses (removal of HRS) might be governed by the level of repairable DNA lesions.     

Occupational exposure to ionizing radiation and the occurrence of cataract

Radiation cataract is one of ensuing effects of ionizing radiation, since its threshold dose under which it does not occur, and above which it shows dose dependency, has been observed. Clinical course of radiation cataract is identical for all the types of ionizing radiation and is very typical. Minimal dose for progressive cataract formation is determined by the type of radiation, i.e., its relative biological efficacy, dose, and the duration of the exposure period. Theoretically, threshold dose existence does not exclude the incidence of cataract formation under significantly smaller doses, as well. The aim of this study was to analyze the incidence of cataract formation among the medical staff professionally exposed to ionizing radiation. Neither of the diagnosed cataracts had typical morphology, nor was the correlation established between the dose, exposure time, and the cataract formation. All the diagnosed cataracts were described as premature, and therefore ionizing radiation was considered as a co-factor in premature cataract formation in the examined groups.     

Effective doses in radiology and diagnostic nuclear medicine: a catalog

Medical uses of radiation have grown very rapidly over the past decade, and, as of 2007, medical uses represent the largest source of exposure to the U.S. population. Most physicians have difficulty assessing the magnitude of exposure or potential risk. Effective dose provides an approximate indicator of potential detriment from ionizing radiation and should be used as one parameter in evaluating the appropriateness of examinations involving ionizing radiation. The purpose of this review is to provide a compilation of effective doses for radiologic and nuclear medicine procedures. Standard radiographic examinations have average effective doses that vary by over a factor of 1000 (0.01-10 mSv). Computed tomographic examinations tend to be in a more narrow range but have relatively high average effective doses (approximately 2-20 mSv), and average effective doses for interventional procedures usually range from 5-70 mSv. Average effective dose for most nuclear medicine procedures varies between 0.3 and 20 mSv. These doses can be compared with the average annual effective dose from background radiation of about 3 mSv.     

Candidate protein biodosimeters of human exposure to ionizing radiation

Purpose: To conduct a literature review of candidate protein biomarkers for individual radiation biodosimetry of exposure to ionizing radiation.

Materials and methods: Reviewed ～300 publications (1973 – April 2006) that reported protein effects in mammalian systems after either in vivo or in vitro radiation exposure.

Results: We found 261 radiation-responsive proteins including 173 human proteins. Most of the studies used high doses of ionizing radiation (>4 Gy) and had no information on dose- or time-responses. The majority of the proteins showed increased amounts or changes in phosphorylation states within 24 h after exposure (range: 1.5- to 10-fold). Of the 47 proteins that are responsive at doses of 1 Gy and below, 6 showed phosphorylation changes at doses below 10 cGy. Proteins were assigned to 9 groups based on consistency of response across species, dose- and time-response information and known role in the radiation damage response.

Conclusions: ATM (Ataxia telengiectasia mutated), H2AX (histone 2AX), CDKN1A (Cyclin-dependent kinase inhibitor 1A), and TP53 (tumor protein 53) are top candidate radiation protein biomarkers. Furthermore, we recommend a panel of protein biomarkers, each with different dose and time optima, to improve individual radiation biodosimetry for discriminating between low-, moderate-, and high-dose exposures. Our findings have applications for early triage and follow-up medical assessments.     

Analysis of chromosome aberrations by FISH and Giemsa assays in lymphocytes of cancer patients undergoing whole-body irradiation: comparison of in vivo and in vitro irradiation.

PURPOSE: To study the cytogenetic effects of fractionated radiotherapy in peripheral blood lymphocytes of five cancer patients. In vitro experiments were performed in parallel using the same dose range and a comparison was made of the induced frequencies of stable and unstable chromosome aberrations. The object was to clarify the use of an in vitro calibration curve for immediate and retrospective dosimetry in cases of radiation accidents. MATERIALS AND METHODS: Patients were exposed to 60Co gamma-rays at a single dose of 11.5 cGy each day up to a total dose of 57.5 cGy, given in 5 days. For measurement of chromosome aberrations, blood was collected from patients before irradiation and after each exposure. Blood taken before treatment was used as a control and for in vitro irradiation experiments in the dose range 8-50 cGy. Chromosome aberration frequency (stable as well as unstable) was determined using fluorescence in situ hybridization (FISH) assay with specific DNA libraries for chromosomes 1, 4 and 8 and a pancentromertic probe for the whole genome. Giemsa-stained preparations were used to score unstable aberrations following in vivo and in vitro exposure. RESULTS: A linear dose-response curve was determined for both dicentrics and translocations. The in vivo frequency of translocations was higher than for dicentrics. Dose-response curves generated for translocations following in vivo and in vitro irradiation yielded similar frequencies. In contrast, for dicentrics, in vitro irradiation yielded a higher frequency when compared with data generated following in vivo exposure. CONCLUSIONS: For dose reconstruction purposes, translocations frequency seems to be a more adequate end-point than the scoring of dicentrics. The established in vitro calibration curve for dicentrics may underestimate absorbed radiation dose in cases of protracted exposure.     

河南“4.26”60Co源辐射事故一例受照者患非霍奇金淋巴瘤的病因探讨

关于电离辐射是否可诱发非霍奇金淋巴瘤（NHL）,目前的研究结果尚未获得一致结论。笔者报道了河南“4.26” 60Co源辐射事故中1例中度骨髓型急性放射病患者受照后第13年患NHL的病例,结合患者的受照史、病史特点、诊断及国际多项大型研究,从流行病学资料和影响因素两方面分析了患者“天”患非霍奇金淋巴瘤与电离辐射的关系,为电离辐射致NHL提供辐射流行病学依据。     

Dosimetric aspects of exposure of the population to ionizing radiation

Radiation carcinogenesis is generally considered to be the most important detrimental effect of exposure to ionizing radiation. The collective effective dose-equivalent values due to medical procedures amount to values between 10 and 20 per cent of the doses received from natural radiation. Risk factors have been derived up to the present from three large epidemiological studies, notably atomic bomb survivors, spondylitis patients and female patients treated for cancer of the cervix. The assessment of the absorbed doses received by the inhabitants of Hiroshima and Nagasaki has received continuous attention and the latest estimates are summarized. On the basis of original radiotherapy records the absorbed doses in organs adjacent to the primary treatment field can be derived from computerized dosimetry and this source of information should be further exploited. European co-operation has been established to investigate dosimetric problems for medical applications and radiation protection. The risk factors obtained up to the present are derived at relatively high dose levels (in excess of 0.3 Gy). The uncertainties in the extrapolation of these values to the area of low doses administered at low dose rates are discussed.     

Analysis of chromosome aberrations by FISH and Giemsa assays in lymphocytes of cancer patients undergoing whole-body irradiation: comparison of in vivo and in vitro irradiation

Purpose : To study the cytogenetic effects of fractionated radiotherapy in peripheral blood lymphocytes of five cancer patients. In vitro experiments were performed in parallel using the same dose range and a comparison was made of the induced frequencies of stable and unstable chromosome aberrations. The object was to clarify the use of an in vitro calibration curve for immediate and retrospective dosimetry in cases of radiation accidents. Materials and methods : Patients were exposed to 60 Co γ-rays at a single dose of 11.5 cGy each day up to a total dose of 57.5 cGy, given in 5 days. For measurement of chromosome aberrations, blood was collected from patients before irradiation and after each exposure. Blood taken before treatment was used as a control and for in vitro irradiation experiments in the dose range 8-50 cGy. Chromosome aberration frequency (stable as well as unstable) was determined using fluorescence in situ hybridization (FISH) assay with specific DNA libraries for chromosomes 1, 4 and 8 and a pancentromertic probe for the whole genome. Giemsa-stained preparations were used to score unstable aberrations following in vivo and in vitro exposure. Results : A linear dose-response curve was determined for both dicentrics and translocations. The in vivo frequency of translocations was higher than for dicentrics. Dose-response curves generated for translocations following in vivo and in vitro irradiation yielded similar frequencies. In contrast, for dicentrics, in vitro irradiation yielded a higher frequency when compared with data generated following in vivo exposure. Conclusions : For dose reconstruction purposes, translocations frequency seems to be a more adequate end-point than the scoring of dicentrics. The established in vitro calibration curve for dicentrics may underestimate absorbed radiation dose in cases of protracted exposure.     

Comparison of the risks of cancer incidence and mortality following radiation therapy for benign and malignant disease with the cancer risks observed in the Japanese A-bomb survivors

PURPOSES: To compare the radiation-associated relative risks of cancer incidence and mortality in groups exposed to ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions with those in the Japanese A-bomb survivor cancer incidence and mortality data. MATERIALS AND METHODS: Comparison of the excess relative risk coefficients derived from published information for each study with the excess relative risk coefficient in comparable (age at exposure, time since exposure, sex) matched subsets of the Japanese A-bomb survivor cancer incidence and mortality data. RESULTS: Sixty-five studies of persons who have received appreciable doses of ionizing radiation in the course of treatment and for whom there is adequate ascertainment of cancer incidence or mortality are identified, from which 116 cancer-site-specific estimates of excess relative risk are derived. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The most marked discrepancies between the relative risks in the medical series and in the A-bomb survivors are for leukaemia, where 12 of the 17 medical studies have significantly lower relative risks than those observed in the Japanese data. However, the ratio between the relative risks in the medical studies and in the Japanese data tends to diminish with increasing average or maximal therapy dose. This is observed for all cancer sites and is particularly marked for leukaemia. After taking account of cell sterilization and dose fractionation the apparent differences between the relative risks for leukaemia in the Japanese A-bomb survivors and in the medical series largely disappear. This suggests that cell sterilization largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Other factors, such as the differences in underlying cancer risks between the Japanese A-bomb survivors and the medical series, and dose-fractionation effects, may also contribute. CONCLUSIONS: The relative risks of cancer in studies of persons exposed to appreciable doses of ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions are generally less than those in comparable subsets of the Japanese A-bomb survivor cancer incidence and mortality data. Cell sterilization effects can largely explain the discrepancy between the Japanese and the medical series.     

Occupational radiation exposure: population studies

Occupational exposure to ionizing radiation in the medical setting differs from the acute exposure received by survivors of atomic bomb blasts. Yet, atomic bomb survivors' disease and mortality outcomes have been the standard data source on the effects of ionizing radiation on humans. Therefore, the prevailing estimated risks of ionizing radiation may not apply to radiologic technologists and other medical radiation workers. Carefully designed epidemiological trials provide evidence that helps determine the strength of association between exposure and onset of disease in selected populations. This article reviews radiation effects, explains some basic design concepts of epidemiologic trials and surveys the epidemiology literature related to radiation exposure to humans, with special attention to radiology staff.     

Dosimetric Aspects of Exposure of the Population to Ionizing Radiation

Summary

Radiation carcinogenesis is generally considered to be the most important detrimental effect of exposure to ionizing radiation. The collective effective dose-equivalent values due to medical procedures amount to values between 10 and 20 per cent of the doses received from natural radiation. Risk factors have been derived up to the present from three large epidemiological studies, notably atomic bomb survivors, spondylitis patients and female patients treated for cancer of the cervix. The assessment of the absorbed doses received by the inhabitants of Hiroshima and Nagasaki has received continuous attention and the latest estimates are summarized. On the basis of original radiotherapy records the absorbed doses in organs adjacent to the primary treatment field can be derived from computerized dosimetry and this source of information should be further exploited. European co-operation has been established to investigate dosimetric problems for medical applications and radiation protection. The risk factors obtained up to the present are derived at relatively high dose levels (in excess of 0·3 Gy). The uncertainties in the extrapolation of these values to the area of low doses administered at low dose rates are discussed.     

Patient Radiation Exposure: Imaging During Radiation Oncology Procedures: Executive Summary of NCRP Report No. 184

The National Council on Radiation Protection and Measurements (NCRP) recently assessed patient radiation exposure in the United States, which was summarized in its 2019 NCRP Report No. 184. This work involved an estimation of the number of medical procedures using ionizing radiation, as well as the associated effective doses from these procedures. The NCRP Report No. 184 committee elected to not incorporate radiation dose from radiotherapy into its calculated population dose exposures, as the assessment of effective dose for the population undergoing radiotherapy is more complex than that for other medical radiation exposures. However, the aim of NCRP Report No. 184 was to raise awareness of ancillary radiation exposures to patients undergoing radiotherapy. Overall, it was estimated that annually, in 2016, approximately 800,000 patients received approximately 1 million courses of radiation therapy. Each of these treatments includes various types of imaging that may not be familiar to radiologists or others. Exposures from radiotherapy planning and delivery are reviewed in the report and summarized in this executive summary. The imaging techniques, use of this imaging, and associated tissue doses are described. Imaging can contribute a few percent to the planned treatment doses (which are prescribed to specified target volumes) as well as exposing patients to radiation outside of the target volume (in the imaging field of view).