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![Excess relative risk of solid cancers as a function of dose in atomic bomb survivors. Reprinted with permission from figure 3 of "Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases." [8]. Estimated excess relative risk (ERR-equal to relative risk minus one) of solid cancer development vs. mean total colon dose for atomic bomb survivors. These estimates represent the risk of solid cancer development by age 70 to a person exposed at 30 years of age after controlling for the influence of gender and city (Hiroshima vs. Nagasaki) using models specified by Ozasa and others [8]. Black points represent central estimates for each exposure group. Vertical bars represent 95% confidence intervals. Linear (L) and linear-quadratic (LQ) dose response models were both fit to the data and appear as labeled. A linear-quadratic model fit to doses below 2 Gy is shown as well (LQ (<2Gy)). The apparent quadratic component of ERR increase with dose is most pronounced for exposures less than 2 Gy. This curvature is presumably a consequence of the relatively lower than expected solid cancer development risks in the dose range 0.3-0.7 Gy for which neither Ozasa and others nor earlier reports offer an explanation.](profile/Gayle-Woloschak/publication/286444454/figure/fig1/AS:613954711719978@1523389618842/Excess-relative-risk-of-solid-cancers-as-a-function-of-dose-in-atomic-bomb-survivors.png)
Excess relative risk of solid cancers as a function of dose in atomic bomb survivors. Reprinted with permission from figure 3 of "Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases." [8]. Estimated excess relative risk (ERR-equal to relative risk minus one) of solid cancer development vs. mean total colon dose for atomic bomb survivors. These estimates represent the risk of solid cancer development by age 70 to a person exposed at 30 years of age after controlling for the influence of gender and city (Hiroshima vs. Nagasaki) using models specified by Ozasa and others [8]. Black points represent central estimates for each exposure group. Vertical bars represent 95% confidence intervals. Linear (L) and linear-quadratic (LQ) dose response models were both fit to the data and appear as labeled. A linear-quadratic model fit to doses below 2 Gy is shown as well (LQ (<2Gy)). The apparent quadratic component of ERR increase with dose is most pronounced for exposures less than 2 Gy. This curvature is presumably a consequence of the relatively lower than expected solid cancer development risks in the dose range 0.3-0.7 Gy for which neither Ozasa and others nor earlier reports offer an explanation.
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Introduction:
The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than a...
Context in source publication
Context 1
... BEIR VII report, like reports from most national and international radiation protection agencies, use data from the lifespan study (LSS) of Japanese atomic bomb survivors as their pri- mary source to estimate cancer risk following radiation exposure. Survivors experienced excess risks of cancer development and mortality that increased with the dose received (Fig ...
Citations
... [85] The conclusions regarding DDREF based on the studies of nuclear workers receiving doses largely compatible with broad-range NRB are unfounded, [38,39] as well as the statements that the linear no-threshold theory (LNT) for low radiation doses is unrejectable: [86] to reject the LNT, it suffices to prove hormesis. Some mathematical models suggested DDREF values from two up to infinity; [87] the latter agrees with the hormesis concept. ...
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... This recommendation is obviously unreasonable for dose rates compatible with those from the natural radiation background. The topic of DDREF has been comprehensively discussed elsewhere [50,51]. ...
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... Recent studies with animal models have made significant contributions to provide quantitative data and mechanistic insights [7][8][9]. The application of animal data to human populations remains in debate, but, the information, including the biological mechanisms, is apparently the clue to understand the dose-rate effects of ionizing radiation comprehensively [10,11]. ...
... Nevertheless, the uncertainties inherent to these studies hinder conclusion on whether the cancer risk at low dose rate is smaller than that inferred from studies of acute exposure, such as to atomic-bomb radiation [20]. On the other hand, a large number of experimental studies were reported in the past century and identified generally reduced cancer development in animals exposed at low dose rate as compared with those at high dose rate [8,27,28]. More recent efforts have integrated and re-analyzed archived data of such studies [29][30][31]. ...
While epidemiological data are available for the dose and dose-rate effectiveness factor (DDREF) for human populations, animal models have contributed significantly to providing quantitative data with mechanistic insights. The aim of the current review is to compile both the in vitro experiments with reference to the dose-rate effects of DNA damage and repair, and the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. In particular, the review focuses especially on the results pertaining to underlying biological mechanisms and discusses their possible involvement in the process of radiation-induced carcinogenesis. Because the concept of adverse outcome pathway (AOP) together with the key events has been considered as a clue to estimate radiation risks at low doses and low dose-rates, the review scrutinized the dose-rate dependency of the key events related to carcinogenesis, which enables us to unify the underlying critical mechanisms to establish a connection between animal experimental studies with human epidemiological studies.
... Animal experiments provide important information regarding the biological effects of radiation, and they complement epidemiological studies. Reanalysis of archival animal data can produce new important information required in many fields including radiological protection [8][9][10][11]. To date, many animal studies have addressed the interaction of radiation with various non-radiation factors [1]. Nevertheless, the interaction in these animal studies has only rarely been assessed quantitatively [12,13]. ...
Cancer risk after exposure to ionizing radiation can vary between individuals and populations, but the impact of factors governing those variations is not well understood. We previously conducted a series of carcinogenesis experiments using a rat model of breast cancer, in which 1654 rats born in 2002–2012 were exposed to γ rays at various doses and ages with or without non-radiation factors including high-fat diet, parity and chemical carcinogens. We herein reanalyze the incidence data from these archival experiments to clarify the effect of age at exposure, attained age, radiation dose and non-radiation factors (i.e. fat, parity, chemicals and birth cohorts) on radiation-related mammary cancer incidence. The analysis used excess relative risk (ERR) and excess absolute risk (EAR) models as well as generalized interaction models. Age-at-exposure dependence displayed a peak of susceptibility at puberty in both the ERR and EAR models. Attained age decreased ERR and increased EAR per unit radiation dose. The dose response was concordant with a linear model. Dietary fat exhibited a supra-multiplicative interaction, chemicals represented a multiplicative interaction, and parity and birth cohorts displayed interactions that did not significantly depart from additivity or multiplicativity. Treated as one entity, the four non-radiation factors gave a multiplicative interaction, but separation of the four factors significantly improved the fit of the model. Thus, the present study supports age and dose dependence observed in epidemiology, indicates heterogenous interactions between radiation and various non-radiation factors, and suggests the potential use of more flexible interaction modeling in radiological protection.
... Since 2014, this group is reviewing the current scientific evidence on low dose and LDR effects, including radiation-induced effects from molecular and cellular studies, studies on experimental animals, and epidemiological studies on humans. Results of this activity have been published regularly in the peerreviewed literature (Haley et al. 2015;Rühm et al. 2015Rühm et al. , 2016Rühm et al. , 2017Rühm et al. , 2018Shore et al. 2017;Tran and Little 2017;Wakeford et al. 2019;Little et al. 2020). ...
... The development of a meta-analysis of animals from largescale databases permitted a reassessment of the DDREF as had been reported by the BEIR VII Committee in the US (Haley et al. 2015). It determined that the values used were based on the use of low doses without direct comparisons of dose rate, so were considered inaccurate. ...
Despite decades of research to understand the biological effects of ionising radiation, there is still much uncertainty over the role of dose rate. Motivated by a virtual workshop on the “Effects of spatial and temporal variation in dose delivery” organised in November 2020 by the Multidisciplinary Low Dose Initiative (MELODI), here, we review studies to date exploring dose rate effects, highlighting significant findings, recent advances and to provide perspective and recommendations for requirements and direction of future work. A comprehensive range of studies is considered, including molecular, cellular, animal, and human studies, with a focus on low linear-energy-transfer radiation exposure. Limits and advantages of each type of study are discussed, and a focus is made on future research needs.
... National laboratories in US and equivalent institutions in Europe, Asia and Australia dedicated decades to research of radiation effects in a variety of animal model systems (e.g. [2][3][4][5][6][7][8]). Unfortunately, only a limited portion of this work found its way into documents that serve as basis for radiation protection policies [9]; efforts to preserve these data and make them available for additional research are ongoing since 1990's when most of the radiation biology initiatives world-wide lost funding as the period of cold war has ended [10][11][12]. ...
... Consequently, interest in effects of low and moderate doses of radiation has increased, paralleled by development of new open-sources in biology permitting access to large volumes of data. Computational approaches have drastically changed as well, making use of individual animal data simple and unlike the work that served as basis for BEIRVII report [6]. This study used individual animal data from all publicly available radiation archives, limited to moderate total doses of radiation (up to 4 Gy) delivered either acutely or in several fractions. ...
... This document used a combination of averaged human and animal data and stated that the risk of fatal cancer development in a population increases 3-12% per Sievert of low dose or protracted ionizing radiation that the population is exposed to. Many more recent studies argued that this estimate is lower or higher than it should be [15][16][17][18], or argued that the addition of post 2006 animal data does not fit the linear quadratic model used as the basis of BEIR VII estimates [6]. Hormesis was even noticed for specific dose ranges in some of these studies; this is not surprising considering that most stresses have a window within which they are hormetice.g. ...
Ionizing radiation is omnipresent and unavoidable on Earth; nevertheless, the range of doses and modes of radiation delivery that represent health risks remain controversial. Radiation protection policy for civilians in US is set at 1 mSv per year. Average persons from contemporary populations are exposed to several hundred milliSieverts (mSv) over their lifetimes from both natural and human made sources such as radon, cosmic rays, CT-scans (20-50 mSv partial body exposure per scan), etc. Health risks associated with these and larger exposures are focus of many epidemiological studies, but uncertainties of these estimates coupled with individual and environmental variation make it is prudent to attempt to use animal models and tightly controlled experimental conditions to supplement our evaluation of radiation risk question. Data on 11,528 of rodents of both genders exposed to x-ray or gamma-ray radiation in facilities in US and Europe were used for this analysis; animal mortality data argue that fractionated radiation exposures have about 2 fold less risk per Gray than acute radiation exposures in the range of doses between 0.25 and 4 Gy.
... The argumentation about DDREF on the basis of INWORKS and other nuclear worker studies is unconvincing as radiogenic nature of diseases under discussion is unproven [140]. Certain mathematical models suggested that protracted exposures are between 2.0 and infinitely times safer than acute exposures at comparable doses [141] (i.e. DDREF up to infinity). ...
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SUMMARY: Certain writers exaggerating medical and ecological consequences of anthropogenic increase in the radiation background contribute to a strangulation of atomic energy. Nuclear power has returned to the agenda because of the concerns about energy demand and climate changes. Health burdens are the greatest for power stations based on coal and oil. The burdens are lower for natural gas and still lower for atomic energy. The same ranking applies to the greenhouse gas emissions and hence probably for the climate change. Among limitations of epidemiological studies are the dose-dependent selection and self-selection. It can be reasonably assumed that people knowing their higher doses would be more motivated to undergo medical checkups being at the same time given more attention. Therefore, diagnostics is on the average more efficient in people with higher doses. In this connection the literature on the post-Chernobyl thyroid and renal cancer, urinary bladder, cataracts and other lesions is reviewed here. Results of some Chernobyl-related studies should be re-interpreted, taking into account that many cancers found by the screening during the first decade after the accident, or brought from non-contaminated areas and recorded as Chernobyl victims, were in fact advanced neglected malignancies. The misinterpretation of such tumors as aggressive radiogenic cancers should not mislead towards overtreatment. Examples of the overtreatment are reviewed here. Ionizing radiation is a known carcinogen but there is no evidence of carcinogenicity below a certain level. Apparently, living organisms have adapted to the natural radiation background. The background has been decreasing during the time of life existence. The screening effect and increased attention of exposed people to their own health will probably result in new reports on the enhanced cancer and other health risks in areas with an elevated natural or anthropogenic radiation background. This will prove no causality. A promising approach to the research of dose-response relationships are lifelong animal experiments.
... These results took no account of smoking data in the relevant datasets (Cahoon et al. 2017b;Ronckers et al. 2010), which could conceivably confound; nevertheless, analyses concentrating on lifelong smokers, or in which the baseline rates in the LSS were adjusted for smoking status and numbers of cigarettes per day smoked yielded ERR that were fairly close to the unadjusted ERR (Table 4). However, recent reanalysis of some large animal datasets did not yield very strong evidence for the ameliorating effects of low dose-rate or low dose exposure on cancer risk (Tran and Little 2017), although evidence of such dose rate effects is stronger when the less relevant endpoint of life shortening is used (Haley et al. 2015). This evidence relating to possible effects of dose rate is fairly weak, since we are comparing risks in moderate and high dose rate studies with those at low dose rate among very different study populations, with different periods of follow-up; nevertheless, what we have done is in the spirit of similar exercises that have been conducted in the epidemiological literature that attempt to assess dose rate effects (Hoel 2018;Jacob et al. 2009;Kocher et al. 2018;Little et al. 2021d;Shore et al. 2017;Walsh et al. 2021). ...
... This suggests that at low doses (0.01 Gy or less spread over a year) it is unlikely that temporally and spatially separate electron tracks could cooperatively produce DNA damage (Brenner et al. 2003), so that in this very low dose region DNA damage at a cellular level would be proportional to dose. It is known that the efficiency of cellular repair processes varies with dose and dose rate (National Council on Radiation Protection and Measurements (NCRP) 2001; United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 1993), and this may be the reason for the curvature that is observed in the cancer dose response at higher levels of dose (e.g. for leukaemia (Hsu et al. 2013) and some solid cancers ) and dose rate effects observed in epidemiological (United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2008) and animal (Haley et al. 2015;Tran and Little 2017; United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 1993) data. DNA double strand breakage, and clustered damage (two or more lesions in close proximity) (United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2012) are thought to be the most critical lesion induced by radiation (United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 1993). ...
Background: The detrimental health effects associated with the receipt of moderate (0.1–1 Gy) and high (>1 Gy) acute doses of sparsely ionising radiation are well established from human epidemiological studies. There is accumulating direct evidence of excess risk of cancer in a number of populations exposed at lower acute doses or doses received over a protracted period. There is evidence that relative risks are generally higher after radiation exposures in utero or in childhood.
Methods and findings: We reviewed and summarised evidence from 60 studies of cancer or benign neoplasms following low- or moderate-level exposure in utero or in childhood from medical and environmental sources. In most of the populations studied the exposure was predominantly to sparsely ionising radiation, such as X-rays and gamma-rays. There were significant (p < 0.001) excess risks for all cancers, and particularly large excess relative risks were observed for brain/CNS tumours, thyroid cancer (including nodules) and leukaemia.
Conclusions: Overall, the totality of this large body of data relating to in utero and childhood exposure provides support for the existence of excess cancer and benign neoplasm risk associated with radiation doses < 0.1 Gy, and for certain groups exposed to natural background radiation, to fallout and medical X-rays in utero, at about 0.02 Gy.
... The argumentation about DDREF based on the epidemiological research [40] is questionable because radiogenic nature of discussed conditions is unproven. Certain models suggested that protracted exposures are between 2.0 and infinitely times safer than acute ones [69]. The latter would correspond to a threshold or hormesis concept. ...
... The latter would correspond to a threshold or hormesis concept. DDREF assessments should be based primarily on direct comparisons of acute and protracted exposures [69]. Further research in this direction would better quantify the radiosensitivity of different animal species enabling more precise extrapolations to humans [70]. ...
Limitations of some epidemiological studies on low-dose lowrate exposures to ionizing radiation include dose comparisons disregarding natural radiation background, unfounded classification of sporadic diseases as radiogenic and conclusions about causality of dose-effect relationships. Other bias, confounders and inter-study heterogeneity have been pointed out. Some dose-effect correlations can be explained by a dose-dependent selection, self-selection and recall bias. It can be reasonably assumed that individuals knowing their higher doses would be more motivated to undergo medical examinations being at the same time given more attention. Reported dose-effect relationships between low-dose low-rate exposures and non-neoplastic diseases call in question the causality of such relationships for cancer detected by the same researchers. Reliable evidence in regard to biological effects of low radiation doses can be obtained in large-scale animal experiments with registration of life duration. The monitoring of human populations exposed to low-dose radiation is important but conclusions should be made with caution considering potential bias and economical motives to strangulate nuclear energy production in accordance with the interests of fossil fuel producers. Of note, health burdens are the greatest for power stations based on coal and oil; the burdens are smaller for natural gas and still lower for the nuclear power. The same ranking applies for the greenhouse gas emissions.
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... LDEF is used to derive the degree of over-(if LDEF > 1) or under-estimation (if LDEF < 1) of low-dose risk by linear extrapolation from effects at higher doses. There has been much recent work associated with the work of ICRP TG91 that assesses LDEF and DREF in experimental radiobiologic data (Haley et al. 2015;Tran and Little 2017;Zander et al. 2020) and also deriving estimates of LDEF from epidemiologic studies (Little et al. 2020). The measure of DDREF used by ICRP to some extent combines these two different quantities, DREF and LDEF. ...
... There is much (quite old) experimental data yielding information on LDEF, and the somewhat related idea of DREF which is the focus of the paper (Rühm et al. 2015). The findings on LDEF of Little et al. (2020) are consistent with this older body of data (Rühm et al. 2015), also moderately consistent with results of recent re-analysis of various large bodies of experimental animal data (Haley et al. 2015;Tran and Little 2017;Zander et al. 2020). The LDEF of about 2 found by Little et al. (2020) for most malignant endpoints is consistent with the DDREF of 2 adopted by (ICRP 2007). ...
Epidemiological studies of cancer rates associated with external and internal exposure to ionizing radiation have been subject to extensive reviews by various scientific bodies. It has long been assumed that radiation-induced cancer risks at low doses or low-dose rates are lower (per unit dose) than those at higher doses and dose rates. Based on a mixture of experimental and epidemiologic evidence the International Commission on Radiological Protection recommended the use of a dose and dose-rate effectiveness factor for purposes of radiological protection to reduce solid cancer risks obtained from moderate-to-high acute dose studies (e.g. those derived from the Japanese atomic bomb survivors) when applied to low dose or low-dose rate exposures. In the last few years there have been a number of attempts at assessing the effect of extrapolation of dose rate via direct comparison of observed risks in low-dose rate occupational studies and appropriately age/sex-adjusted analyses of the Japanese atomic bomb survivors. The usual approach is to consider the ratio of the excess relative risks in the two studies, a measure of the inverse of the dose rate effectiveness factor. This can be estimated using standard meta-analysis with inverse weighting of ratios of relative risks using variances derived via the delta method. In this paper certain potential statistical problems in the ratio of estimated excess relative risks for low-dose rate studies to the excess relative risk in the Japanese atomic bomb survivors are discussed, specifically the absence of a well-defined mean and the theoretically unbounded variance of this ratio. A slightly different method of meta-analysis for estimating uncertainties of these ratios is proposed, motivated by Fieller’s theorem, which leads to slightly different central estimates and confidence intervals for the dose rate effectiveness factor. However, given the uncertainties in the data, the differences in mean values and uncertainties from the dose rate effectiveness factor estimated using delta-method-based meta-analysis are not substantial, generally less than 70%.
