No-threshold Model Research Articles

“The History of the Linear No-Threshold Model” video series

Centre for Haematology, Department of Immunology and Inflammation Imperial College London, UK London and Department of Haematological Oncology Sun Yat-sen Cancer Centre Guangzhou, China Oak Ridge Center for Risk AnalysisOak Ridge, TN 37830 The authors declare no conflicts of interest.

Physics Essentials Enable Deeper Understanding in Signaling and Crosstalk of the Carcinogenesis Paradigm "Epistemology of the Origin of Cancer".

Radioactivity and radiation-induced mutations are believed to be primary causal examples of cancer-initiating events (stimulus). The assumption that an increase in cancer risk develops from any amount of radiation gave rise to the linear no-threshold model. This also led to the assumption that cancer is caused by somatic mutations as described by the somatic mutation theory. Against this backdrop, in actuality only ~5%-10% of cancers result from somatic mutations or its various modifications, while ~80% of cancers are still termed as 'sporadic', meaning that their cause is unknown. Therefore, both the linear no-threshold model and the somatic mutation theory have resulted in an incongruity in thinking. Decades of molecular and clinical research since 2012 led to the development of the cancer paradigm, "Epistemology of the origin of cancer", which explains why the majority of cancers originate as a result of a sixstep sequence of events. An understanding of the essentials of physics helps to explain the interconnections between physics and the biology of cancer. This allows for a much-needed reconciliation of past errors and leads to a deeper understanding of carcinogenesis.

Is the linear no-threshold (LNT) model relevant for radiotherapy?

Initially considered as a kind of radiobiological law, the linear no-threshold (LNT) model, which by definition supports the absence of any threshold for cancer risk induction after irradiation, is nowadays more reasonably described as a pragmatic and prudent approach by the International Organizations. However, it remains today a dogma in radiological protection. Actually, this model had been essentially developed for the radiological protection of a general population against low, and sometimes very low, doses of irradiation. Radiation oncologists are dealing with a totally different situation since they deliver, on purpose, high doses of radiations in more or less limited volumes of the body of cancer patients, patients for whom no other alternatives do exist to get rid of their malignant tumors. Simultaneously, the radiation oncologists inevitably give low and even very low doses at distance from the so-called target volumes. In such a specific situation, what is the carcinogenicity of these low doses and the relevance of the LNT model in radiotherapy? Thus, this paper addresses three critical questions: 1) what is the risk acceptability of the radiation doses delivered by radiotherapy of malignant tumors? 2) what is the real carcinogenic risk of (very) low doses delivered at distance from the target volume? 3) are the clinical radiotherapy data, i.e., the number of second primary cancers, accumulated since more than a century, consistent with the LNT model? In conclusion, the LNT model appears to be poorly adapted to the high doses locally delivered to cancer patients and dramatically overestimates, in most cases, the risk of secondary radio-induced cancers. In fine, the real risk of the LNT model in radiotherapy would be to promote radiophobia in cancer patients and to see some of them turning away from a life-saving treatment.

Review of the effect of reduced levels of background radiation on living organisms

It is well understood that all life is subject to continuous low levels of ionizing radiation, most prominently from the natural background of the biosphere, differing appreciably in particular situations across the surface of the globe. Added to this, albeit in much more isolated situations inclusive of particular workplaces and different environments, are exposures from ionizing radiations traced to human activities. Accordingly, studies of the effects of background-level radiations are subject to complex multifactorial influences. The radiation safety regulations and limits for lower levels of exposure are based on extrapolation from more elevated doses and dose rates, embodied in the linear no-threshold (LNT) model. The LNT model assumes the relationship between biological effects and radiation dose at low levels to be linear, all doses in excess of normal background carrying risk. Substantiated for high dose exposures, the validity of the model is unknown for low doses, the elucidation of possible beneficial hormetic and adaptive effects remaining a challenge. Herein, an overview of the effect on organisms of reduced low-levels of radiations is presented using available evidence and discussion of theoretical possibilities.

The Use of Lead Protection for Staff in Mobile Radiographic Settings: Can Staff Abandon Its Use?

The use of lead protection in patient contexts has recently come under scrutiny, with organisations moving towards ceasing its use in plain film radiography. The use of lead shielding in protecting staff in low-dose settings, such as plain film and mobile radiography, is therefore an important aspect of practice to be reviewed. The objective of this review is to evaluate the use of lead shielding in protecting staff in plain film and mobile radiography, while also exploring the evolution of occupational doses and perceptions of lead protection. While literature is limited on the use of lead protection for staff in mobile settings, lead protection has been shown to reduce staff and adjacent patient dose from scatter. Furthermore, despite the increased frequency of medical imaging procedures in contemporary radiography, the occupational doses of medical radiation workers have reduced over time. With literature demonstrating gaps in current understandings of radiobiological mechanisms at low doses, the linear no-threshold model utilised to estimate radiation risk and develop protection standards cannot be rejected. Thus, this review finds the need for further research to be undertaken to improve risk estimates at low doses in larger cohorts of medical radiation workers, for the demonstration of long-term effects from occupational exposure, prior to ceasing staff lead protection.

Naturally Occurring Radioactive Materials in Bracelets and Necklaces: Radiological Risk Evaluation.

A particular category of jewelry is one involving bracelets and necklaces that are deliberately made to contain naturally occurring radioactive material (NORM)—purveyors making unsubstantiated claims for health benefits from the release of negative ions. Conversely, within the bounds of the linear no-threshold model, long-term use presents a radiological risk to wearers. Evaluation is conducted herein of the radiological risk arising from wearing these products and gamma-ray spectrometry is used to determine the radioactivity levels and annual effective dose of 15 commercially available bracelets (samples B1 to B15) and five necklaces (samples N16 to N20). Various use scenarios are considered; a Geant4 Monte Carlo (Geant4 MC) simulation is also performed to validate the experimental results. The dose conversion coefficient for external radiation and skin equivalent doses were also evaluated. Among the necklaces, sample N16 showed the greatest levels of radioactivity, at 246 ± 35, 1682 ± 118, and 221 ± 40 Bq, for 238U, 232Th, and 40K, respectively. For the bracelets, for 238U and 232Th, sample B15 displayed the greatest level of radioactivity, at 146 ± 21 and 980 ± 71 Bq, respectively. N16 offered the greatest percentage concentrations of U and Th, with means of 0.073 ± 0.0002% and 1.51 ± 0.0015%, respectively, giving rise to an estimated annual effective dose exposure of 1.22 mSv, substantially in excess of the ICRP recommended limit of 1 mSv/year.

What Would Become of Nuclear Risk if Governments Changed Their Regulations to Recognize the Evidence of Radiation's Beneficial Health Effects for Exposures That Are Below the Thresholds for Detrimental Effects?

The 1953 Atoms for Peace Speech to the United Nations proposed applying nuclear energy to essential needs, including abundant electrical energy. The widespread fear of ionizing radiation from nuclear facilities and medical procedures began after the United States National Academy of Sciences performed a study of radiation dangers to the human genome. This study, initiated and managed by an oil industry benefactor, recommended in 1956 that the risk of radiation-induced mutations be assessed using the linear no-threshold dose-response model instead of the threshold model. It was followed by a study that wrongly linked low radiation to cancer among the atomic bomb survivors. The ensuing controversy resulted in a compromise. The National Committee on Radiation Protection adopted the precautionary principle policy in 1959, justified by fear of cancer and lack of knowledge. The United States and all other countries followed this recommendation, which remains unchanged 62 years later. Its impact on nuclear energy and medicine has been profound. Many costly regulations have been enacted to prevent very unlikely human or equipment failures—failures that would lead to radiation exposures that are below the dose thresholds for lasting harmful effects. Potential low-dose radiation therapies, against inflammation, cancer, autoimmune, and neurodegenerative diseases, are shunned.

How Safe Are Radiation Doses in Diagnostic Radiology? A Historical Perspective and Review of Current Evidence.

The “no dose is safe” linear no-threshold (LNT) model forms the basis for radiation safety in radiology practice. This model has its origins in observations of germline mutations in fruit flies exposed to X-rays. After World War II, quantitative risk estimates of radiation injury are primarily derived from the atomic bomb survivor Life Span Study. Current understanding of tissue response to radiation has raised doubts about the validity of LNT model at low doses encountered in the practice of diagnostic radiology. This article traces the evolution of basic radiation safety concepts and provides a bird's eye view of the Life Span Study and other studies which throw light on the matter. The arguments for an alternative, threshold, or even hermetic models of dose response are examined. The relevance of these developments to the nuclear power industry is also outlined.

Aortic Elasticity and Arsenic Exposure: A Step Function rather than a Linear Function.

While the dose-response relationship for the carcinogenic effects of arsenic exposure indicates nonlinearity with increases only above about 150 μg/L arsenic in drinking water, similar analyses of noncarcinogenic effects of arsenic exposure remain to be conducted. We present here an alternative analysis of data on a measure of aortic elasticity, a risk factor for hypertension, and its relationship to urinary arsenic levels. An occupational health study from Ankara, Turkey by Karakulak etal. compared urinary arsenic levels and a measure of aortic elasticity (specifically, aortic strain) in workers with a linear no-threshold model. We have examined these data with three alternative models-a fitted step-function, a stratified, and a weighted linear regression model. Discontinuity within the data revealed two subsets of data, one for workers with urinary arsenic levels ≤ 160 μg/L whose mean aortic strain level was 11.3% and one for workers with arsenic levels > 160 μg/L whose mean aortic stain level was 5.33 % (p < 0.0001). Several alternative models were examined that indicated the best model to be the threshold model with a threshold at a urinary arsenic level of 160 μg/L. Observation of a discontinuity in the data revealed their better fit to a threshold model (at a urinary arsenic level of 160 μg/L) than to a linear-no threshold model. Examinations with alternative models are recommended for studies of arsenic and hypertension and possibly other noncarcinogenic effects.

Historical perspective on the role of cell proliferation in carcinogenesis for DNA-reactive and non-DNA-reactive carcinogens: Arsenic as an example

Our understanding of the etiology of cancer has developed significantly over the past fifty years, beginning with a single-hit linear no-threshold (LNT) conceptual model based on early studies conducted in Drosophila. Over the past several decades, multiple lines of evidence have accumulated to support a contemporary model of chemical carcinogenesis: a multi-hit model involving a prolonged stress environment that over time may drive the mutation of multiple cells into an injured state that ultimately could lead to uncontrolled proliferation via clonal expansion of mutation-carrying daughter cells. Arsenic carcinogenicity offers a useful case study for further exploration of advanced conceptual models for chemical carcinogenesis. A threshold for arsenic carcinogenicity is supported by its mode of action, characterized by repeating cycles of cytotoxicity and cellular regeneration. Furthermore, preliminary meta-analyses of epidemiology dose-response data for inorganic arsenic (iAs) and bladder cancer, correlated to dose-response data measured in vitro, support a threshold of effect in humans on the order of 50−100 μg/L in drinking water. In light of recent developments in our understanding of cancer etiology, we urge strong consideration of the existing mode-of-action evidence supporting a threshold of effect for arsenic carcinogenicity, as well as consideration of the potential methodological pitfalls in evaluating epidemiology dose-response data that could potentially bias in the direction of low-dose linearity.

A review of low-dose arsenic risks and human cancers

The linear no-threshold (LNT) model has historically been the default assumption in assessing carcinogenic risk from arsenic ingestion based on epidemiological studies. This contrasts with the threshold model used in assessing carcinogenic risk from arsenic ingestion derived from toxicological investigations of experimental animals. We present here a review of our epidemiological work that has examined models that may better explain the human cancer risk from the ingestion of arsenic, particularly from low level exposures, than does the LNT model. While previous epidemiology studies have demonstrated increased risks of bladder, lung, and skin cancers at arsenic exposures of 200 ug/L or greater, we seek here to examine the dose-response patterns at lower exposure levels. These include ecological, case/control, and cohort designs. Methodologic issues include choice of continuous or stratified analysis of exposure data, search for sources of non-conformity or variability, and distinctions in water sources and geography. Multiple studies have yielded useful data-based models, including threshold models, hockey-stick models, and “J-shaped” linear-quadratic models. These models have found that increased cancer risk may only begin at specific arsenic exposure levels greater than zero. These results provide guidance in seeking toxicological explanations and public health reference levels.

ASSESSMENT OF OCCUPATIONAL RADIATION DOSES OF MEDICAL RADIATION WORKERS IN TWO COMMUNITY HOSPITALS.

The International Commission on Radiological Protection recommends the adoption of the linear, no-threshold model as a predictive risk model for radiation protection purposes since the relationship between low-dose radiation exposure and cancer risk is unclear. Medical radiation workers are subject to occupational exposures and differences in workload, area of work and types of exposure can lead to variations in exposures between different occupational groups. We investigated the occupational exposures of 572 workers from four departments in two community hospitals and stratified into 22 occupational groups in order to identify groups with the highest radiation exposure. The occupational doses from 2015 to 2019 were analyzed to identify the dose distribution of each occupational group, total number of monitored workers, annual and collective deep (Hp(10)), eye (Hp(3)) and shallow (Hp(0.07)) doses. We further determined the individual and occupational group lifetime doses as well as the probability that monitored workers' lifetime doses will exceed a specified lifetime dose level. The occupational groups with the highest radiation exposures were the nuclear medicine technologists, diagnostic imaging radiologists and diagnostic cardiologists. Although our data suggest that occupational doses reported are low, it is essential that exposure of occupationally exposed personnel are always kept as low as reasonably achievable with an effective radiation protection program.

Underground Radiobiology: A Perspective at Gran Sasso National Laboratory.

Scientific community and institutions (e. g., ICRP) consider that the Linear No-Threshold (LNT) model, which extrapolates stochastic risk at low dose/low dose rate from the risk at moderate/high doses, provides a prudent basis for practical purposes of radiological protection. However, biological low dose/dose rate responses that challenge the LNT model have been highlighted and important dowels came from radiobiology studies conducted in Deep Underground Laboratories (DULs). These extreme ultra-low radiation environments are ideal locations to conduct below-background radiobiology experiments, interesting from basic and applied science. The INFN Gran Sasso National Laboratory (LNGS) (Italy) is the site where most of the underground radiobiological data has been collected so far and where the first in vivo underground experiment was carried out using Drosophila melanogaster as model organism. Presently, many DULs around the world have implemented dedicated programs, meetings and proposals. The general message coming from studies conducted in DULs using protozoan, bacteria, mammalian cells and organisms (flies, worms, fishes) is that environmental radiation may trigger biological mechanisms that can increase the capability to cope against stress. However, several issues are still open, among them: the role of the quality of the radiation spectrum in modulating the biological response, the dependence on the biological endpoint and on the model system considered, the overall effect at organism level (detrimental or beneficial). At LNGS, we recently launched the RENOIR experiment aimed at improving knowledge on the environmental radiation spectrum and to investigate the specific role of the gamma component on the biological response of Drosophila melanogaster.

Aortic Strain -Threshold Analysis of Non-Cancer Outcome from Arsenic Exposure

Background: While arsenic has been shown in many studies to behave as a threshold carcinogen, analyses of non-cancer outcomes (e.g., cardiovascular) have generally been presented only using linear models. Alternative models have received little consideration. We choose here to examine aortic strain data, a known risk factor for hypertension and cardiovascular disease, on arsenic-exposed workers with alternative analytic modeling.Method: A previously published study (Karakulak et al., 2016) of aortic strain measurements in arsenic-exposed workers had demonstrated that aortic strain was markedly reduced among workers with high levels of arsenic exposure (urinary arsenic in ug/L). The original analysis was limited to a linear model without model validation. We have analyzed the data using alternative models.Results: Examination of the linear analysis and its residuals demonstrated significant heteroscedascity with unequal variances, particularly at urinary levels of &gt; 160 ug arsenic per liter (ug/L). The test of equal variances from samples with &gt;160 and samples &lt;= 160 demonstrated inequality (p &lt; 0.0001). The better alternative model was a step-function with a mean aortic strain of 11.3% for those with urinary arsenic &lt;= 160 ug/L and with a mean aortic strain of 5.3% for those with urinary arsenic &gt; 160 ug/L. A further stratified analysis with bins of 40 ug/L showed no effect on aortic strain for the urinary arsenic range of &lt;= 160 ug/L and, separately, no effect for the urinary arsenic range of &gt; 160 ug/L.Conclusion: Aortic elasticity parameters show an adverse effect from arsenic exposure only at urinary exposure levels of &gt; 160 ug/L and not below, indicating a step-function rather than a linear function. Restriction of analyses to a linear no-threshold model may have blinded the finding of a more useful demonstration of a dose-response pattern that may offer different toxicological interpretations.

Le cancer radio-induit, le kangourou, et le petit lapin. Ou « la déclinaison radiobiologique du mythe de la Licorne Rose »

The linear no-threshold (LNT) model, which has become a dogma in its own right, leads to affirming the existence of the harmfulness of low doses of ionizing radiation as long as their harmlessness could not be demonstrated. It seems important to understand how we came to make dogmatic a scientifically “non-theory”. We propose in this article, after having shown how much RLSS stems from a myth and not from a scientific approach, to expose its origins and genesis, essential to the understanding of its current character of so-called incontestable truth, then to illustrate the worrying practical and epistemological consequences that this reference to RLSS entails. We rely for this on the critical analysis of some of the epidemiological studies that claim to demonstrate or confirm it.

There's Plenty of Room at the Bottom: Low Radiation as a Biological Extreme

The effects of high radiation as a biological extreme have historically been, and continue to be, extensively researched in the fields of radiation biology and astrobiology. However, the absence of radiation as an extreme has received relatively limited attention from the scientific community, with its effects on life remaining unclear. The currently accepted model of the radiation dose-damage relationship for organisms is the linear no-threshold (LNT) model, which predicts a positive linear correlation between dose and damage that intercepts at zero dose corresponding to zero damage. Despite its wide-spread implementation, the LNT model is continuously being challenged by various new models, with the hormesis model as one of its main competitors. This model also postulates damage at high doses but, in contrast to the LNT model, it predicts beneficial stimulation of growth at low doses. Experiments to date have not yet been able to conclusively validate or dismiss either of these models. The aim of the collaborative Subsurface Experiment of Life in Low Radiation (SELLR) project was to test these competing models on prokaryotes in a well-characterised environment and provide a robust experimental set up to investigate low radiation in terrestrial and non-terrestrial environments. Bacterial growth assays using Bacillus subtilis and Escherichia coli were performed under ultra low ionising radiation in the Boulby International Subsurface Astrobiology Laboratory (BISAL) facilities of the Boulby mine (Cleveland, UK) and were used to investigate effects on viability. No significant effect on bacterial growth was observed from exposure to radiation doses ranging from 0.01 times the levels of background radiation typically found in terrestrial surface environments to 100 times that background. These data suggest that the extremes of low radiation do not alter growth parameters of these two organisms and that an improved model should be considered for prokaryotes, consisting of a dose-damage response with a threshold at ultra low radiation. We discuss the implications of these data for low radiation as a novel microbiological “extreme”.

Dismantling Fixations on Failed Fictions: A-Bomb Survivor Study Denies The Low-Dose Radiogenic Cancer Narrative

The linear no-threshold (LNT) model of low dose ionizing radiation's (LDIR) role in radiogenic cancer incidence has long served as a pseudo-scientific belief arising from evidence that has never been proven, but has been contested. One source of current evidence that favors the LNT model is the Radiation Effects Research Foundation’s (RERF) Life Span Study (LSS) cohort of Japanese atomic bomb survivors. The RERF has managed the input data, model development, and data analyses for the LSS cohort for 45 years, publishing research papers and reports updating the RERF’s progress. In recent years, the RERF has attempted to identify other cancer risk factors that may have played a role in the cancer incidence of cohort survivors, and this effort has drawn attention to the fact that many earlier years of papers and reports from the RERF have never considered these risk factors, making such publications of questionable merit. This investigation examines two recent papers from the RERF that denominate how the RERF now analyzes specific cancer incidence for cohort members, how it treats lifestyle and other risk factors for various cancers that have arisen in the cohort, and how it continues to find and assert that bomb-blast LDIR remains a distinguishable source of radiogenic cancer in the cohort. The investigation observes that the cohort input data and modeling have extensive deficiencies and defects, many having been identified by RERF authors themselves, that substantially compromise the findings of these two papers, and offers concluding evidence that the LDIR radiogenic cancer model is highly implausible if not impossible. From such evidence, a final conclusion must arise that supports a threshold model for the dose–response relationship between LDIR exposure and radiogenic cancer.

Consequences of a large-scale nuclear accident and guidelines for evacuation: a cost-effectiveness analysis

Purpose We aimed for a quantitative evaluation that justifies guidelines for evacuation which take into consideration both the human and economic costs. To the best of our knowledge, such an evaluation has not been performed yet. The present guidelines published by the International Atomic Energy Agency (IAEA) are probably based on averting radiation risk only; IAEA did not cite any quantitative estimation of the human cost of evacuation. Materials and methods Quantitative estimation of the human and monetary costs of evacuation and, alternatively, the human and monetary costs of radiation exposure (non-evacuation). Associating human life with monetary value is psychologically difficult and somewhat challenging ethically; however, there is no escape from such an association (cost-effectiveness analysis) when making decisions regarding public health and safety, since extraneous public expenditures lead to a statistical life shortening. Estimating worst-case health consequences of irradiation, we used the conservative linear no-threshold (LNT) model because this model is widely used in spite of its controversy. In our estimation of the human cost of evacuation, we considered three factors: (a) direct loss of life (after Fukushima, 1% of the evacuees died within 2 years due to causes directly related to their evacuation), (b) loss of quality of life, and (c) loss of wealth leading to loss of life. The connection of economic loss with loss of life was performed according to the median cost-effectiveness threshold of 50–100 thousand USD per quality-adjusted life year. Results Even according to mortality calculations based on LNT, the overall loss of life due to evacuation is higher than the loss of life due to irradiation if the population-averaged first-year radiation dose is 500 mSv or less. Conclusions Based on the performed analysis, we suggest avoiding evacuation if the projected first-year dose is below 500 mSv. This suggested action level is about five-fold higher than the action level presently recommended by the IAEA (100 mSv per year).

Until There Is a Resolution of the Pro-LNT/Anti-LNT Debate, We Should Head Toward a More Sensible Graded Approach for Protection From Low-Dose Ionizing Radiation.

Current regulation of ionizing radiation is based on the linear no-threshold (LNT) model where any radiation dose increases cancer risk and is independent of dose rate, resulting in large amounts of time and money being spent protecting from extremely small radiation exposures and hence extremely small risk. There are animal studies which demonstrate that LNT is incorrect at low doses, supporting a threshold or hormesis model and thus indicating that there is no need to protect from very low doses. This has led to a sometimes bitter debate between pro-LNT and anti-LNT camps, and the debate has been at a stalemate for some time. This commentary is not aimed at taking either side of the debate. It is likely that the public, workers, and the environment are adequately protected under current regulation, which is the most important outcome. Until those on one side of the debate can convince the other, it would be sensible to move forward toward a graded (risk-based) approach to regulation, where the stringency of control is commensurate with the risk, resulting hopefully in more sensible practical thresholds. This approach is gradually being put forward by international radiation protection advisory bodies.

Zero-Fluoroscopy Ablation at the Texas Heart Institute.

Zero-Fluoroscopy Ablation at the Texas Heart Institute.