The Linear No-Threshold Model of Low-Dose Radiogenic Cancer: A Failed Fiction.

The linear no-threshold (LNT) model for low-dose, radiogenic cancer has been a fixture of radiation protection and regulatory requirements for decades, but its validity has long been contested. This article finds, yet again, more questionable data and analyses purporting to support the model, this within the "gold-standard" data set for estimating radiation effects in humans. Herein is addressed a number of significant uncertainties in the Radiation Effects Research Foundation's Life Span Study (LSS) cohort of atomic bomb survivors, especially in its latest update of 2017, showing that the study's support of the LNT model is not evidence based. We find that its latest 2 analyses of solid cancer incidence ignore biology and do not support the LNT model. Additionally, we identify data inconsistencies and missing causalities in the LSS data and analyses that place reliance on uncertain, imputed data and apparently flawed modeling, further invalidating the LNT model. These observations lead to a most credible conclusion, one supporting a threshold model for the dose-response relationship between low-dose radiation exposure and radiogenic cancer in humans. Based upon these findings and those cited from others, it becomes apparent that the LNT model cannot be scientifically valid.

A Critical Assessment of the Linear No-Threshold Hypothesis: Its Validity and Applicability for Use in Risk Assessment and Radiation Protection.

The Society of Nuclear Medicine and Molecular Imaging convened a task group to examine the evidence for the risk of carcinogenesis from low-dose radiation exposure and to assess evidence in the scientific literature related to the overall validity of the linear no-threshold (LNT) hypothesis and its applicability for use in risk assessment and radiation protection. In the low-dose and dose-rate region, the group concluded that the LNT hypothesis is invalid as it is not supported by the available scientific evidence and, instead, is actually refuted by published epidemiology and radiation biology. The task group concluded that the evidence does not support the use of LNT either for risk assessment or radiation protection in the low-dose and dose-rate region.

RADAR Dose Estimate Report: A Compendium of Radiopharmaceutical Dose Estimates Based on OLINDA/EXM Version 2.0.

A compendium of about 100 radiopharmaceuticals, based on the OLINDA/EXM version 2.0 software, is presented. A new generation of voxel-based, realistic human computational phantoms developed by the RADAR committee of the Society of Nuclear Medicine and Molecular Imaging, based on 2007 recommendations of the International Commission on Radiological Protection, was used to develop the dose estimates, and the most recent biokinetic models were used as well. These estimates will be made available in electronic form and can be modified and updated as models are changed and as new radiopharmaceuticals are added.

The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure.

This paper examines the birthing process of the linear no-threshold model with respect to genetic effects and carcinogenesis. This model was conceived >70 years ago but still remains a foundational element within much of the scientific thought regarding exposure to low-dose ionizing radiation. This model is used today to provide risk estimates for cancer resulting from any exposure to ionizing radiation down to zero dose, risk estimates that are only theoretical and, as yet, have never been conclusively demonstrated by empirical evidence. We are literally bathed every second of every day in low-dose radiation exposure due to natural background radiation, exposures that vary annually from a few mGy to 260 mGy, depending upon where one lives on the planet. Irrespective of the level of background exposure to a given population, no associated health effects have been documented to date anywhere in the world. In fact, people in the United States are living longer today than ever before, likely due to always improving levels of medical care, including even more radiation exposure from diagnostic medical radiation (eg, x-ray and computed tomography imaging examinations) which are well within the background dose range across the globe. Yet, the persistent use of the linear no-threshold model for risk assessment by regulators and advisory bodies continues to drive an unfounded fear of any low-dose radiation exposure, as well as excessive expenditures on putative but unneeded and wasteful safety measures.

The BEIR VII Estimates of Low-Dose Radiation Health Risks Are Based on Faulty Assumptions and Data Analyses: A Call for Reassessment.

The 2006 National Academy of Sciences Biologic Effects of Ionizing Radiation (BEIR) VII report is a well-recognized and frequently cited source on the legitimacy of the linear no-threshold (LNT) model-a model entailing a linear and causal relationship between ionizing radiation and human cancer risk. Linearity means that all radiation causes cancer and explicitly excludes a threshold below which radiogenic cancer risk disappears. However, the BEIR VII committee has erred in the interpretation of its selected literature; specifically, the in vitro data quoted fail to support LNT. Moreover, in vitro data cannot be considered as definitive proof of cancer development in intact organisms. This review is presented to stimulate a critical reevaluation by a BEIR VIII committee to reassess the validity, and use, of LNT and its derived policies.

Mass scaling of S values for blood-based estimation of red marrow absorbed dose: the quest for an appropriate method.

As a first step in performing patient-specific absorbed dose calculations, it may be necessary to scale dose conversion factors (e.g., S values in the MIRD system or dose factors in the RADAR system) by patient organ mass. The absorbed dose to active marrow is of particular interest for radionuclide therapy. When using the blood-based model of red marrow (RM) absorbed dose estimation, there are only 2 S values of concern, representing RM self-dose and cross-dose terms. Linear mass scaling has generally been performed for the self-dose term, whereas the cross-dose term is considered to be mass independent. We will illustrate that each radionuclide may need to have its mass-based correction determined to assess whether the conventionally used linear mass scaling is appropriate and should be applied not only to the self-dose S value but also to the cross-dose term.

Posttherapy radiation safety considerations in radiomicrosphere treatment with 90Y-microspheres.

Radiomicrosphere treatment involves the intrahepatic arterial administration of (90)Y-resin or (90)Y-glass microspheres. The microspheres are biocompatible, but not biodegradable, and little to no (90)Y leaches from the microspheres. Without any bioelimination, the beta-dose delivery is generally confined to the liver. Although U.S. Nuclear Regulatory Commission requirements permit patients treated with these microspheres to be released without the need for dose determination or patient instructions, there are important radiation safety issues that need scientific clarification. We carefully evaluated the radiation exposure mechanisms, including the bremsstrahlung radiation doses to others, for a variety of lifestyle behaviors. Dose estimates were also made for several practical and theoretic situations involving the patient's gonads, an embryo or fetus, and a nursing infant. For the infant, we evaluated the potential beta-dose that might be introduced via breast milk ingestion. The bremsstrahlung component of the decay scheme of the pure beta-emitter (90)Y has traditionally been ignored in internal and external dose calculations. Because the production of in vivo bremsstrahlung with the high-energy pure beta-particle-emitting radionuclides used for therapeutic purposes is sufficient to permit external detection and imaging, we believe that the contribution of such radiation should be considered with regard to patient release; we therefore chose to evaluate this potential external radiation hazard. In all cases, the estimated doses were very small, indicating that no patient restrictions are required for radiation safety purposes after the release of a patient who has been treated with (90)Y-microspheres.

Licensee over-reliance on conservatisms in NRC guidance regarding the release of patients treated with 131I.

Medical licensees are required to comply with U.S. Nuclear Regulatory Commission (NRC) regulations pertaining to the release of patients administered radioactive material. However, use of the associated NRC guidance expressed in NUREG-1556, Volume 9, is completely optional and has been shown to be overly conservative. Rigid adherence to the guidance recommendations has placed an undue burden on nuclear medicine therapy patients and their families, as well as licensees responsible for ensuring compliance with NRC requirements. More realistic guidance has been published by other responsible professional societies and will be presented in this work. These more realistic calculations allow for higher releasable activity levels than the widely adopted NUREG levels, particularly for thyroid cancer patients. The guidance-suggested releasable activity limit is similar to our calculational result for hyperthyroid patients, 2.1 GBq (57 mCi) compared to 2.3 GBq (62 mCi), but is significantly lower for thyroid cancer patients, 6.6 GBq (179 mCi) vs. 16.9 GBq (457 mCi) using the regulatory definition of the total effective dose equivalent (TEDE). Higher limits are both possible and reasonable, if the permissible extra-regulatory definition of the TEDE is used in which the effective dose equivalent (EDE), rather than the deep-dose equivalent (DDE), is determined. We maintain that professionals evaluating compliance with the NRC requirements for patient release, pursuant to 10 CFR 35.75, should use the procedures presented here and not rely automatically on the NUREG.

Preserving the Anti-Scientific Linear No-Threshold Myth: Authority, Agnosticism, Transparency, and the Standard of Care.

The linear no-threshold (LNT) assumption is over 70 years old and holds that all ionizing radiation exposure leaves cumulative effects, all of which are harmful regardless of how low the dose or dose rate is. The claimed harm centers on the risk of future radiogenic cancer. This has been shown countless times to be fallacious, and hundreds of scientific studies-both experimental and observational/epidemiological-demonstrate that at low enough doses and dose rates, ionizing radiation stimulates an evolved adaptive response and therefore is beneficial to health, lowering rather than raising the risk of cancer. Yet the myth of uncorrected lifetime cumulative risk still pervades the field of radiation science and underlies the policies of virtually all regulatory agencies around the world. This article explores some of the motivations behind, and methods used to assure, the extreme durability of the LNT myth in the face of the preponderance of contrary evidence and the manifest harms of radiophobia. These include subservience to the voice of authority, tactics such as claiming agnosticism on behalf of the entire field, transparent references to contrary evidence while dismissing the findings without refutation, and seeking shelter behind the legally protective medical standard of care.

Subjecting Radiologic Imaging to the Linear No-Threshold Hypothesis: A Non Sequitur of Non-Trivial Proportion.

Radiologic imaging is claimed to carry an iatrogenic risk of cancer, based on an uninformed commitment to the 70-y-old linear no-threshold hypothesis (LNTH). Credible evidence of imaging-related low-dose (<100 mGy) carcinogenic risk is nonexistent; it is a hypothetical risk derived from the demonstrably false LNTH. On the contrary, low-dose radiation does not cause, but more likely helps prevent, cancer. The LNTH and its offspring, ALARA (as low as reasonably achievable), are fatally flawed, focusing only on molecular damage while ignoring protective, organismal biologic responses. Although some grant the absence of low-dose harm, they nevertheless advocate the "prudence" of dose optimization (i.e., using ALARA doses); but this is a radiophobia-centered, not scientific, approach. Medical imaging studies achieve a diagnostic purpose and should be governed by the highest science-based principles and policies. The LNTH is an invalidated hypothesis, and its use, in the form of ALARA dosing, is responsible for misguided concerns promoting radiophobia, leading to actual risks far greater than the hypothetical carcinogenic risk purportedly avoided. Further, the myriad benefits of imaging are ignored. The present work calls for ending the radiophobia caused by those asserting the need for dose optimization in imaging: the low-dose radiation of medical imaging has no documented pathway to harm, whereas the LNTH and ALARA most assuredly do.

Dose Optimization to Minimize Radiation Risk for Children Undergoing CT and Nuclear Medicine Imaging Is Misguided and Detrimental.

A debate exists within the medical community on whether the linear no-threshold model of ionizing radiation exposure accurately predicts the subsequent incidence of radiogenic cancer. In this article, we evaluate evidence refuting the linear no-threshold model and corollary efforts to reduce radiation exposure from CT and nuclear medicine imaging in accord with the as-low-as-reasonably-achievable principle, particularly for children. Further, we review studies demonstrating that children are not, in fact, more radiosensitive than adults in the radiologic imaging dose range, rendering dose reduction for children unjustifiable and counterproductive. Efforts to minimize nonexistent risks are futile and a major source of persistent radiophobia. Radiophobia is detrimental to patients and parents, induces stress, and leads to suboptimal image quality and avoidance of imaging, thus increasing misdiagnoses and consequent harm while offering no compensating benefits.

Does Imaging Technology Cause Cancer? Debunking the Linear No-Threshold Model of Radiation Carcinogenesis.

In the past several years, there has been a great deal of attention from the popular media focusing on the alleged carcinogenicity of low-dose radiation exposures received by patients undergoing medical imaging studies such as X-rays, computed tomography scans, and nuclear medicine scintigraphy. The media has based its reporting on the plethora of articles published in the scientific literature that claim that there is "no safe dose" of ionizing radiation, while essentially ignoring all the literature demonstrating the opposite point of view. But this reported "scientific" literature in turn bases its estimates of cancer induction on the linear no-threshold hypothesis of radiation carcinogenesis. The use of the linear no-threshold model has yielded hundreds of articles, all of which predict a definite carcinogenic effect of any dose of radiation, regardless of how small. Therefore, hospitals and professional societies have begun campaigns and policies aiming to reduce the use of certain medical imaging studies based on perceived risk:benefit ratio assumptions. However, as they are essentially all based on the linear no-threshold model of radiation carcinogenesis, the risk:benefit ratio models used to calculate the hazards of radiological imaging studies may be grossly inaccurate if the linear no-threshold hypothesis is wrong. Here, we review the myriad inadequacies of the linear no-threshold model and cast doubt on the various studies based on this overly simplistic model.

Epidemiology Without Biology: False Paradigms, Unfounded Assumptions, and Specious Statistics in Radiation Science (with Commentaries by Inge Schmitz-Feuerhake and Christopher Busby and a Reply by the Authors).

Radiation science is dominated by a paradigm based on an assumption without empirical foundation. Known as the linear no-threshold (LNT) hypothesis, it holds that all ionizing radiation is harmful no matter how low the dose or dose rate. Epidemiological studies that claim to confirm LNT either neglect experimental and/or observational discoveries at the cellular, tissue, and organismal levels, or mention them only to distort or dismiss them. The appearance of validity in these studies rests on circular reasoning, cherry picking, faulty experimental design, and/or misleading inferences from weak statistical evidence. In contrast, studies based on biological discoveries demonstrate the reality of hormesis: the stimulation of biological responses that defend the organism against damage from environmental agents. Normal metabolic processes are far more damaging than all but the most extreme exposures to radiation. However, evolution has provided all extant plants and animals with defenses that repair such damage or remove the damaged cells, conferring on the organism even greater ability to defend against subsequent damage. Editors of medical journals now admit that perhaps half of the scientific literature may be untrue. Radiation science falls into that category. Belief in LNT informs the practice of radiology, radiation regulatory policies, and popular culture through the media. The result is mass radiophobia and harmful outcomes, including forced relocations of populations near nuclear power plant accidents, reluctance to avail oneself of needed medical imaging studies, and aversion to nuclear energy-all unwarranted and all harmful to millions of people.

Establishing a clinically meaningful predictive model of hematologic toxicity in nonmyeloablative targeted radiotherapy: practical aspects and limitations of red marrow dosimetry.

In either heavily pretreated or previously untreated patient populations, dosimetry holds the promise of playing an integral role in the physician's ability to adjust therapeutic activity prescriptions to limit excessive hematologic toxicity in individual patients. However, red marrow absorbed doses have not been highly predictive of hematopoietic toxicity. Although the accuracy of red marrow dose estimates is expected to improve as more patient-specific models are implemented, these model-calculated absorbed doses more than likely will have to be adjusted by parameters that adequately characterize bone marrow tolerance in the heavily pretreated patients most likely to receive nonmyeloablative radiolabeled antibody therapy. Models need to be established that consider not only absorbed dose but also parameters that are indicative of pretherapy bone marrow reserve and radiosensitivity so that a clinically meaningful predictive model of hematologic toxicity can be established.

Radiation Dose and Hazard Assessment of Potential Contamination Events During Use of 223Ra Dichloride in Radionuclide Therapy.

An analysis is presented of the possible dosimetric consequences of various potential contamination events involving 223Ra dichloride (Xofigo), the FDA-approved therapeutic agent used in the treatment of bone metastases in patients with castration-resistant prostate cancer. Three exposure scenarios are considered: inhalation dose to an individual due to the hypothetical inhalation of 219Rn and its progeny assumed to be released into the air from a liquid spill on the floor, external dose from direct photon exposure of an individual assigned to clean up a spill, and skin dose to an individual should the liquid material come into contact with their skin. Doses from the first two scenarios were very small; 2.8 × 10(-3) mSv and 8.1 × 10(-4) mSv, respectively. Using extremely conservative assumptions, the skin dose was estimated to be 72 mSv; in a realistic scenario, this dose would likely be an order of magnitude or more lower. These doses are very small compared to regulatory limits, and good health physics practices likely to be employed in such incidents would lower them still further. The authors conclude that the medical use of Xofigo does not pose any significant radiation safety issue with respect to potential contamination events, even if multiple incidents might occur during the course of a year, since all worst-case potential contamination events considered in this study will not result in significant radiation exposures to workers.

Calculating the absorbed dose from radioactive patients: the line-source versus point-source model.

UNLABELLED: In calculations of absorbed doses from radioactive patients, the activity distribution in such patients is generally assumed to be an unattenuated point source and the dose to exposed individuals at a given distance is therefore calculated using the inverse square law. In many nuclear medicine patients, the activity distribution is widely dispersed and does not simulate a point source. In these cases, a line-source model is proposed to more accurately reflect this extended activity distribution. METHODS: Calculations of dose rate per unit activity were performed for a point source and for line sources of lengths of 20, 50, 70, 100, and 174 cm, and the ratios of line-source values to point-source values were calculated. In addition, radionuclide-independent conversion factors, to convert exposure rate constants to dose rates per unit activity, for these line-source lengths at various distances were determined. RESULTS: The calculated values, substantiated by published data, indicate that the inverse square law approximation is not valid for a line source until a certain distance is reached, dependent on the length of the line source. For the 20-, 50-, 70-, 100-, and 174-cm line sources, the dose rate values estimated by the inverse square law approximation are within approximately 10% of the values estimated using the line-source approach at distances of 20, 45, 60, 85, and 145 cm, respectively. At closer distances, use of the point-source model for a patient with an extended activity distribution will overestimate the radiation absorbed dose to exposed individuals, sometimes by a very significant amount. CONCLUSION: The line-source model is a more realistic and practical approach than the traditional point-source model for determining the dose to individuals exposed to radioactive patients with widespread activity distributions.

A practical methodology for patient release after tositumomab and (131)I-tositumomab therapy.

UNLABELLED: A methodology was developed determining patient releasability after radioimmunotherapy with tositumomab and (131)I-tositumomab for the treatment of non-Hodgkin's lymphoma. METHODS: Dosimetry data were obtained and analyzed after 157 administrations of (131)I-tositumomab to 139 patients with relapsed or refractory non-Hodgkin's lymphoma. Tositumomab and (131)I-tositumomab therapy included dosimetric (low activity) and therapeutic (high activity) administrations. For each patient, the total-body residence time was calculated after the dosimetric administration from total-body counts obtained over 6 or 7 d and was then used to determine the appropriate therapeutic activity to deliver a specific total-body radiation dose. Patient dose rates at 1 m were measured immediately after the therapeutic infusion. Patient-specific calculations based on the measured total-body residence time and dose rate for (131)I-tositumomab were derived to determine the patient's maximum releasable dose rate at 1 m, estimated radiation dose to maximally exposed individuals, and the amount of time necessary to avoid close contact with others. RESULTS: The mean administered activity (+/-SD), determined by dosimetry studies for each patient before therapy, was 3,108 +/- 1,073 MBq (84 +/- 29 mCi) (range, 1,221 +/- 5,957 MBq [33--161 mCi]). Immediately after treatment, the mean measured dose rate (+/- SD) at 1 m was 0.109 +/- 0.032 mSv/h (10.9 +/- 3.2 mrem/h; range, 0.04--0.24 mSv/h [4--24 mrem/h]). The measured dose rates were 60% (range, 37%--90%; P < 0.0001) of the theoretic dose rates from a point source in air predicted using the dose equivalent rate per unit activity of (131)I (5.95 x 10(-5) mSv/MBq h [0.22 mrem/mCi h] at 1 m). The mean estimated radiation dose to the maximally exposed individual was 3.06 mSv (306 mrem) (range, 1.95--4.96 mSv [195--496 mrem]). On the basis of current regulatory patient-release criteria, all (131)I-tositumomab--treated patients were determined to be releasable by comparing the dose rate at 1 m with a predetermined maximum releasable dose rate. Detailed instructions were provided to limit family members' exposure. CONCLUSION: A methodology has been developed for the release of patients administered radioactive materials based on the new Nuclear Regulatory Commission regulations. This approach uses a patient-specific dose calculation based on the measured total-body residence time and dose rate. This analysis shows the feasibility of outpatient radioimmunotherapy with tositumomab and (131)I-tositumomab.

Accurate dose calibrator activity measurement of 90Y-ibritumomab tiuxetan.

UNLABELLED: This investigation examined the accuracy of dose calibrator activity measurement of the beta-emitting radiopharmaceutical (90)Y-ibritumomab tiuxetan. METHODS: Five different facilities independently measured (90)Y in a 10-mL syringe geometry with 30 dose calibrator models from 3 different manufacturers. The activities ranged from 81.4 MBq (2.2 mCi) to 1,406 MBq (38 mCi) over the volume range of 3-9 mL. RESULTS: The mean dial settings for (90)Y measurement were 375, 51 x 10, and 897 x 100 for Atomlab, CRC, and Mark V dose calibrators, respectively. The maximum volume dependence was 0.28%/mL. CONCLUSION: This study demonstrated that when measuring all volumes of (90)Y-ibritumomab tiuxetan activity prescriptions, only a single dial setting for a given manufacturer's dose calibrator is required for accurate measurements. Volume corrections are not necessary. For best accuracy, an individually determined dial value should be used.