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The Department of Energy conduced ten large-scale neutron irradiation experiments at Argonne National Laboratory between 1972 and 1989. Using a new approach to utilize experimental controls to determine whether a cross comparison between experiments was appropriate, we amalgamated data on neutron exposures to discover that fractionation significantly improved overall survival. A more detailed investigation showed that fractionation only had a significant impact on the death hazard for animals that died from solid tumors, but did not significantly impact any other causes of death. Additionally, we compared the effects of sex, age first irradiated, and radiation fractionation on neutron irradiated mice versus cobalt 60 gamma irradiated mice and found that solid tumors were the most common cause of death in neutron irradiated mice, while lymphomas were the dominant cause of death in gamma irradiated mice. Most animals in this study were irradiated before 150 days of age but a subset of mice was first exposed to gamma or neutron irradiation over 500 days of age. Advanced age played a significant role in decreasing the death hazard for neutron irradiated mice, but not for gamma irradiated mice. Mice that were 500 days old before their first exposures to neutrons began dying later than both sham irradiated or gamma irradiated mice., Competing Interests: The authors declare no competing interests. The corresponding author of this paper, Gayle E. Woloschak, is a section editor for PLOS ONE. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The risk assessment quantities called lifetime attributable risk (LAR) and risk of exposure-induced cancer (REIC) are used to calculate the cumulative cancer incidence risks for astronauts, attributable to radiation exposure accumulated during long term lunar and Mars missions. These risk quantities are based on the most recently published epidemiological data on the Life Span Study (LSS) of Japanese A-bomb survivors, who were exposed to γ-rays and neutrons. In order to analyze the impact of a different neutron RBE on the risk quantities, a model for the neutron relative biological effectiveness (RBE) relative to gammas in the LSS is developed based on an older dataset with less follow-up time. Since both risk quantities are based on uncertain quantities, such as survival curves, and REIC includes deterministic radiation induced non-cancer mortality risks, modelled with data based on the general population, the risks for astronauts may not be optimally estimated. The suitability of these risk assessment measures for the use of cancer risk calculation for astronauts is discussed. The work presented here shows that the use of a higher neutron RBE than the value of 10, traditionally used in the LSS risk models, can reduce the risks up to almost 50%. Additionally, including an excess absolute risk (EAR) baseline scaling also increases the risks by between 0.4% and 8.1% for the space missions considered in this study. Using just an EAR model instead of an equally weighted EAR and excess relative risk (ERR) model can decrease the cumulative risks for the considered missions by between 0.4% and 4.1% if no EAR baseline scaling is applied. If EAR baseline scaling is included, the calculated risks with the EAR- and the mixed model, as well as the risks calculated with just the ERR model are almost identical and only small differences in the uncertainties are visible., (Copyright © 2020. Published by Elsevier B.V.)

Proton therapy has shown dosimetric advantages over conventional radiation therapy using photons. Although the integral dose for patients treated with proton therapy is low, concerns were raised about late effects like secondary cancer caused by dose depositions far away from the treated area. This is especially true for neutrons and therefore the stray dose contribution from neutrons in proton therapy is still being investigated. The higher biological effectiveness of neutrons compared to photons is the main cause of these concerns. The gold-standard in neutron dosimetry is measurements, but performing neutron measurements is challenging. Different approaches have been taken to overcome these difficulties, for instance with newly developed neutron detectors. Monte Carlo simulations is another common technique to assess the dose from secondary neutrons. Measurements and simulations are used to develop analytical models for fast neutron dose estimations. This article tries to summarize the developments in the different aspects of neutron dose in proton therapy since 2017. In general, low neutron doses have been reported, especially in active proton therapy. Although the published biological effectiveness of neutrons relative to photons regarding cancer induction is higher, it is unlikely that the neutron dose has a large impact on the second cancer risk of proton therapy patients.

Background/aim: Neutrons are used as a type of high linear energy transfer (LET) radiation and they have stronger carcinogenic effects compared to low LET radiation. We sought to clarify the features of mammary carcinomas for which the incidence increases when these were exposed to neutron radiation., Materials and Methods: We compared mammary carcinomas from female Sprague-Dawley rats irradiated at 7 weeks of age with 0.485 Gy neutron beams or 0.5-Gy γ rays, with carcinomas of non-irradiated rats. Tumors were classified into luminal and non-luminal subtypes based on immunohistochemistry, while their copy number aberrations were determined using microarrays., Results: Neutrons and γ rays significantly increased the incidence of luminal carcinomas. The carcinomas in the three groups contained multiple aberrations affecting 46 genes for which mutations have been reported in human breast cancer., Conclusion: Neutrons and γ rays increase the incidence of luminal mammary carcinoma in rats, probably via genetic aberrations similar to those found in human breast cancer patients., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Murine experiments were conducted at the JANUS reactor in Argonne National Laboratory from 1970 to 1992 to study the effect of acute and protracted radiation dose from gamma rays and fission neutron whole body exposure. The present study reports the reanalysis of the JANUS data on 36,718 mice, of which 16,973 mice were irradiated with neutrons, 13,638 were irradiated with gamma rays, and 6107 were controls. Mice were mostly Mus musculus, but one experiment used Peromyscus leucopus. For both types of radiation exposure, a Cox proportional hazards model was used, using age as timescale, and stratifying on sex and experiment. The optimal model was one with linear and quadratic terms in cumulative lagged dose, with adjustments to both linear and quadratic dose terms for low-dose rate irradiation (<5 mGy/h) and with adjustments to the dose for age at exposure and sex. After gamma ray exposure there is significant non-linearity (generally with upward curvature) for all tumours, lymphoreticular, respiratory, connective tissue and gastrointestinal tumours, also for all non-tumour, other non-tumour, non-malignant pulmonary and non-malignant renal diseases (p < 0.001). Associated with this the low-dose extrapolation factor, measuring the overestimation in low-dose risk resulting from linear extrapolation is significantly elevated for lymphoreticular tumours 1.16 (95% CI 1.06, 1.31), elevated also for a number of non-malignant endpoints, specifically all non-tumour diseases, 1.63 (95% CI 1.43, 2.00), non-malignant pulmonary disease, 1.70 (95% CI 1.17, 2.76) and other non-tumour diseases, 1.47 (95% CI 1.29, 1.82). However, for a rather larger group of malignant endpoints the low-dose extrapolation factor is significantly less than 1 (implying downward curvature), with central estimates generally ranging from 0.2 to 0.8, in particular for tumours of the respiratory system, vasculature, ovary, kidney/urinary bladder and testis. For neutron exposure most endpoints, malignant and non-malignant, show downward curvature in the dose response, and for most endpoints this is statistically significant (p < 0.05). Associated with this, the low-dose extrapolation factor associated with neutron exposure is generally statistically significantly less than 1 for most malignant and non-malignant endpoints, with central estimates mostly in the range 0.1-0.9. In contrast to the situation at higher dose rates, there are statistically non-significant decreases of risk per unit dose at gamma dose rates of less than or equal to 5 mGy/h for most malignant endpoints, and generally non-significant increases in risk per unit dose at gamma dose rates ≤5 mGy/h for most non-malignant endpoints. Associated with this, the dose-rate extrapolation factor, the ratio of high dose-rate to low dose-rate (≤5 mGy/h) gamma dose response slopes, for many tumour sites is in the range 1.2-2.3, albeit not statistically significantly elevated from 1, while for most non-malignant endpoints the gamma dose-rate extrapolation factor is less than 1, with most estimates in the range 0.2-0.8. After neutron exposure there are non-significant indications of lower risk per unit dose at dose rates ≤5 mGy/h compared to higher dose rates for most malignant endpoints, and for all tumours (p = 0.001), and respiratory tumours (p = 0.007) this reduction is conventionally statistically significant; for most non-malignant outcomes risks per unit dose non-significantly increase at lower dose rates. Associated with this, the neutron dose-rate extrapolation factor is less than 1 for most malignant and non-malignant endpoints, in many cases statistically significantly so, with central estimates mostly in the range 0.0-0.2.

Background: Out-of-field organs can be affected by secondary radiations originating from high energy linear accelerators, leading to an increased risk of carcinogenesis. The aim of this work was to determine the risk of second primary cancers (SPC) in the organs distal to the prostate during 3D conformal radiotherapy., Materials and Methods: Based on previously measured peripheral photon and neutron doses in a Rando phantom using an 18MV photon beam, SPC risks in the out-of-field organs were estimated using the linear-no-threshold and the competitive risk models. Whole body as well as organ specific risk coefficients were used to calculate the SPC risks in order to estimate upper and lower risk limits, given the uncertainties associated with the coefficients., Results: The corresponding estimated average SPC risks ranged from 1.5±0.3% for thyroid to 4.5±4.2% for colon using whole body risk coefficients and 0.12±0.03% and 1.45±1.34%, respectively, using organ specific risk coefficients. The linear-no-threshold and the competitive risk models resulted in the same risk estimates (within the estimated errors) in the dose range received by out-of-field organs (≤1Gy). Distally located organs such as lungs, oesophagus, and thyroid received higher neutron versus photon dose., Conclusions: The findings have important radiation protection implications when using high energy linear accelerators, as radiation protective measures could be employed to minimize the secondary out-of-field radiation for patients undergoing high energy external beam irradiation of the prostate., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

This is a real case study to minimize the neutron dose equivalent (H) to a fetus using spot scanning proton beams with favorable beam energies and angles. Minimum neutron dose exposure to the fetus was achieved with iterative planning under the guidance of neutron H measurement. Two highly conformal treatment plans, each with three spot scanning beams, were planned to treat a 25-year-old pregnant female with aggressive recurrent chordoma of the base of skull who elected not to proceed with termination. Each plan was scheduled for delivery every other day for robust target coverage. Neutron H to the fetus was measured using a REM500 neutron survey meter placed at the fetus position of a patient simulating phantom. 4.1 and 44.1 μSv/fraction were measured for the two initial plans. A vertex beam with higher energy and the fetal position closer to its central axis was the cause for the plan that produced an order higher neutron H. Replacing the vertex beam with a lateral beam reduced neutron H to be comparable with the other plan. For a prescription of 70 Gy in 35 fractions, the total neutron H to the fetus was estimated to be 0.35 mSv based on final measurement in single fraction. In comparison, the passive scattering proton plan and photon plan had an estimation of 26 and 70 mSv, respectively, for this case. While radiation therapy in pregnant patients should be avoided if at all possible, our work demonstrated spot scanning beam limited the total neutron H to the fetus an order lower than the suggested 5 mSv regulation threshold. It is far superior than passive scattering beam and careful beam selection with lower energy and keeping fetus further away from beam axis are essential in minimizing the fetus neutron exposure., (© 2016 The Authors.)

Purpose: Second primary malignancies (SPMs) are among the most serious late adverse effects after radiotherapy experienced over time by the increasing population of cancer survivors worldwide. The study aim was to determine the rate and distribution of SPMs for neutron- and photon-emitting brachytherapy (BT) sources for patients treated for cervical cancer., Methods and Materials: The cohort comprised 662 patients with invasive cervical cancer (Stages IIB and IIIB) and contributed 5,224 patient-years (PY) of observation. These patients were treated by radiotherapy during the 1989-1999 year period with cobalt-60 source ((60)Co) teletherapy. The first group of patients (N = 375; 3,154 PY) received high-dose-rate (HDR) californium-252 source ((252)Cf) BT, whereas the second group (N = 287; 2,070 PY) received HDR (60)Co BT., Results: Over a 25-year period, 35 SPMs were observed, amounting to 5.3% of all observed patients: in 16 (2.4%) heavily, 2 (0.3%) moderately, 14 (2.1%) lightly irradiated body sites, and 3 (0.5%) other sites. Of these, 21 cases (5.6%) were observed in the HDR (252)Cf BT group, whereas 14 cases (4.9%) were observed in the HDR (60)Co BT group. Exposures received during (60)Co teletherapy and HDR BT with either (252)Cf or (60)Co had statistically equivalent (p = 0.68) effects on SPM development., Conclusions: Cure rates are improving, and therefore, there are more long-term survivors from cervical cancer. This study shows no significant difference in rates or distribution of SPMs in women treated with neutron BT compared with photon BT (p = 0.68). After reviewing related literature and our research results, it is evident that a detailed investigation of SPM frequency, localization, and dose to adjacent organs is a suitable topic for further research., (Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the life span and risk of cancer following whole-body exposure of mice to neutrons generated by a passively scattered clinical spread-out Bragg peak (SOBP) proton beam., Methods and Materials: Three hundred young adult female FVB/N mice, 152 test and 148 control, were entered into the experiment. Mice were placed in an annular cassette around a cylindrical phantom, which was positioned lateral to the mid-SOBP of a 165-MeV, clinical proton beam. The average distance from the edge of the mid-SOBP to the conscious active mice was 21.5 cm. The phantom was irradiated with once-daily fractions of 25 Gy, 4 days per week, for 6 weeks. The age at death and cause of death (ie, cancer and type vs noncancer causes) were assessed over the life span of the mice., Results: Exposure of mice to a dose of 600 Gy of proton beam-generated neutrons, reduced the median life span of the mice by 4.2% (Kaplan-Meier cumulative survival, P=.053). The relative risk of death from cancer in neutron exposed versus control mice was 1.40 for cancer of all types (P=.0006) and 1.22 for solid cancers (P=.09). For a typical 60 Gy dose of clinical protons, the observed 22% increased risk of solid cancer would be expected to decrease by a factor of 10., Conclusions: Exposure of mice to neutrons generated by a proton dose that exceeds a typical course of radiation therapy by a factor of 10, resulted in a statistically significant increase in the background incidence of leukemia and a marginally significant increase in solid cancer. The results indicate that the risk of out-of-field second solid cancers from SOBP proton-generated neutrons and typical treatment schedules, is 6 to 10 times less than is suggested by current neutron risk estimates., (Copyright © 2014 Elsevier Inc. All rights reserved.)

It has generally been assumed that the neutron and γ-ray absorbed doses in the data from the life span study (LSS) of the Japanese A-bomb survivors are too highly correlated for an independent separation of the all solid cancer risks due to neutrons and due to γ-rays. However, with the release of the most recent data for all solid cancer incidence and the increased statistical power over previous datasets, it is instructive to consider alternatives to the usual approaches. Simple excess relative risk (ERR) models for radiation-induced solid cancer incidence fitted to the LSS epidemiological data have been applied with neutron and γ-ray absorbed doses as separate explanatory covariables. A simple evaluation of the degree of independent effects from γ-ray and neutron absorbed doses on the all solid cancer risk with the hierarchical partitioning (HP) technique is presented here. The degree of multi-collinearity between the γ-ray and neutron absorbed doses has also been considered. The results show that, whereas the partial correlation between the neutron and γ-ray colon absorbed doses may be considered to be high at 0.74, this value is just below the level beyond which remedial action, such as adding the doses together, is usually recommended. The resulting variance inflation factor is 2.2. Applying HP indicates that just under half of the drop in deviance resulting from adding the γ-ray and neutron absorbed doses to the baseline risk model comes from the joint effects of the neutrons and γ-rays-leaving a substantial proportion of this deviance drop accounted for by individual effects of the neutrons and γ-rays. The average ERR/Gy γ-ray absorbed dose and the ERR/Gy neutron absorbed dose that have been obtained here directly for the first time, agree well with previous indirect estimates. The average relative biological effectiveness (RBE) of neutrons relative to γ-rays, calculated directly from fit parameters to the all solid cancer ERR model with both colon absorbed dose covariables, is 65 (95 %CI: 11; 170). Therefore, although the 95 % CI is quite wide, reference to the colon doses with a neutron weighting of 10 may not be optimal as the basis for the determination of all solid cancer risks. Further investigations into the neutron RBE are required, ideally based on the LSS data with organ-specific neutron and γ-ray absorbed doses for all organs rather than the RBE weighted absorbed doses currently provided. The HP method is also suggested for use in other epidemiological cohort analyses that involve correlated explanatory covariables.

The Janus series of radiation experiments, conducted from 1970 to 1992, explored the effects of gamma and neutron radiation on animal lifespan and disease development. Data from these experiments presents an opportunity to conduct a large scale analysis of both tumor and non-tumor disease development. This work was focused on a subset of animals from the Janus series of experiments, comparing acute or fractionated exposures of gamma or neutron radiation on the hazards associated with the development of tumor and non-tumor diseases of the liver, lung, kidney or vascular system. This study also examines how the co-occurrence of non-tumor diseases may affect tumor-associated hazards. While exposure to radiation increases the hazard of dying with tumor and non-tumor diseases, dose fractionation modulates these hazards, which varies across different organ systems. Finally, the effect that concurrent non-cancer diseases have on the hazard of dying with a tumor also differs by organ system. These results highlight the complexity in the effects of radiation on the liver, lung, kidney and vascular system.

Secondary neutron fluence created during proton therapy can be a significant source of radiation exposure in organs distant from the treatment site, especially in pediatric patients. Various published studies have used computational phantoms to estimate neutron equivalent doses in proton therapy. In these simulations, whole-body patient representations were applied considering either generic whole-body phantoms or generic age- and gender-dependent phantoms. No studies to date have reported using patient-specific geometry information. The purpose of this study was to estimate the effects of patient–phantom matching when using computational pediatric phantoms. To achieve this goal, three sets of phantoms, including different ages and genders, were compared to the patients' whole-body CT. These sets consisted of pediatric age specific reference, age-adjusted reference and anatomically sculpted phantoms. The neutron equivalent dose for a subset of out-of-field organs was calculated using the GEANT4 Monte Carlo toolkit, where proton fields were used to irradiate the cranium and the spine of all phantoms and the CT-segmented patient models. The maximum neutron equivalent dose per treatment absorbed dose was calculated and found to be on the order of 0 to 5 mSv Gy(-1). The relative dose difference between each phantom and their respective CT-segmented patient model for most organs showed a dependence on how close the phantom and patient heights were matched. The weight matching was found to have much smaller impact on the dose accuracy except for very heavy patients. Analysis of relative dose difference with respect to height difference suggested that phantom sculpting has a positive effect in terms of dose accuracy as long as the patient is close to the 50th percentile height and weight. Otherwise, the benefit of sculpting was masked by inherent uncertainties, i.e. variations in organ shapes, sizes and locations.Other sources of uncertainty included errors associated with beam positioning, neutron weighting factor definition and organ segmentation. This work demonstrated the importance of hybrid phantom height matching for more accurate organ dose calculation in proton therapy and the potential limitations of reference phantoms released by regulatory bodies for radiation therapy applications.

Determination and understanding of out-of-field neutron and photon doses in accelerator-based radiotherapy is an important issue since linear accelerators operating at high energies (>10 MV) produce secondary radiations that irradiate parts of the patient's anatomy distal to the target region, potentially resulting in detrimental health effects. This paper provides a compilation of data (technical and clinical) reported in the literature on the measurement and Monte Carlo simulations of peripheral neutron and photon doses produced from high-energy medical linear accelerators and the reported risk and/or incidence of second primary cancer of tissues distal to the target volume. Information in the tables facilitates easier identification of (1) the various methods and measurement techniques used to determine the out-of-field neutron and photon radiations, (2) reported linac-dependent out-of-field doses, and (3) the risk/incidence of second cancers after radiotherapy due to classic and modern treatment methods. Regardless of the measurement technique and type of accelerator, the neutron dose equivalent per unit photon dose ranges from as low as 0.1 mSv/Gy to as high as 20.4 mSv/Gy. This radiation dose potentially contributes to the induction of second primary cancer in normal tissues outside the treated area.

From studies of the atomic bomb survivors, it is well known that ionizing radiation causes several forms of leukemia. However, since the specific mechanism behind this process remains largely unknown, it is difficult to extrapolate carcinogenic effects at acute high-dose exposures to risk estimates for the chronic low-dose exposures that are important for radiation protection purposes. Recently, it has become clear that the induction of acute myeloid leukemia (AML) in CBA/H mice takes place through two key steps, both involving the Sfpi1 gene. A similar mechanism may play a role in human radiation-induced AML. In the present paper, a two-mutation carcinogenesis model is applied to model AML in several data sets of X-ray- and neutron-exposed CBA/H mice. The models obtained provide good fits to the data. A comparison between the predictions for neutron-induced and X-ray-induced AML yields an RBE for neutrons of approximately 3. The model used is considered to be a first step toward a model for human radiation-induced AML, which could be used to estimate risks of exposure to low doses., (© Springer-Verlag 2010)

Theoretical calculations have shown that proton therapy can reduce the incidence of radiation-induced secondary malignant neoplasms (SMN) compared with photon therapy for patients with prostate cancer. However, the uncertainties associated with calculations of SMN risk had not been assessed. The objective of this study was to quantify the uncertainties in projected risks of secondary cancer following contemporary proton and photon radiotherapies for prostate cancer. We performed a rigorous propagation of errors and several sensitivity tests to estimate the uncertainty in the ratio of relative risk (RRR) due to the largest contributors to the uncertainty: the radiation weighting factor for neutrons, the dose-response model for radiation carcinogenesis and interpatient variations in absorbed dose. The interval of values for the radiation weighting factor for neutrons and the dose-response model were derived from the literature, while interpatient variations in absorbed dose were taken from actual patient data. The influence of each parameter on a baseline RRR value was quantified. Our analysis revealed that the calculated RRR was insensitive to the largest contributors to the uncertainty. Uncertainties in the radiation weighting factor for neutrons, the shape of the dose-risk model and interpatient variations in therapeutic and stray doses introduced a total uncertainty of 33% to the baseline RRR calculation.

The purpose of this study was to compare the predicted risks of second malignant neoplasm (SMN) incidence and mortality from secondary neutrons for a 9-year-old girl and a 10-year-old boy who received proton craniospinal irradiation (CSI). SMN incidence and mortality from neutrons were predicted from equivalent doses to radiosensitive organs for cranial, spinal and intracranial boost fields. Therapeutic proton absorbed dose and equivalent dose from neutrons were calculated using Monte Carlo simulations. Risks of SMN incidence and mortality in most organs and tissues were predicted by applying risks models from the National Research Council of the National Academies to the equivalent dose from neutrons; for non-melanoma skin cancer, risk models from the International Commission on Radiological Protection were applied. The lifetime absolute risks of SMN incidence due to neutrons were 14.8% and 8.5%, for the girl and boy, respectively. The risks of a fatal SMN were 5.3% and 3.4% for the girl and boy, respectively. The girl had a greater risk for any SMN except colon and liver cancers, indicating that the girl's higher risks were not attributable solely to greater susceptibility to breast cancer. Lung cancer predominated the risk of SMN mortality for both patients. This study suggests that the risks of SMN incidence and mortality from neutrons may be greater for girls than for boys treated with proton CSI.

Purpose: To investigate microsatellite instability (MSI) in radiation-induced murine tumours, its dependence on tissue (haemopoietic, intestinal, mammary, brain and skin) and radiation type., Materials and Methods: DNA from spontaneous, X-ray or neutron-induced mouse tumours were used in Polymerase Chain Reactions (PCR) with mono- or di-nucleotide repeat markers. Deviations from expected allele size caused by insertion/deletion events were assessed by capillary electrophoresis., Results: Tumours showing MSI increased from 16% in spontaneously arising tumours to 23% (P = 0.014) in X-ray-induced tumours and rising again to 83% (P << 0.001) in neutron-induced tumours. X-ray-induced Acute Myeloid Leukaemias (AML) had a higher level of mono-nucleotide instability (45%) than di-nucleotide instability (37%). Fifty percent of neutron-induced tumours were classified as MSI-high for mono-nucleotide markers and 10% for di-nucleotide markers. Distribution of MSI varied in the different tumour types and did not appear random., Conclusions: Exposure to ionising radiation, especially neutrons, promotes the development of MSI in mouse tumours. MSI may therefore play a role in mouse radiation tumourigenesis, particularly following high Linear Energy Transfer (LET) exposures. MSI events, for a comparable panel of genome-wide markers in different tissue types, were not randomly distributed throughout the genome.

Experiments were conducted to assay whether monoenergetic neutron-induced genetic damage in parental germline cells can give rise to development of cancer in the offspring. Seven-week-old C3H male mice were irradiated with monoenergetic neutrons with energy levels of 0.2 or 0.6 MeV at doses of 0, 50, 100 or 200 cGy. Two weeks after irradiation, when the male mice showed an increased incidence of sperm abnormalities, they were mated with virgin 9-week-old C57BL females. Litter size was decreased and embryo lethalities were increased in a dose-dependent manner. Furthermore, tumor incidence in male offspring born to male mice irradiated with 25 or 50 cGy at 0.6 MeV showed a tendency for increase as compared to the non-irradiated group value. Liver tumors in the 50 cGy group were significantly increased (P=0.03). It is concluded that the increased hepatic tumor risk in the F1 generation may have been caused by genetic transmission of some hepatoma-associated trait(s) induced by monoenergetic neutron irradiation.

The purpose of this work was to compare the risk of developing a second cancer after craniospinal irradiation using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Craniospinal irradiation of a male phantom was calculated for passively-scattered and scanned-beam proton treatment units. Organ doses were estimated from treatment plans; for the proton treatments, the amount of stray radiation was calculated separately using the Monte Carlo method. The organ doses were converted to risk of cancer incidence using a standard formalism developed for radiation protection purposes. The total lifetime risk of second cancer due exclusively to stray radiation was 1.5% for the passively scattered treatment versus 0.8% for the scanned proton beam treatment. Taking into account the therapeutic and stray radiation fields, the risk of second cancer from intensity-modulated radiation therapy and conventional radiotherapy photon treatments were 7 and 12 times higher than the risk associated with scanned-beam proton therapy, respectively, and 6 and 11 times higher than with passively scattered proton therapy, respectively. Simulations revealed that both passively scattered and scanned-beam proton therapies confer significantly lower risks of second cancers than 6 MV conventional and intensity-modulated photon therapies.

Proton beam radiotherapy unavoidably exposes healthy tissue to stray radiation emanating from the treatment unit and secondary radiation produced within the patient. These exposures provide no known benefit and may increase a patient's risk of developing a radiogenic cancer. The aims of this study were to calculate doses to major organs and tissues and to estimate second cancer risk from stray radiation following craniospinal irradiation (CSI) with proton therapy. This was accomplished using detailed Monte Carlo simulations of a passive-scattering proton treatment unit and a voxelized phantom to represent the patient. Equivalent doses, effective dose and corresponding risk for developing a fatal second cancer were calculated for a 10-year-old boy who received proton therapy. The proton treatment comprised CSI at 30.6 Gy plus a boost of 23.4 Gy to the clinical target volume. The predicted effective dose from stray radiation was 418 mSv, of which 344 mSv was from neutrons originating outside the patient; the remaining 74 mSv was caused by neutrons originating within the patient. This effective dose corresponds to an attributable lifetime risk of a fatal second cancer of 3.4%. The equivalent doses that predominated the effective dose from stray radiation were in the lungs, stomach and colon. These results establish a baseline estimate of the stray radiation dose and corresponding risk for a pediatric patient undergoing proton CSI and support the suitability of passively-scattered proton beams for the treatment of central nervous system tumors in pediatric patients.

Purpose: To estimate the risk of a second malignancy after treatment of a primary brain cancer using passive scattered proton beam therapy. The focus was on the cancer risk caused by neutrons outside the treatment volume and the dependency on the patient's age., Methods and Materials: Organ-specific neutron-equivalent doses previously calculated for eight different proton therapy brain fields were considered. Organ-specific models were applied to assess the risk of developing solid cancers and leukemia., Results: The main contributors (>80%) to the neutron-induced risk are neutrons generated in the treatment head. Treatment volume can influence the risk by up to a factor of approximately 2. Young patients are subject to significantly greater risks than are adult patients because of the geometric differences and age dependency of the risk models. Breast cancer should be the main concern for females. For males, the risks of lung cancer, leukemia, and thyroid cancer were significant for pediatric patients. In contrast, leukemia was the leading risk for an adult. Most lifetime risks were <1% (70-Gy treatment). The only exceptions were breast, thyroid, and lung cancer for females. For female thyroid cancer, the treatment risk can exceed the baseline risk., Conclusion: The risk of developing a second malignancy from neutrons from proton beam therapy of a brain lesion is small (i.e., presumably outweighed by the therapeutic benefit) but not negligible (i.e., potentially greater than the baseline risk). The patient's age at treatment plays a major role.

Hospital-based proton facilities may represent a major advance in radiation therapy, in part because of excellent dose distributions around the tumor, and in part because of the potentially lower whole-body dose compared with photon radiotherapy. Most current proton beams are spread out to cover the tumor using beam scattering and collimation techniques (passive scattering); this will necessarily result in an extra whole-body neutron dose, due to interactions of the protons with the scattering and collimating beam elements. However, the clinical significance of this whole-body low-dose neutron exposure has remained controversial. The number of proton facilities worldwide is increasing rapidly, and most of these facilities are/will be based on passive scattering. Thus it is important to assess and, ideally, minimize, the potential for second cancer induction by secondary neutrons. We discuss here the neutron doses involved, and the associated potential second cancer risks, with an emphasis on the uncertainties involved.

Dose to the total body from induced radiation resulting from primary exposure to radiotherapeutic beams is not detailed in routine treatment planning though this information is potentially important for better estimates of health risks including secondary cancers. This information can also allow better management of patient treatment logistics, suggesting better timing, sequencing, and conduct of treatment. Monte Carlo simulations capable of taking into account all interactions contributing to the dose to the total body, including neutron scattering and induced radioactivity, provide the most versatile and accurate tool for investigating these effects. MCNPX code version 2.2.6 with full IAEA library of photoneutron cross sections is particularly suited to trace not only photoneutrons but also protons and heavy ion particles that result from photoneutron interactions. Specifically, the MCNPX code is applied here to the problem of dose calculations in traditional (non-IMRT) photon beam therapy. Points of calculation are located in the head, where the primary irradiation has been directed, but also in the superior portion of the torso of the ORNL Mathematical Human Phantom. We calculated dose contributions from neutrons, protons, deutrons, tritons and He-3 that are produced at the time of photoneutron interactions in the body and that would not have been accounted for by conventional radiation oncology dosimetry.

Cancer mortality risk coefficients for neutrons have recently been assessed by a procedure that postulates for the neutrons a linear dose dependence, invokes the excess risk of the A-bomb survivors at a gamma-ray dose D(1) of 1 Gy, and assumes a neutron RBE as a function of D(1) between 20 and 50. The excess relative risk (ERR) of 0.008/mGy has been obtained for R(1) = 20 and 0.016/mGy for R(1) = 50. To compare these results to the current ICRP nominal risk coefficient for solid cancer mortality (0.045/Sv for a population of all ages; 0.036/Sv for a working population), the ERR is translated into lifetime attributable risk and is then related to effective dose. The conversion is not trivial, because the neutron effective dose has been defined by ICRP not as a weighted genuine neutron dose (neutron kerma), but as a weighted dose that includes the dose from gamma rays that are induced by neutrons in the body. If this is accounted for, the solid cancer mortality risk for a working population is found to agree with the ICRP nominal risk coefficient for neutrons in their most effective energy range, 0.2 MeV to 0.5 MeV. In radiation protection practice, there is an added level of safety, because the effective dose, E, is-for monitoring purposes-assessed in terms of the operational quantity H*, which overestimates E substantially for neutrons between 0.01 MeV and 2 MeV.

A previous investigation has uncoupled the solid cancer risk coefficient for neutrons from the low dose estimates of the relative biological effectiveness (RBE) of neutrons and the photon risk coefficient, and has related it to two more tangible quantities, the excess relative risk (ERR1) due to an intermediate reference dose D1 = 1 Gy of gamma-rays and the RBE of neutrons, R1, against this reference dose. With tentatively assumed RBE values between 20 and 50 and in terms of organ-averaged doses--rather than the usually invoked colon doses--the neutron risk factor was seen to be in general agreement with the current risk estimate of the International Commission on Radiation Protection (ICRP). The present assessment of the risk coefficient for gamma-rays incorporates--in terms of the unchanged A-bomb dosimetry system, DS86--this treatment of the neutrons, but is otherwise largely analogous to the evaluation of the A-bomb data for the ICRP report and for the recent report of the United Nations Scientific Committee on the effects of ionizing radiation, UNSCEAR. The resulting central estimate of the lifetime attributable risk (LAR) for solid cancer mortality is 0.043/Gy for a working population (ages 25-65), and is nearly the same whether the age at exposure or the attained age model is used for risk projection. For a population of all ages 0.042/Gy is obtained with the attained age model and 0.068/Gy with the age at exposure model. The values do not include a dose and dose rate effectiveness factor (DDREF), and they are only half as large as the new UNSCEAR estimates of 0.082/Gy (attained age model and all ages) and 0.13/Gy (age at exposure model and all ages). The difference is only partly due to the more explicit treatment of the neutrons. It reflects also the fact that UNSCEAR has converted ERR into LAR in a way that differs from the ICRP procedure, and that it has summed the overall risk coefficient for solid tumor mortality and incidence from separate estimates for eight solid tumor categories, whereas the present study employs a combined computation for all solid tumors and uses the ICRP procedure for the conversion of ERR into LAR. The appendix gives results for the solid cancer incidence data.

The effectiveness of fission neutrons is compared to that of gamma rays and X rays with regard to the induction of malignancies in male Sprague-Dawley rats. The analysis is based on autopsy results. It is focused on tumors that tend to be present in animals dying early, which is indicative of a high degree of lethality. The relative biological effectiveness (RBE) is deduced from a comparison of the cumulative hazard functions. Different nonparametric models-the constant relative risk model, a time shift model, and an acceleration model-are employed in the comparison, and the resulting values of RBE are seen to be substantially independent of the choice of model. The results are in good agreement with earlier studies of nonlethal lung tumors in the same series of experiments. At neutron doses of 20 to 60 mGy, the RBE of fission neutrons is about 50.

Following the hormonal treatment of rats with high prolactin levels and glucocorticoid deficiency (Prl+/Glc-) for 48 days (Day +48), total recoverable mammary DNA was increased by more than sevenfold, tritiated thymidine uptake by nearly fourfold, and total mammary clonogens by about fivefold. Irradiation with 4, 40, and 80 cGy X-rays on Day +48 increased total mammary carcinomas per rat-day-at-risk linearly with dose, and 40 and 80 cGy significantly decreased first carcinoma latency. A dose of 40 cGy X-rays before hormone treatment (Day -1) yielded tumor latencies and frequencies insignificantly different from unirradiated controls but significantly different from those when the dose was given on Day +48. Total carcinomas per rat-day-at-risk were fitted better by a function of dose to the power 0.4 than by a linear function after exposure to 1, 10. and 20 cGy fission neutrons, and 10 and 20 cGy significantly shortened the time to appearance of the first cancer. In contrast to results with X-rays, 10 cGy neutrons on Day -1 yielded tumor frequencies and latencies insignificantly different from 10 cGy neutrons on Day +48. The carcinogenic action of X-rays, but not of neutrons, was thus influenced by total clonogen numbers and/or proliferation rates.

The risk of induction of a second primary cancer after a therapeutic irradiation with conventional photon beams is well recognized and documented. However, in general, it is totally overwhelmed by the benefit of the treatment. The same is true to a large extent for the combinations of radiation and drug therapy. After fast neutron therapy, the risk of induction of a second cancer is greater than after photon therapy. Neutron RBE increases with decreasing dose and there is a wide evidence that neutron RBE is greater for cancer induction (and for other late effects relevant in radiation protection) than for cell killing. Animal data on RBE for tumor induction are reviewed, as well as other biological effects such as life shortening, malignant cell transformation in vitro, chromosome aberrations, genetic effects. These effects can be related, directly or indirectly, to cancer induction to the extent that they express a "genomic" lesion. Almost no reliable human epidemiological data are available so far. For fission neutrons a RBE for cancer induction of about 20 relative to photons seems to be a reasonable assumption. For fast neutrons, due to the difference in energy spectrum, a RBE of 10 can be assumed. After proton beam therapy (low-LET radiation), the risk of secondary cancer induction, relative to photons, can be divided by a factor of 3, due to the reduction of integral dose (as an average). The RBE of heavy-ions for cancer induction can be assumed to be similar to fission neutrons, i.e. about 20 relative to photons. However, after heavy-ion beam therapy, the risk should be divided by 3, as after proton therapy due to the excellent physical selectivity of the irradiation. Therefore a risk 5 to 10 times higher than photons could be assumed. This range is probably a pessimistic estimate for carbon ions since most of the normal tissues, at the level of the initial plateau, are irradiated with low-LET radiation.

The risk of secondary cancer induction after a therapeutic irradiation with conventional photon beams is well recognised and documented. However, in general, it is totally overwhelmed by the benefit of the treatment. The same is true to a large extent for the combinations of radiation and drug therapy. After fast neutron therapy, the risk of secondary cancer induction is greater than after photon therapy. This can be expected from the whole set of radiobiological data, accumulated so far, which shows systematically a greater relative biological effectiveness (RBE) for neutrons for all the biological systems which have been investigated. Furthermore, the neutron RBE increases with decreasing dose and there is extensive evidence that neutron RBE is greater for cancer induction and for other late effects relevant in radiation protection than for cell killing at high doses as used in therapy. Almost no reliable human epidemiological data are available so far, and the aim of this work is to derive the best risks estimate for cancer induction after neutron irradiation and in particular fast neutron therapy. Animal data on RBE for tumour induction are analysed. In addition, other biological effects are reviewed, such as life shortening, malignant cell transformation in vitro, chromosome aberrations, genetic effects. These effects can be related, directly or indirectly, to cancer induction to the extent that they express a "genomic" lesion. Since neutron RBE depends on the energy spectrum, the radiation quality has to be carefully specified. Therefore, the microdosimetric spectra are reported each time they are available. Lastly, since heavy-ion beam therapy is being developed at several centres worldwide, the available data on RBE at low doses are reviewed. It can be concluded from this review that the risk of induction of a secondary cancer after fast neutron therapy should not be greater than 10-20 times the risk after photon beam therapy. For heavy ions, and in particular for carbon ions, the risk estimate should be divided by a factor of about 3 due to the reduced integral dose. The risk has to be balanced against the expected improvement in cure rate when the indication for high-LET therapy has been correctly evaluated in well-selected patient groups.

While it is recognized that neutrons contributed to the excess cancer incidence and mortality among the atomic bomb survivors in Hiroshima, there is no possibility to deduce the magnitude of this contribution from the data. This remains true even if the neutron doses in the dosimetry system DS86 are corrected upwards in line with recent neutron activation measurements. In spite of this fact, important information can be obtained in the form of an inverse relation of the risk coefficients for gamma-rays and neutrons. Such an interrelation must apply because the observed excess incidence or mortality is made up of a gamma-ray and a neutron component; increased attribution to neutrons decreases the attribution to photons. Computations with the uncorrected and the corrected DS86 are performed for the mortality and the incidence of solid tumors combined. They refer to doses up to 2 Gy and employ the constant relative risk model and a linear-quadratic dose dependence with variable ratio-the neutron relative biological effectiveness (RBE) at low doses-of the linear component for neutrons and gamma-rays. In line with past analyses, no quadratic component is obtained with the uncorrected DS86. but it is seen, even in these calculations, that the assumption of increased neutron RBEs does not translate into proportional increases of the risk coefficients of neutrons, because it leads to substantially reduced risk estimates for gamma-rays. Calculations with the corrected dosimetry bring out this reciprocity even more clearly. High values of the neutron RBE reduce-in line with recent suggestions by Rossi and Zaider-the risk estimates for gamma-rays substantially. Even a purely quadratic dose relation for gamma-rays is consistent with the data; it requires no major increase of the nominal risk coefficients for neutrons over the currently assumed values. The cancer data from Hiroshima can still provide 'prudent' risk estimates for photons, but with the corrected DS86, they do not prove that there is a linear component in the dose dependence for photons.

To establish an in vivo radiation carcinogenesis model using glutathione S-transferase placental form positive (GST-P+) hepatic foci, newborn rats were irradiated once by 0.5 Gy and 2 Gy of gamma ray or 0.15 Gy and 0.6 Gy of neutron with or without 0.05% phenobarbital (PB). When the rats were sacrificed at the 12th or 21st week, the incidence of GST-P+ foci induction by radiation alone was very low. The neutron was more sensitive than the gamma ray at week 12 and the reverse phenomenon was observed in the groups at week 21. PB combination showed an increased incidence of GST-P+ foci in gamma ray irradiated groups. The neutron irradiation combined with PB did not show any significant difference compared with the corresponding PB untreated groups. We also investigated the combined effect of diethylnitrosamine (DEN) and 0.75 Gy of gamma ray irradiation. Intraperitoneal injection of 0.15 mumol/g body weight of DEN at 1 hour after gamma ray irradiation showed significantly increased the number and area of GST-P+ foci compared with those of DEN alone or DEN at 1 hour before gamma radiation (P < 0.001). From these data, after more defined experiments, an in vivo radiation carcinogenesis model will be established by radiation alone or a combination of radiation and carcinogens.

There is now a substantial body of evidence for end points such as oncogenic transformation in vitro, and carcinogenesis and life shortening in vivo, suggesting that dose protraction leads to an increase in effectiveness relative to a single, acute exposure--at least for radiations of medium linear energy transfer (LET) such as neutrons. Table I contains a summary of the pertinent data from studies in which the effect is seen. [table: see text] This phenomenon has come to be known as the "inverse dose rate effect," because it is in marked contrast to the situation at low LET, where protraction in delivery of a dose of radiation, either by fractionation or low dose rate, results in a decreased biological effect; additionally, at medium and high LET, for radiobiological end points such as clonogenic survival, the biological effectiveness is independent of protraction. The quantity and quality of the published reports on the "inverse dose rate effect" leaves little doubt that the effect is real, but the available evidence indicates that the magnitude of the effect is due to a complex interplay between dose, dose rate, and radiation quality. Here, we first summarize the available data on the inverse dose rate effect and suggest that it follows a consistent pattern in regard to dose, dose rate, and radiation quality; second, we describe a model that predicts these features; and, finally, we describe the significance of the effect for radiation protection.

This study was designed to examine the dose-response relationships for tumor induction after neutron irradiation in female BALB/c mice, with emphasis on the response in the dose range 0 to 50 rad. Tumors induced after radiation exposure included ovarian tumors, lung adenocarcinomas, and mammary adenocarcinomas. For comparison the dose responses for induction of these tumors after 137Cs gamma irradiation were also examined. As previously described for the female RFM mouse, the data for ovarian tumor induction after neutron and gamma irradiation were consistent with a threshold model. For lung and mammary tumors the dose-response curve after neutron irradiation appeared to "bend over" in the dose range 10 to 20 rad. The factors responsible for this bend-over and their relative contributions to the overall form of the dose-response relationship are not presently known. However, these data strongly indicate that extrapolation from data above 50 rad could result in a significant underestimate of risks. Further, it is clear that current models of neutron carcinogenesis are inadequate, since such a bend-over is not predicted at these low dose levels.

166 Sprague-Dawley Rats (148 males and 118 females) submitted to different hormonal conditions were exposed to 3 repeated whole-body irradiations of 14.8 MeV neutrons or sham-irradiated between 50 and 65 days of age (total absorbed doses: 3 x 2 rad and 3 x 8 rad). They were observed for 11 months. In the male group, a small number of tumors was obtained. In the female group, 75 breast neoplasms were scored in 41 of 78 irradiated animals (54 fibroadenomas, 20 adenocarcinomas and 1 fibrosarcoma). A second group of benign and malignant tumors was observed from 200 days on. The neoplastic response to fast neutron fractionated irradiations was increased by pregnancy with subsequent lactation. Estradiol and progesterone receptors were measured in 34 tumor samples. Fibroadenomas (1;5) and adenocarcinomas (1;3) bound labelled steroids. Like in human breast cancer metastases, steroid receptors are found in recurrences only if present in the primary tumor.

Male BALB/c mice, 12 weeks old, were given a single exposure of either 137Cs gamma rays or d(50)-Be neutrons at a dose rate of 3 Gy/min. The animals were kept until death, and causes of death or possible causes of death were ascertained by autopsy and histology. The data were evaluated by competing risk methods. The survival time dose-effect curve for both types of exposure was linear and did not differ significantly (slopes: 55.8 +/- 4.0 days/Gy for neutrons and 46.2 +/- 4.3 days/Gy for gamma rays). The incidence of different diseases also was similar for both groups except that more carcinomas, sarcomas, and myeloid leukemias seemed to occur after neutron exposure and that nonstochastic lung and kidney diseases seemed to arise at lower doses.