This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

GUEST EDITORIAL PART I: ICRP STATEMENT ON TISSUE REACTIONS PART II: EARLY AND LATE EFFECTS OF RADIATION IN NORMAL TISSUES AND ORGANS - THRESHOLD DOSES FOR TISSUE REACTIONS IN A RADIATION PROTECTION CONTEXT ABSTRACT PREFACE EXECUTIVE SUMMARY GLOSSARY 1. INTRODUCTION 1.1. Purpose of report 1.2. Definition and nature of tissue reactions to ionising radiation 1.3. General principles of radiation effects in cells and tissues 1.4. References 2. RESPONSE OF TISSUES AND ORGANS TO RADIATION 2.1. Haematopoietic and immune systems 2.2. Digestive system 2.3. Reproductive system 2.4. Skin 2.5. Cardiovascular and cerebrovascular systems 2.6. Eye 2.7. Respiratory system 2.8. Urinary tract 2.9. Musculoskeletal system 2.10. Endocrine system 2.11. Nervous system 2.12. References 3. MODIFIERS OF NORMAL TISSUE RESPONSE 3.1. Terminology 3.2. Mechanisms of action 3.3. Influence of modifiers on radiation response in tissue 3.4. References 4. THRESHOLD DOSES IN RELATION TO RADIOSENSITIVITY OF ORGANS AND TISSUES 4.1. Introduction 4.2. Haematopoietic and immune systems 4.3. Digestive system 4.4. Reproductive system 4.5. Skin 4.6. Cardiovascular and cerebrovascular systems 4.7. Eye 4.8. Respiratory system 4.9. Urinary tract 4.10. Musculoskeletal system 4.11. Endocrine system 4.12. Nervous system 4.13. Conclusions 4.14. References ANNEX A. SUMMARY OF STUDIES OF EXPOSURE AND OPACITIES OR CATARACTS

ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs -- threshold doses for tissue reactions in a radiation protection context

Dose calculation methods for photon beams are reviewed in the context of radiation therapy treatment planning. Following introductory summaries on photon beam characteristics and clinical requirements on dose calculations, calculation methods are described in order of increasing explicitness of particle transport. The simplest are dose ratio factorizations limited to point dose estimates useful for checking other more general, but also more complex, approaches. Some methods incorporate detailed modelling of scatter dose through differentiation of measured data combined with various integration techniques. State-of-the-art methods based on point or pencil kernels, which are derived through Monte Carlo simulations, to characterize secondary particle transport are presented in some detail. Explicit particle transport methods, such as Monte Carlo, are briefly summarized. The extensive literature on beam characterization and handling of treatment head scatter is reviewed in the context of providing phase space data for kernel based and/or direct Monte Carlo dose calculations. Finally, a brief overview of inverse methods for optimization and dose reconstruction is provided.

https://iopscience.iop.org/article/10.1088/0031-9155/44/11/201/pdf

Dose calculations for external photon beams in radiotherapy

Toxicity of the respiratory system is a common side effect and complication of anticancer therapy that can result in significant morbidity. The range of respiratory compromise can extend from acute lethal events to degrees of chronic pulmonary decompensation, manifesting years after the initial cancer therapy. This review examines the anatomic-histologic background of the lung and the normal functional anatomic unit. The pathophysiology of radiation and chemotherapy induced lung injury is discussed as well as the associated clinical syndromes. Radiation tolerance doses and volumes are assessed in addition to chemotherapy tolerance and risk factors and radiation-chemotherapy interactions. There are a variety of measurable endpoints for detection and screening. Because of the wide range of available quantitative tests, it would seem that the measurement of impaired lung function is possible. The development of staging systems for acute and late toxicity is discussed and a new staging system for Late Effects in Normal Tissues (LENT) is proposed.

Injury to the lung from cancer therapy: Clinical syndromes, measurable endpoints, and potential scoring systems

Tissue Inhomogeneity Corrections for Megavoltage Photon Beams

Purpose : Three-dimensional single photon emission computed tomography lung perfusion scans (SPECT) provide a unique quantitative 3-dimensional map of the distribution of functioning pulmonary vascular/alveolar subunits, information not provided by other imaging modalities. This report describes our initial experience utilizing these scans to assist in the design of radiation treatment beams and to assess changes in regional lung function following irradiation. Methods and Materials : Patients were immobilized and scanned in the treatment position with appropriate fuducial markers. Four millicuries of technetium 99M microaggregated albumin were injected and SPECT images of the lung were generated. Pre-treatment SPECT images were used to help design radiation beams to minimize irradiation of functioning lung. Pre- and post-treatment scans were compared to assess changes in regional function. These changes in function were then correlated with the regional radiation dose. Results : Pre-radiotherapy SPECT scans were obtained in 18 patients (11 with lung cancer). Marked variations in regional function were frequently noted. In patients with primary lung tumors, these variations were not necessarily immediately adjacent to the tumor volume. In general, patients with poor pulmonary function pre-treatment, in whom one would like to spare as much normal lung as possible, had the most non-uniform distribution throughout the lung of functioning vascular/alveolar subunits. In these cases, pre-treatment scans were most useful in designing radiation portals to minimize irradiation of functioning lung. SPECT scans were also used to detect changes in regional lung function secondary to radiotherapy in four patients. With doses in excess of 40 Gy, reductions in regional function were noted 1–6 months following completion of radiotherapy. These reductions were not necessarily accompanied by reductions in conventional pulmonary function tests, which are assessments of whole lung function and may not reflect regional lung injury if the volume affected is small. Conclusions : SPECT lung scans provide an excellent means of assessing regional lung function, superior to that obtainable with planar images. The functional data provided by the SPECT images is useful in designing “optimal” radiation treatment beams and in assessing the effect of radiotherapy on regional lung functions. Efforts are continuing in our laboratory to develop a dose response curve for regional lung damage using the tools of SPECT scanning and 3-dimensional dose calculations.

The utility of SPECT lung perfusion scans in minimizing and assessing the physiologic consequences of thoracic irradiation

Results of the tests carried out on fifteen 65 × 50 × 4 mm (nine specimens with long leg connected and six with long leg out) and nine 55 × 55 × 4 mm eccentrically loaded cold-formed single angles are presented. The test specimens were connected at the ends to the test frame by bolts on one leg and were subjected to eccentric thrust (eccentricity about both principal axes). Three different slenderness ratios (80, 120, and 170) and three different end connections (one-, two-, and three-bolt) were used in the test program. Experimental failure loads are compared with the loads computed according to the general theory of torsional–flexural buckling, ASCE Manual No. 52, and the ECCS recommendations. The effect of the location of shear centre and the magnitude of warping constant on the ultimate strength of cold-formed single angles is discussed.

Ultimate strength of eccentrically loaded cold-formed angles

This paper presents a numerical model for the thermo-elasto-plastic behavior of an isotropic material The model is based on the assumption that the yielding of the material obeys von Mises distortion energy theory and the material exhibits isotropic strain hardening This unique model can be used both for isothermal and non-isothermal cases The original formulation for the non-isothermal three-dimensional case has been specialized for plane stress conditions and the equations for the computation of warping and thickness change are provided The finite element implementation of this model is also outlined

A numerical model for the thermo‐elasto‐plastic behaviour of a material

Purpose: To develop a clinical procedure to treat field within a field (concomitant boost) portals with a single compensated field Methods and Materials: An ordinary manual cerrobend block former was used to produce styrofoam molds from simulator film data A special gypsum compound was poured into the molds The compensator block is independently mounted to the treatment machine via a custom-made compensator holder Results: Measurements confirm that the inhomogeneous dose distribution has been reliably delivered via this technique The accuracy of placement of the high dose region is sufficient for clinical use Conclusion: The procedure enables the concomitant boost effect to be easily implemented in the clinic without increasing clinical setup time

Clinical use of a concomitant boost technique using a gypsum compensator.

Scatter dose may be calculated by summing the scatter contribution from individual volume elements. These contributions may be represented by differential scatter–air ratios (dSAR). Determination of dSAR from measured data is only approximately correct for second and higher orders of scatter and yields values often limited to one significant figure. Monte Carlo calculation, on the other hand, is time intensive, requires some knowledge of the beam’s x‐ray spectrum, and mastering the complexities of a program such as EGS4. Total scatter dose at a point may be determined by measuring depth dose or tissue–air ratios and partitioning the dose into its primary and scatter components. Scatter may be represented by scatter–air ratios, which can be characterized by the sum of first, second, and higher orders of scatter. The first scatter dose may be computed exactly by summing the first scatter contribution from individual elements, determined from the first principle. Separation of dSAR into primary attenuation and depth‐independent terms allows the latter to be precomputed once for a given energy and stored in tabular form. Second scatter may be treated in a similar manner. The higher orders of scatter are computed by subtracting the sum of calculated first and second scatter doses from the total scatter dose. Elements close to and approximately 1 cm above the point of calculation contribute most heavily to the first scatter dose. Compared to the first scatter dose, the second scatter dose contribution is lower, particularly for elements close to the point of calculation. First scatter dose constitutes most of the scatter dose for small field sizes and shallow depths. For larger field sizes and greater depths, second and higher orders of scatter dose become more significant. As beam energy increases, the first scatter dose comprises a greater fraction of total scatter dose.

Sujit K. Ray

Papers

The utility of SPECT lung perfusion scans in minimizing and assessing the physiologic consequences of thoracic irradiation

Ultimate strength of eccentrically loaded cold-formed angles

A numerical model for the thermo‐elasto‐plastic behaviour of a material

Clinical use of a concomitant boost technique using a gypsum compensator.

Determination of differential scatter-air ratios (dSAR) for three-dimensional scatter integration.