Biological Effects and Exposure Limits for ''Hot Particles'': Recommendations of the National Council on Radiation Protection and Measurements (Ncrp Report, No. 130)

NCRP REPORT No. 130

BIOLOGICAL EFFECTS A N D EXPOSURE LIMITS FOR "HOT PARTICLES"

Recommendations of tlie NATIONAL COUNCIL O N RADIATION PROTECTION AND MEASUREMENTS

Issued December 10, 1999

National Council on Radiation Protection and Measurements 7910 Woodmont Avenue I Bethesda, M D 20814-3095

LEGAL NOTICE This Report was prepared by the National Council on Radiation Protection and Measurements (NCRP). The Council strives to provide accurate, complete and useful information in its documents. However, neither the NCRP, the members of NCRP, other persons contributing to or assisting in the preparation of this Report, nor any person acting on the behalf of any of these parties: (a) makes any warranty or representation, express or implied, with respect to the accuracy, completeness or usefulness of the information contained in this Report, or that the use of any information, method or process disclosed in this Report may not infringe on privately owned rights; or (b) assumes any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this Report, under the Civil Rights Act of 1964, Section 701 et seq. as amended 42 U.S.C. Section 2000e et seq. (Title VII) or any other statutory or common law theory governing liability.

Library of Congress Cataloging-in-Publication Data National Council on Radiation Protection and Measurements. Biological effects and exposure limits for "hot particlesn/National Council on Radiation Protection and Measurements. (NCRP report ; no. 130) p.;cm. "Supercedes NCRP report no. 106, Limit for exposure to 'sot particles" on skin, published in 1989"-Ref. "SC September 1999." Includes bibliographic& references and index. ISBN 0-929600-63-0 1. Ionizing radiation -Safety measures. 2. Ionizing radiation -Dosage-Standards. 3. [DNLM: 1. Maximum Permissible Exposure Level. 2. Radiation Effects. 3. Radioisotopes. WN 620 N2745b 19991 RA569.N353 1999 99-050234 612'.01448-dc21

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Copyright O National Council on Radiation Protection and Measurements 1999 All rights reserved. This publication is protected by copyright. No part of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyrightowner, except for brief quotation in critical articles or reviews.

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For detailed information on the availability of NCRP documents see page 245.

Preface This Report addresses in considerable detail the consequences of hot particles on and near the skin, in the eye, ear, respiratory system, and gastrointestinal tract. Limits for exposures from hot particles are recommended. If exposures are maintained below the recommended limits, few, if any, deterministic biological effects are expected to be observed, and those effects would be transient in nature. If effects from a hot-particle exposure are observed, the result is an easily treated medical condition involvingan extraordinarily small stochastic risk. Such occurrences would be indicative of the need for improvement in radiation protection practices, but should not be compared in seriousness to exceeding whole-body exposure limits. This Report supercedes NCRP Report No. 106,Limit for Exposure to "Hot Particles" on the Skin, published in 1989. This Report was prepared a t the request of and with the support of the U.S. Nuclear Regulatory Commission. I t was drafted by Scientific Committee 86 on Limits for Exposure to "Hot Particles." Serving on the Committee were: Thomas F. Gesell, Chairman Idaho State University Pocatello, Idaho

Members J o h n W. Baum Baum & Associates, Inc. Patchogue, New York

Bobby Scott

J o h n W. Hopewell University of Oxford Headington, Oxford, United Kingdom

Stephen M. Seltzer National Institute of Standards and Technology Gaithersburg, Maryland

Michael W. Lantz Arizona Public Service Company Phoenix, Arizona

Roy E.Shore New York University Medical Center New York, New York

Inhalation Toxicology Research Institute Albuquerque, New Mexico

iv

1

PREFACE

James W. Osborne University of Iowa Iowa City, Iowa

Basil V. Worgul College of Physicians and Surgeons of Columbia University New York, New York Consultants

Warren D. Reece Texas A&M University College Station, Texas

Matthew J. Scannell Sterling, Massachusetts

NCRP Secretariat William M. Beckner,Senior Staff Scientist Cindy L. O'Brien, Managing Editor The Council wishes to express its appreciation to the Committee members for the time and effort devoted to the preparation of this Report.

Charles B. Meinhold President, NCRP

Contents Preface

.......................................................................................

. ........................................................................ 2. Origin a n d N a t u r e of H o t P a r t i c l e s ............................... 1 Introduction

2.1 Distribution of Hot Particles Found in Reactor

Plants

..............................................................................

2.2 Hot Particles Originating from Fuel ............................. 2.3 Hot Particles Originating from Activation Products .....

.

3 Dosimetry of H o t Particles .............................................. 3.1 Models and Calculations ................................................ 3.1.1 Empirical Point Kernels ....................................... 3.1.2 Moments-Method Point Kernels .......................... 3.1.3 Monte Carlo Calculations .................................... 3.1.3.1 E T W and ITS ...................................... 3.1.3.2 Electron Gamma Shower ........................ 3.1.3.3 Other Monte Carlo Codes ....................... 3.1.4 The VARSKIN Code ............................................. 3.1.5 New Point-Kernel-Based Calculations ................ 3.1.5.1 Beta Particles ........................................... 3.1.5.2 Photons ..................................................... 3.1.6 Comparisons for Pertinent Hot-Particle

Geometries

............................................................

3.2 Hot-Particle Measurements ........................................... 3.2.1 Laboratory Measurements ................................... 3.2.1.1 Radiochromic Dye Films ......................... 3.2.1.2 Extrapolation Chamber ........................... 3.2.1.3 Exoelectron Dosimeters ........................... 3.2.1.4 Thermoluminescent Dosimeters ............. 3.2.2 Field Measurements ............................................. 3.2.2.1 Survey Instrument Dose Assessments ... 3.2.2.2 Calculation of Dose Based on Particle

Characteristics .........................................

~i

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CONTENTS

.the Ear ..................................................................................

4 Biology and Radiation Response of Skin Including

4.1 Structure and Function of Skin and Ear ...................... 4.1.1 The Epidermis ....................................................... 4.1.2 The Dermis ............................................................ 4.1.3 The Skin Appendages ........................................ 4.1.4 The Ear-Anatomical Structure and Function 4.2 Radiation Response of Skin ........................................... 4.2.1 Deterministic Effects ............................................ 4.2.1.1 Large-Field Irradiation -Biological

.....

Responses

.................................................

4.2.1.2 Dose- and Field-Size Effects

Relationships

............................... . . ......

...... .........

4.2.1.3 Summary of Large Field Irradiation 4.2.1.4 Hot-Particles Biological Reactions 4.2.1.4.1 High- and Intermediate-

Energy Beta-Particle Emitting Radionuclides ........................... 4.2.1.4.2 Low-Energy Beta-Particle Emitting Radionuclides ........... 4.2.1.5 Effect of Beta-Ray Energy or Biological Response .................................................... 4.2.1.5.1 High- and IntermediateEnergy Beta-Emitting Radionuclides ........................... 4.2.1.5.2 Low-Energy Beta-Emitting Radionuclides ........................... 4.2.1.5.3 Hot Particles Off the Skin ...... 4.2.1.6 Summary of Deterministic Effects in Response of Skin to Hot-Particle Irradiation ..........;..................................... 4.2.2 Skin Cancer Risk from Ionizing Radiation ......... 4.2.2.1 Skin Cancer Lethality ......;.................... 4.2.2.2 Risk Modifying Factors ........................... 4.2.2.3 Risk Coefficients for Radiation-Induced Skin Cancer ............................................. 4.2.2.4 Projection of Lifetime Risks of Radiation-Induced Skin Cancer ............. 4.3 Radiation Response of Ear ............................ . . ............

.

5 The Eye ................................................................................. 5.1 Structure and Physiology ............................................... 5.1.1 Fibrous Tunic ........................................................ 5.1.2 Uvea .......................................................................

CONTENTS

.

/

vii

5.1.3 Retina .................................................................. 96 5.1.4 Lens ...................................................................... 98 5.1.5 Vitreous .................................................................99 5.1.6 Eyelids .................................................................. 100 5.2 The Effects of Large Radiation Fields on the Eye ....... 101 5.2.1 Eyelids ................................................................. 106 5.2.2 Cornea ...................................................................107 5.2.3 Lens ....................................................................... 107 5.2.4 Retina .................................................................... 112 5.3 Hot Particles and the Eye .............................................. 113 5.4 Conclusions Regarding the Eye .................................... 119

6 Respiratory Tract ...............................................................120 6.1 Structure and Physiology ...............................................120 6.1.1 Nose .......................................................................120 6.1.2 Pharynx .................................................................123 6.1.3 Larynx ...................................................................123 6.1.4 Trachea .................................................................124 6.1.5 Bronchi and Bronchioles ...................................... 124 6.1.6 Gas Exchange Airways ......................................... 125 6.1.7 The Lymphatic System ........................................ 125 6.1.8 Mechanisms of Particle Deposition in the Respiratory Tract ..................................................127 6.1.8.1 Impaction .................................................128 6.1.8.2 Sedimentation ..........................................128 6.1.8.3 Brownian Diffusion ................................. 128 6.1.8.4 Interception ..............................................129 6.1.8.5 Electrically Charged Particles ................ 129 6.1.9 Retention and Clearance of Deposited Particles .... 129 6.1.9.1 Upper Respiratory Tract ......................... 130 6.1.9.2 Tracheobronchial Region ......................... 130 6.1.9.3 Pulmonary Region ................................... 132 6.2 Radiation Response ........................................................ 132 6.2.1 Deterministic Effects ........................................ 132 6.2.1.1 Large Radiation Fields ............................ 132 6.2.1.1.1 Large-Field Effects in Upper Respiratory Tract and Trachea .....................................133 6.2.1.1.2 Large-Field Effects in Lung .... 134 6.2.1.2 Hot Particles ............................................ 137 6.2.2 Stochastic Effects ............................................... 140 6.2.2.1 Large Radiation Fields ............................ 140 6.2.2.1.1 Nasal Cavity. Pharynx. Larynx and Trachea ............................. 140 6.2.2.1.2 Lung .......................................... 141

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CONTENTS

6.2.2.1.3 Relative Radiosensitivities of Respiratory Tract Components ... 142 6.2.2.2 Hot Particles ............................................ 143 6.2.3 Summary of Hot-Particle Irradiation in the Respiratory Tract ..................................................146

7 Gastrointestinal Tract ...................................................... 148 7.1 Structure and Function .................................................. 148 7.2 Radiation Effects ............................................................ 155 7.2.1 Deterministic Effects in the Esophagus .............. 155 7.2.1.1 Patient (Human) Studies ........................ 155 7.2.1.2 Animal (Non-Human) Studies ................ 157 7.2.1.3 Summary of Radiation Effects in the Esophagus ................................................ 158 7.2.2 Deterministic Effects in the Stomach ................. 159 7.2.2.1 Patient (Human) Studies ........................ 159 7.2.2.2 Animal (Non-Human) Studies ................ 160 7.2.2.3 Summary of Radiation Effects on the Stomach .................................................... 162 7.2.3 Deterministic Effects in Small Intestine ............ 163 7.2.3.1 Patient (Human) Studies ........................ 163 7.2.3.2 Animal (Non-Human) Studies ................ 164 7.2.3.3 Summary of Radiation Effects on the Small Intestine ........................................ 165 7.2.4 Deterministic Effects in Large Intestine ............ 165 7.2.4.1 Patient (Human) Studies ........................ 166 7.2.4.2 Animal (Non-Human) Studies ................ 167 7.2.4.3 Summary of Radiation Effects in the Large Intestines .......................................167 7.2.5 Stochastic Effects to the Gastrointestinal Tract .... 168 7.2.5.1 Stomach Cancer Induction by Radiation .................................................. 168 7.2.5.2 Colon Cancer Induction by Ionizing Radiation .................................................. 172 7.2.5.3 Esophagus Cancer Induction by Ionizing Radiation .................................................. 177 7.2.5.4 Small Intestine Cancer Induction by Ionizing Radiation ...................................177 7.3 Dosimetric Modeling of the Gastrointestinal Tract ..... 177 7.4 Overall Evaluation of Risk Posed by Hot Particles in the Gastrointestinal Tract ............................................. 179

.

8 Approaches to Limits ........................................................ 181 8.1 Review of Approaches to Limits in Previous Recommendations ....................................................... 181

CONTENTS

1

i~

8.1.1 Approaches to Limiting the Risk of Hot-Particle Stochastic Effects .................................................. 181 8.1.1.1 Approach in NCRP Report NO. 46 .......... 181 8.1.1.2 Other Approaches .................................... 182 8.1.2 Approaches to Limiting Hot-Particle Deterministic Effects ............................................184 8.1.2.1 Approach in NCRP Report NO. 106 ........ 184 8.1.2.2 Approach in ICRP Publication 59 .......... 184 8.1.2.3 Approach in ICRP Publication 60 and NCRP Report No . 116 ............................. 184 8.1.3 Approaches for Large Fields ................................ 185 8.1.3.1 Approaches to Limiting the Risk of Stochastic Effects ..................................... 185 8.1.3.2 Approaches to Limiting Deterministic Effects .......................................................185 8.2 Approaches to Limits i n this Report ............................. 185 8.2.1 Approach to Dose Limitation for Hot-Particle Exposure of the Skin ............................................185 8.2.2 Approach to Dose Limitation for Hot-Particle Exposure of the Eye .............................................190 8.2.3 Approach to Dose Limitation for Hot-Particle Exposure of the Respiratory System ................... 191 8.2.4 Approach to Dose Limitation for Hot-Particle Exposure of the Gastrointestinal System ........... 193 8.3 Some Practical Considerations ...................................... 194

.

9 Recommendations on Radiation Exposure Limits for Hot Particles ................................................................. 196 9.1 Skin and Ear ................................................................... 196 9.2 Eye ................................................................................... 196 9.3 Respiratory System ........................................................197 9.4 Gastrointestinal System .................................................197 References

................................................................................. 199

The NCRP ................................................................................. NCRP Publications Index

236

................................................................ 245

........................................................................................... 254

1. Introduction Irradiation by beta or betalgamma emitting radionuclides in small particles has become of increasing concern for radiological protection.' These particles have been termed '?lot particles," "high-activity particles," "fleas," "specks," "discrete radioactive particles," and even "punctiform sources." The term "hot particles" will be used in this Report. The subject of direct exposures of the skin to hot particles containing high-energy beta-emitting radionuclides has been treated previously by the National Council on Radiation Protection and Measurements [NCRP (1989)l. A limit was recommended based on the cumulative number of beta particles emitted from hot particles rather than dose. Recommendations on exposure of the skin have also been made by the International Commission on Radiological Protection [ICRP (1991a; 1991b)l. In this Report, the treatment is extended to the cases of hot particles near the skin and in the ear, eye, respiratory system, and gastrointestinal (GI) tract. It also extends to the consideration of hot particles containing lower energy betaemitting radionuclides. Although human exposure to radioactive particles was the subject of a n article in the first volume of the Health Physics (Schwendiman, 1958), the origin, dosimetry and control of hot particles in nuclear reactor facilities, primarily power plants, has only recently become of greater interest, leading to numerous publications (e.g., Dionne and Baum, 1991). More sensitive personnel monitoring equipment has resulted in increased frequency of detection of hot particles and increased awareness of hot particles in nuclear reactor facilities. The majority of hot particles contain =OCowith the remainder containing various combinations of fission products. The primary source of hot particles containing wCo is fragments of wear-resistant alloys from valve seats, reactor coolant pumps, etc. These alloys contain a high percentage of stable cobalt, which has been activated through neutron bombardment in the reactor core via the reaction 59Co(n,y)wCo. The source of hot particles that contain fission products is the reactor fuel, particularly fuel elements that have defects in their cladding. Although most of the reports in the literature are concerned with 'Alpha-emitting radionuclides in small particles have been addressed previously

(NCRP, 1975).

2

1

1. INTRODUCTION

nuclear power plants, hot particles can occur in research reactor facilities and other nuclear facilities. Most of the current concern for hot particles in nuclear facilities centers around dose to skin from hot particles on or near the body surface. There are very few reports published in the open literature on hot particles in the ear (Horan, 1966) and in the nasal region (Calhoun, 1991; Vargo et al., 1993). Hot particles in the eye have been identified in a company report from Finland (Tossavainen, 1990) and mentioned in a published article (Lang et al., 1995), but the Council is unaware of any published reports for hot particles in the GI system. Nevertheless, concern has been expressed about the potential effects of hot particles deposited in various locations including the lung and the GI tract. Except for the case of a hot particle in the ear that resulted in a bloody discharge (Horan, 1966), there have been no reported clinically observable human injuries due to hot-particle exposures in the workplace. Hot particles in reactor facilities are usually difficult to see with the naked eye because they are small, with most ranging in size from a few to 250 pm. Hot particles usually are electrically charged and therefore tend to be fairly mobile, "hopping" from one surface to another (Warnocket al., 1987). Hot particles are not water soluble and if embedded in clothing are difficult to remove, even by laundering. "Clean" laundry has been implicated as the source of hot particles in some contamination event^.^ The origin and nature of hot particles is discussed in Section 2. Recently, hot particles associated with nuclear facilities have been mostly an "in-plant" problem associated with nuclear reactors, but the possibility that hot particles could inadvertently escape to the outside environment cannot be entirely dismissed. Early in the development of nuclear energy, hot particles released from the stacks a t the Hanford facility near Richland, Washington were of concern (Parker, 1948). Hot particles similar in nature to the 60Coparticles of concern within reactor facilities were discovered on islands and along the shoreline of the Hanford Reach of the Columbia River in the State of Washington (Sula, 1980).The source ofthese 60Coparticles is believed to be the early Hanford production reactors, which discharged water used for direct core cooling into the river. Extensive surveys of this area have been performed (Cooper and Woodruff, 1993), and many hot particles were removed as part of remediation efforts. "Hot particle exposures," presentation by Kindley, W.R. to NCRP Scientific Committee 80-1 on Hot Particles on the Skin (Institute of Nuclear Power Operations, Atlanta).

1. INTRODUCTION

/

3

Hot particles have also been observed in the fallout h m the Chernobyl nuclear power plant accident (Balashazy et al., 1988; Hoffmann and Crawford-Brown, 1989; Hofmann et al., 1988; Lancsarics et al., 1988; Osuch et al., 1989; Salbu et al., 1994; Scott, 1989). Chernobyl hot particles typically have had diameters of several micrometers and are generally divided into two isotopic categories. One type was composed almost exclusively of ruthenium isotopes; the other type was composed of isotopes of zirconium, niobium, ruthenium, cesium and cerium with some transuranic elements. In a study conducted in Poland (Osuch et al., 19891, the activity of the Chernobyl hot particles composed primarily of ruthenium isotopes averaged 19 kBq. The other type averaged about 1 kBq. Unlike the hot particles of concern in reactor facilities, the Chernobyl hot particles proved to be quite fragile, fragmenting in the environment over time. Hot particles were reported near the accident site and as far away as Sweden (Devell et al., 1986; Osuch et al., 1989). Hot particles were also present in fallout from nuclear weapons tests (Crocker et al., 1966; Schmidt-Burbach, 1970) and may have been a factor in the skin burns experienced by the Marshallese and Japanese fishermen as a result of the March 1,1954 thermonuclear device test on Bikini Atoll (BRAVO). However, the large number of hot particles involved approximated uniform contamination. Concern for hot particles that might be emitted as a result of testing and use of nuclear rocket engines stimulated research into the biological effects of hot particles in the 1960s (Dean and Langham, 1969; Dean et al., 1970; Forbes, 1969). More recently, a single hot particle containing l3ICswas discovered in a sample of sludge from a municipal sewage treatment plant in Oak Ridge (Larsen et al., 1992). Hot particles on or very near skin or other organs and tissues can lead to small amounts of tissue being exposed to very large, nonuniform doses. Average doses can be calculated over any defined volume of tissue if the particle can be characterized by nuclide and activity. Even if everything is known about the hot particle, however, the calculated dose will be strongly dependent upon the area and depth or depths over which averaging is performed. Existing methods for assessing skin and other organ and tissue doses are appropriate when large areas or volumes are irradiated by distant or dispersed sources. For skin irradiation of a few square centimeters or less, existing limits (NCRP, 1993) appear to be more restrictive than necessary. For this reason, special limits have been recommended for very small areas of skin irradiation, such as occurs with hot particles directly on the skin (ICRP, 1991a; 1991b; NCRP, 1989). For the purpose of this Report, hot particles are considered to be >10 km but <3,000 km in any dimension. Hot particles smaller

4

1

1. INTRODUCTION

than 10 pm may be treated as general contamination; exposures to hot particles larger than 3,000 km do not exhibit the particular biological response characteristic of exposure from the smaller particles. The upper size limit of hot particles defined here is larger than "approximately 1mm," which was defined as a n upper limit in NCRP Report No. 106 (NCRP, 1989). Minimizing the production and release of hot particles are clearly the preferred control methods, but the possibility of such events occurring cannot be ignored. An assessment of the biological effects of hot particles is required so that appropriate radiation protection criteria can be developed. The nature of hot particles found in nuclear facilities is described in Section 2. In Section 3, the measurement and calculation of doses from hot particles are discussed. In the next four sections, Sections 4 through 7, the pertinent anatomy, physiology, response to large field irradiation, and response to irradiation from hot particles for skin, eye, the respiratory system, and the GI system are discussed. Approaches to limiting exposure due to hot particles are discussed in Section 8 and the recommended limits are given in Section 9.

2. Origin and Nature of

In 1986, an increase in the detection rate of hot particles was noted in the nuclear power industry. This increase in hot-particle detections corresponded to the installation of high sensitivity, portal monitoring devices at the exits of radiologically controlled areas in the plants. Because the increase in the detection rate coincided with installation of more sensitive equipment, it is reasonable to assume that hot particles existed previously within the industry. The two primary types of hot particles derive either from nuclear fuel or from activated wear products such as fragments from valve seats. Hot particles from fuel originate from within the fuel or fuel cladding. The wear products are activated during transit through the reactor core. Hot particles become dispersed throughout the primary coolant system as well as some secondary systems as the coolant is circulated and processed by these systems. Hot particles, including activated wear products, can lodge in "crud traps," lines, hoses, valves and tanks within the reactor system and can be encountered by workers during maintenance activities. The dispersal of hot particles is increased by operations such as fuel transfers to the spent fuel pool or fuel consolidation and reconstitution, in which individual fuel assemblies are dismantled and reassembled. Fuel pins that may be leaking, or to which hot particles are attached, are disturbed during these operations. The vast majority of these hot particles has been smaller than 100 p,m, relatively insoluble, and highly electrically charged. Figure 2.1 is an electron micrograph of a relatively large hot particle.

2.1 Distribution of Hot Particles Found in Reactor Plants

Studies of hot particles and their distribution in nuclear power plants have been made by James (1988),Kelly and Gustafson (19941, and Rogers and Vance (1989)in the United States, and by Mandjukov et al. (1994) in Bulgaria. James (1988) surveyed staff members at 61 operating plants for hot particles and made detailed evaluations of approximately 150 hot particles that had been collected, primarily

6

/

2. ORIGIN AND NATURE OF HOT PARTICLES

Fig. 2.1. Electron micrograph of a relatively large hot particle collected at the Palo Verde Nuclear Generating Station near Phoenix, Arizona. The image was made with 25 keV electrons at a magnification of 300 times.

a t one boiling water reactor (BWR)and one pressurized water reactor (PWR) plant. Personnel a t 16 plants reported having found no hot particles a t that time. Four plants reported only fuel hot particles, while 14 plants reported the discovery of both fuel and activation hot particles. The highest number of facilities, 27, reported finding only hot particles that contained activation products. Staff members a t none of the BWRs in the James study reported finding any fuel hot particles. Most plants reported a t least a few hot particles, with the majority of those being activated wear products. A few plants indicated finding several hundred activation-type hot particles, mostly 60Co.TWOPWR plants with failed fuel elements reported finding more than a thousand fuel hot particles. It is possible that other nuclear power plants had also experienced similar hot-particle problems following fuel element failure, but hot particles were not always systematically tracked (James, 1988). The distribution of the activity of fuel hot particles was found to be log-normal in appearance with an arithmetic average activity of 15 kBq and a geometric mean activity of 3 kBq.More than 80 percent of the fuel hot particles were <11 kBq. The distribution of t h e activity of the 60Co particles was also log-normal in appearance. Cobalt-60 particles found in PWRs tended to have larger activities

2.1 DISTRIBUTION OF HOT PARTICLES

1

7

per particle than those found in BWRs, with an average activity of 22 kBq for the PWRs and 5.9 kBq for the BWRs. The geometric mean activities of the hot particles were 4 kBq for the PWR data and 0.96 kBq for the BWR data. The major radionuclides found in fuel hot particles collected from these facilities that could be identified using gamma-ray spectrome95Zr,lo3Ru,lo6Ruand smaller try generally were '"Ce, 141Ce,95Nb, amounts of 134Cs,137Cs,14"Baand 140La(James, 1988). The primary radionuclides that would not be directly identified by gamma spectrometry were known to be 89Sr,90Sr, '*Pr, 144Prand Io6Rh. The radionuclides in the activation-type hot particles were found to be primarily 60Co.As mentioned above, several plants surveyed by James (1988) indicated that they had found hundreds of hot particles, most being pure Wo. These plants encountered hot particles that were caused by the degradation of Stellitem components within the ~ y s t e mOther .~ facilities found a few activation hot particles that contained a mix of radionuclides including 57Co,6 8 C ~V, O , 54Mn,59Fe,51Crand a few others. These hot particles resulted from pieces of stainless steel or Inconelm that had reached the reactor core and become bombarded by n e u t ~ o n sThese, .~ however, made up only a very small percentage of the hot particles found. Another, more comprehensive survey of the hot particles documented a t 105 United States nuclear power plants was conducted by Kelly and Gustafson (1994). This work covered the period of 1986 through March 1991 and included a significant amount of new data. Although the study was extensive, the data must be reviewed in light of the following qualifications: all hot particles discovered were tracked a t only 26 percent of the nuclear power plant sites, and hot particles involved in personnel contaminations were tracked a t 29 percent of sites. In addition, only hot particles with a n activity >400 Bq were tracked a t 20 percent of the sites. The Kelly and Gustafson survey found that activation-type hot particles dominated those being reported by the industry. Almost 75 percent of the identified hot particles reported were activation products (see Table 2.1). In summary, Kelly and Gustafson concluded that:

3Stellite@is a special alloy used in applications such as valve seats that has a n estimated composition of 1.1percent carbon, 1.5percent silicon, 30 percent chronium, 1 percent iron, 59.4 percent cobalt, 1 percent nickel, 1.5 percent molybdenum, and 4.5 percent tungsten, by weight, and a density of 8 g ~ m - ~ . 'Inconel@is a corrosion-resistant alloy. The major constituents are nickel (about 75 percent) and chromium (about 15 percent).

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1

2. ORIGIN AND NATURE OF HOT PARTICLES

1. Hot particles were discovered in nuclear power plants, including on personnel, twice as often a t PWRs as a t BWRs. 2. Fuel-type hot particles were discovered 15 times as often a t PWRs as a t BWRs. 3. Twice as many hot particles were found during outages a t BWRs as during normal operations. 4. Five times as many hot particles were found during PWR outages as during normal operations. 5. Most hot particles contained <370 kBq a t BWRs and <3,700kBq a t PWRs, but a few ranged up to about 40 Gbq.

2.2 Hot Particles Originating from Fuel Fuel-type hot particles can be generated in several processes within the nuclear power plant fuel. The neutron fission of uranium and plutonium produces a large number of different fission products. The resulting radionuclides have half-lives ranging from fractions of a second to thousands of years. However, fission products with significant activity have half-lives < I 0 0 y. The radionuclides of concern that are found within these pieces of fuel, or hot particles, typically have half-lives in the range of a few days to about 30 y. The activity of short half-life material in hot particles is governed by the radioactive decay that occurs during the time between shutting down the reactor and their potential release which occurs when the primary system is opened for maintenance. The upper end of TABLE2.1-Summary of numbers of hot particles found in nuclear power plants and on personnel." Power Plant Type BWR

Number of sites Number of reactors Hot-particle type Activation Fuel Mixed (fuellactivation) Unknown Total

24 34

PWR

45 71

All Reactor Types

69 105

"From a survey of 105 nuclear reactors a t 69 United States nuclear power plant sites by Kelly and Gustafson (1994).

2.2

HOT PARTICLES ORIGINATING FROM FUEL

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1

the range is governed by the low-fission yield and low activity of the long-lived fission products. James (1988) made a calculation of fuel constituents using the ORIGEN code (Croft, 1980) with reasonable reactor operating parameters. Using a neutron flux of l O I 4 n cm-2s-I and considering 100 to 900 d as the core irradiation times, the radionuclide mix of fuel and its associated hot particles a t the end of the irradiation period was calculated (see Table 2.2). After more than 500 d of irradiation in the core, the initial mix of a fuel-type (fission product) hot particles would be dominated by t h e following radionuclides: 144Cd44Pr, 141Ce,95NbP5Zr,140Ba/140La, laF'r, loaRu, lMRdo6Rh,89Sr, 'lY, and small amounts of 'OSrPY, 134C~, l3ICs, and 147Pm. The initial distribution of various fission products within any particular hot particle can differ because reactors start and stop, and

TABLE2.2 -Calculated relative activity of radionuclides in hot particles (percent) and total specific activity as a function of time exposed in the reactor core (d). Composition (%) as a Function of Core Exposure Time

Beta-/Gamma-Emitting Radionuclides Zr-95 9.7 Nb-95 6.3 Ru-103 7.0 Ru-106 0.3 CS-134 0.0 Cs-137 0.1 Ba-140 14.2 La-140 14.5 Ce-141 12.0 Ce-144 2.7 Pm-147 0.3 Beta-Emitting Radionuclides Sr-89 7.9 Sr-90 0.1 Y-90 0.1 Y-91 8.9 Ru-106 0.5 Pr-143 12.8 Pr-144 2.7 Total specific activity (TBq kg-')

390

470

500

520

525

525

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1

2. ORIGIN AND NATURE OF HOT PARTICLES

because chemical and thermodynamic properties affect the separation or concentration of certain products within the fuel and within the reactor coolant. For example, cesium behaves as a gas within a fuel rod a t operating temperatures. This results in cesium being concentrated in lower temperature regions of a fuel element. In fact, diagnostic evaluations of fuel elements at nuclear power plants have shown bands of 137Csassociated with the failure of some types of fuel elements. Cesium salts are water soluble. Fuel fragments that have been in the reactor coolant for a long time may have released most of the '"Cs to the coolant. Many of the fuel fragments analyzed within the industry have shown substantially less 13'Cs than would have been predicted from relative fission yields and decay times. Ruthenium can form RuO,, a n oxide that is volatile a t fuel operating temperatures. Avery small percentage of the hot particles discovered in the industry have been pure ruthenium isotopes: lo3Ruplus lo6Ruor pure lo%. Differences in these hot particles can be explained by the ages of the hot particles, because the half-life of lo3Ruis only 39 d while that of 'OGRuis about 1y. Pure ruthenium particles have also been observed in fuel reprocessing facilities. Gaseous ruthenium has been observed in underground tunnels near a weapons test site shortly after a weapon detonation. Once it contacts water, RuOl would be expected to react to form a hydrated oxide. These hydrated ruthenium oxides are thermodynamically stable and are chemically resistant to dissolution in aqueous solutions. The fuel-type hot particles found within the industry have often included a small amount of the ruthenium isotopes. Fuel particles may be released and dispersed throughout the primary system if the fuel cladding is damaged. The damage can be the result of either a chemical or physical process. The chemical processes may begin with a manufacturing defect, such as incomplete drying of the fuel elements during assembly. Fuel cladding damage could increase if pin-hole leaks combined with frequent power level changes permitted water to enter a fuel pin. Damage may develop under a localized "crud" deposit where the cladding operates a t a higher temperature than surrounding areas. Radiolysis of water and the fission process both yield hydrogen. Hydrogen is very soluble in ~ i r c a l o ybut , ~ causes the gradual embrittlement of zircaloy as the solubility limit is approached. As more water enters a fuel pin, and a s more hydrogen is produced, the localized areas of the fuel pin begin to form hydride from the inside out. Zirconium hydride, or

'Zircaloy is a n alloy of zirconium containing 1.5 percent tin, which is used in nuclear reactors a s a cladding material for uranium-fuelelements and a s a structural material.

2.2

HOT PARTICLES ORIGINATING FROM FUEL

/

11

ZrH,, is a friable compound, which can crumble away and expose the fuel within a pin to further chemical and physical action. Another process that can create fuel particles is direct physical damage of fuel by foreign material left or generated within the reactor system, or accidental damage during handling. Tiny pieces of lockwire, metal slivers, and straps can become trapped within a fuel bundle and vibrate due to hydraulic forces. This can cause erosion and wear (fuel fretting) and through-wall failures, and the subsequent release of fuel particles. Reactor shutdowns or other reactor coolant flowdeviations caused by power level changes can shiff debris and start the fretting process in other locations. Fuel fragments as large as the major portion of a single fuel pellet have been detected in the accessible work areas of operating power plants. Many fuel fragments were dealt with successfully during the cleanup of Three Mile Island Unit 2 following the accident. Fuel fragments found at Three Mile Island Unit 2 were dominated by SOSrPOYand 13'Cs. The ratios between these radionuclides reportedly varied from 1:20 to 20:l even though fission yield and decay corrections indicated that the ratio should be close to one. The solubility of the radionuclides in water and volatility during the accident explain the variation in radionuclide content among hot particles. In Table 2.3, the percentage distribution of the major radionuclides measured in a representative sample of the fuel particles reported by James (1988) are compared to the calculated distributions (Table 2.2). Calculated distributions for core irradiation times longer than 500 d were found to be reasonably similar to the distribution obtained from measured particle activities.

TABLE 2.3 -Comparison of measured and calculated percentage distribution of radionuclides in hot particles (James, 1988). Measured Distribution Nuclide

(%)

Calculated Distributions for Indicated Days in Core (%) 500 d

600 d

700 d

12

/

2. ORIGIN AND NATURE OF HOT PARTICLES

Calculations with the ORIGEN code also provided an estimate of 525 TBq kg-' for the maximum total specific activity for fuel particles (Table 2.2). Subsequent to 1988, a number of particles from nuclear power plants were evaluated in detail. The maximum specific activity found in these evaluations of fuel particles was about 480 TBq kg-', which is in reasonable agreement with the maximum specific activity calculated with the ORIGEN code. Additionally, in the late 1960s and early 1970, following a series of Chinese above ground nuclear weapons tests, hot particles were found in the atmosphere near Sweden and were studied by Persson and Sisefsky (1971). The distribution of radionuclides in these hot particles was also similar to that for fuel particles as estimated with the ORIGEN code. The highest specific activity found in these atmospheric hot particles was approximately 370 TBq kg-'. Similar hot particles were found in the atmosphere near Norway following the Chernobyl accident. Salbu et al. (1994) found that the higher specific activity Chernobyl hot particles ranged from approximately 370 to 520 TBq kg-'. Using the specific activity of 525 TBq kg-' from the ORIGEN code and a U02 density of approximately 10 g ~ m - the ~ , characteristics of a typical, spherical fuel-type hot particle with a diameter of 100 Fm can be provided. The activities immediately following 500 d of core irradiation are given in Table 2.4. The relative activity of this typical fuel-type hot particle as a function of age is shown in Figure 2.2. The decay of the activity of a 60Coparticle has also been plotted to illustrate the marked difference between the relative activities of TABLE2.4- Typical activities immediately following 500 d of core irradiation for a spherical fuel-type hot particle with a diameter of 100 pm. Nuclide

Approximate total

Activity (kBq)

Nuclide

Activity (kBq)

2,600

2.2 HOT PARTICLES ORIGINATING FROM FUEL

/

13

$ 0.6

.-

I-'

g(FJ

0.4

Time since leaving reactor core (d) Fig. 2.2. Relative activity of a typical hot particle originating from reactor fuel compared to the relative activity of "Co hot particles.

the two types of hot particles as they age. If a fuel particle was encountered just after core irradiation, a complex mix of radionuclides would be found. However, after a short time, the shorter-lived radionuclides decay and 144Ce/144Pr, 106RUP06Rh, and SoSrPOY,which are high-energy beta-emitting radionuclides, dominate the activity. After a few years, only goSrPOy,with a maximum beta energy of 2.3 MeV, is important. The average energy of beta particles emitted by radionuclides in a fuel particle early in its life is approximately 0.3 MeV, but increases rapidly to more than 0.5 MeV. The activities of the gamma-emitting radionuclides in fuel particles can be easily determined in the laboratory through gamma spectrometry, using high-purity germanium detectors. However, to determine the total activity within a fuel particle, the contribution from the pure beta-emitting radionuclides must be determined. Several techniques have been developed. One of these techniques is the use of age-dating of hot particles and correlation to the typical distribution of activity in fuel. The ratio of 144Ce(TIn = 284 d) to 141Ce(TB = 33 d) increases from about 1 to 1,000 over a period of 500 d because of the significant difference in their half-lives. This increasing ratio can be used to estimate how long the particle has been out of the core, i-e., its age. With a n estimated age of the hot particle, the activity of pure beta-emitting radionuclides can then be estimated. Except for very young hot particles, goSrPOyis the significant beta-emitting nuclide.

14

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2. ORIGIN AND NATURE OF HOT PARTICLES

Because of the low energy and, especially, the low yields of the emitted photons of 14Ce and 141Ce,this age-dating technique has a useful limit of approximately 500 d. In addition, the technique is not without uncertainty. It is based on the typical nuclide distribution when the particle leaves the core and this can be variable. Therefore, when possible, direct beta measurements should be made in conjunction with gamma spectrometry for older fuel particles in order to verify the calculated pure beta activities. In principle, the ratio of 95Nbto 95Zrcan also be used to estimate hot-particle age, but the range of this ratio is very limited, only changing from approximately 1.5 to 2.1 over the first 150 d after removal of the hot particles from the core. 2.3 Hot Particles Originating from Activation Products

Essentially all United States nuclear power plants have had experience with 'j°Co hot particles outside the confines of the reactor and its cooling system. Cobalt-60 is an activation product that is produced by the reaction 59Co(n,y)GOCo.Cobalt-58 hot particles are less prevalent than '%o hot particles. Cobalt-58 is produced by the reaction ? N i b , P)~'CO.These reactions occur only in the reactor core. Because the half-life of T o is 5.2 y, long core residence times are required to in the hot particles. Cobalt-58 has produce significant activities of a half-life of about 72 d and, therefore, builds toward an equilibrium activity much more rapidly than Wo. Stable cobalt is introduced into the primary system by corrosion of primary system components, wear of primary system components and from residual debris from maintenance activities. The primary sources of hot particles containing 'j°Co are PWR steam generator tubing, hard facing on valves, fuel bundle straps, control rod drive mechanism latch pins, and bearing surfaces. Steam generator tubes are typically made from Inconel@,' which contains a high percentage of nickel. Hot particles originating from corrosion or wear of the 300series stainless steels (e.g., 316, 321) will contain a mixture of "Co and 60Co,depending on the age of the plant. Less significant radionuclides in such hot particles are 51Cr,"Mn and 59Fe.Cobalt-60 will predominate in importance after the first 3 to 4 y of power operation. The most important 60Cohot particles are believed to originate from hard facing on valves made from StelliteB, an alloy described earlier. Valve operation may cause chipping of Stellitea surfaces. Repair of valves and valve seat lapping or grinding produce many fine particles of Stellitem. According to the Electric Power Research Institute (EPRI), hot particles are likely to be (250 pm (0.01 inch) in size (EPRI, 1983).

2.3

HOT PARTICLES ORIGINATING FROM ACTIVATION PRODUCTS

1

15

Hot particles containing activation radionuclides other than cobalt have been found occasionally throughout the industry. Antimony124 hot particles were found in the steam generator channel heads at a plant that had antimony in the bearing materials of reactor coolant pumps. Because some plastic wire insulation contains antimony, lZ4Sbhot particles can be produced if electrical wire insulation fragments are left near the reactor vessel where neutron activation of stable antimony is possible. Tantalum-182 hot particles were observed at one PWR. The source was believed to be activation of corrosion or erosion products from the control rods.

3. Dosimetry of Hot Particles 3.1 Models and Calculations

Methods to calculate the spatial distribution of absorbed doses from beta-particle sources, for application to a wide variety of geometries, have been the subject of study for more than 50 y. Such calculations play an important role in estimating the radiation dose from hot particles. This may be in the assessment of absorbed doses for specific geometries as they pertain to the interpretation of biological response from experimental irradiations, or for the assignment of a dose for regulatory purposes following an incident. Although there is a n extensive literature on methods of calculation, only those approaches that currently appear to be most appropriate for hotparticle dosimetry calculations are reviewed here. The following subsections outline a number of pivotal developments. These include the computational generalization by Loevinger (1954; 1956) of the absorbed-dose distributions from measurement; the calculation of absorbed doses by Spencer (1955; 1959) through the solution of the transport equation by the method of moments; and the calculation of absorbed doses by Monte Carlo methods. The discussion continues with a description of the VARSKIN code, adopted by the U.S. Nuclear Regulatory Commission (NRC), and a similar, alternative calculation developed for this Report in order to provide independent estimates of absorbed doses (NISTKIN). Central to much of the discussion is the distribution of the absorbed dose from a point-isotropic source in a n infinite, homogeneous medium (usually water, as a substitute for tissue). This spherically symmetric distribution is a function of a single spatial variable ( r ) the distance from the point source. This absorbed-dose distribution is given in terms of the fraction of the energy emitted by the source that is absorbed per unit mass of the medium, and is known also as the point-isotropic specific absorbed fraction or the point kernel (see, e.g., Loevinger and Berman, 1968). The point kernel is most directly applicable to calculations of a n absorbed dose from beta-emitting radionuclides inside the body, where the assumption of a n infinite

3.1 MODELS AND CALCULATIONS

1

17

medium is justified. For sources at or near the airltissue (water) boundary, as in the case of beta-emitting radionuclides on the skin surface, the use of point kernels produces an overestimate of the absorbed dose in the tissue because the backscatter from the significantly less dense air would be less. In addition, point kernels do not account for the different scattering and slowing-down6 properties of the source material (e.g., wear-resistant alloys or fuel materials that have much larger atomic numbers), so that self-absorption and scattering effects in larger hot particles may not be adequately described. To be weighed against these deficiencies are the relative ease and speed with which point kernels can be used to estimate the absorbed dose in a variety of practical problems. 3.1.1 Empirical Point Kernels

One of the most widely used descriptions of beta-particle point kernels has been given in the pioneering work of Loevinger (1954; 1956). Based on fits of available measured data, some of which were transformed from the case of a plane source to a point source, Loevinger proposed a set of formulae for the calculation of the absorbed dose per disintegration as a function of distance from a point source. The formulae involve simple exponential functions and basically two parameters that depend only on the endpoint energy (Em,)and the average energy (E,,) of the beta spectrum. The density of the medium enters in a simple fashion to preserve units and provide for proper scaling. The normalization of the distribution ensures that the integral over all space of the distribution returns the mean energy of the beta particles emitted per disintegration. Although other more accurate results are now available, Loevinger's formula is still used (Bartlett, 1987; Chabot and Skrable, 1988; Peng et al., 1988; Thornhill et al., 1989)because the analytical expression lends itself to integration in a number of pertinent geometrical problems.

3.1.2

Moments-Method Point Kernels

Spencer (1955)developed a moments-method calculation to obtain, from first principles, the distribution of absorbed doses from electrons in an unbounded homogeneous medium. His calculation rests on the assumption of continuous slowing down, wherein the 'Slowing down refers to the property of a material to decelerate electrons.

18

!

3. DOSIMETRY OF HOT PARTICLES

fluctuations in energy loss (energy-loss straggling) in inelastic collisions of the primary electrons with t h e atomic electrons of t h e medium are i g n ~ r e dLess . ~ important limitations include the neglect of the transport of energy by secondary electrons or by bremsstrahlung. Spencer (1959) gave tables of results for point-isotropic sources of monoenergetic electrons, with initial energies ranging from 0.025 to 10 MeV in carbon, aluminum, copper, tin, air and polystyrene, and from 0.1 to 2 MeV in rubidium, and suggested methods for interpolation among these data to other source energies and media. After performing the appropriate interpolation and integration of Spencer's results, Cross (1967a) found good agreement between calculated and measured point-source dose distributions for 15 betaemitting radionuclides with maximum energies of 0.16 to 3.58 MeV. Agreement was found to be within four percent out to a distance within which 95 percent of the energy was absorbed. Beyond this distance the discrepancies were ascribed to the neglect of energyloss straggling in Spencer's theory. Cross (1967b) then published point kernels for 40 radionuclides in air and water. Later he extended his compilation to 95 beta-emitting radionuclides (Cross et al., 1982). Also using Spencer's results, Berger (1971) prepared tables of point kernels in water for monoenergetic sources with energies between 0.025 and 4 MeV, and for 75 radionuclides, in a particularly effective scaled form. Although his point kernels were obtained using somewhat different numerical procedures, Berger found very few cases of appreciable differences with those of Cross. These scaled point kernels of Berger are used as the basis for the popular VARSKIN code, mentioned previously in this Section. Based on fits to Berger's point kernels, Vynckier and Wambersie (1982; 1986) proposed a modification to Loevinger's formula involving a n additional term with a new fitting parameter. By optimizing three parameters for specific beta spectra, they were able to bring the fitted curves into better agreement with Berger's and Cross' results, particularly for distances close tb the source and those near the end of the maximum range, where Loevinger's formula is inaccurate. Using a n alternative approach, Chabot et al. (1988) extracted from t h e point kernels of Cross e t al. (1982) correction factors to a n assumed exponential penetration function and effective stopping power so a s to analytically describe t h e beta point-source dose 'In the continuous slowing down approximation (CSDA), the energy loss is assumed always to be given by the mean energy loss. Actual energy-loss spectra are skewed, with the most-probable energy loss smaller t h a n the mean and a diminishing tail extending to larger values. Calculations that include the fluctuation in energy loss tend to show a n increase in penetration over those done using CSDA.

3.1 MODELS AND CALCULATIONS

1

19

distribution. These results have been used in hot-particle calculations involving pertinent nonhomogeneous materials and geometries (Chabot et al., 1988; 1992; McWilliams et al., 1992).

3.1.3

Monte Carlo Calculations

Monte Carlo methods for the solution of electron transport problems have become quite refined. Based on the direct simulation of the processes that govern the passage of the radiations, Monte Carlo calculations can address inhomogeneous media with complicated boundary conditions and include the effects of energy-loss straggling, the production of bremsstrahlung photons, and the transport of energy by secondary electrons and photons. Although they have excellent flexibility, it is often considered a disadvantage that Monte Carlo calculations require significant amounts of numerical computation to reduce the statistical fluctuations in the results to desired levels. Methods used in Monte Carlo calculations for electrons were thoroughly outlined by Berger (1963), particularly in regard to the use of "condensed" histories in which the net effect of many interactions along each step (i.e., some chosen small path length) in the random walk is sampled from pertinent multiple-scattering theories. More recently, Andreo (1991)surveyed the use of Monte Carlo calculations in mehcal physics, and a review of such methods used in betaparticle dosimetry calculations is included in International Commission on Radiation Units and Measurements (ICRU) Report 56 (ICRU, 1997). It appears fair to state that, given sufEcient information for the source term and boundary conditions, results from current Monte Carlo calculations have accuracies comparable to the best corresponding measurements. The better-known, general-purpose electron Monte Carlo code packages include Electron Transport (ETRAN), Integrated TIGER Series (ITS),and Election Gamma Shower (EGS), which are discussed below.

3.1.3.1 E T W and ITS. Although the ETRAN code (Berger and Seltzer, 1968; Seltzer, 1988; 1991) considers only homogeneous media in simple geometries, it has also provided the transport model and cross-section information for codes that provide more generality. An early extension to slab geometry with multiple materials was made in the ZEBRA code (Berger and Buxton, 1971). However, the code neglected energy-loss straggling plus secondary electron and bremsstrahlung transport, thus treating the transport physics with the same approximations a s Spencer's moments-method

20

1

3. DOSIMETRY OF HOT PARTICLES

calculations. The ZEBRA code has been reintroduced as ELTRAN (Shen et al., 1987) and extended to cover some three-dimensional geometries (Chung et al., 1991a; 1991b) for applications in betaparticle dosimetry. The SANDYL code (Colbert, 1974)contained a fairly general geometry package and was based mainly on the early ETRAN model. Independently, the ETRAN model was extended in a series of developments to include various geometries: the TIGER code for multiple slab targets (Halbleib and Morel, 1979; Halbleib and Vandevender, 19751, the CYLTRAN code for general cylindrical geometries (Halbleib and Vandevender, 1976), and the ACCEPT code, which uses rather general three-dimensional, combinatorial geometry (Halbleib, 1980).These codes were organized into the ITS (Halbleib, 1988; Halbleib and Mehlhorn, 1984; 1986), evolving to its current versions (Halbleib et al., 1992a; 1992b; 1995).The ITS/IETRAN algorithms are also emulated in the treatment of electron transport incorporated into the MCNP4A code (Briesmeister, 1993; Hughes, 19951, a well-known neutronlphoton Monte Carlo transport code. From ETRAN calculations, Berger (1973) obtained point kernels for monoenergetic electrons in an infinite water medium with energies up to 10 MeV. The beta dosimetry calculations of Kocher and Eckerman (1987) and of Prestwich et al. (1989) are based on the Berger (1973) point kernels. These earlier results are somewhat in error because of a defective treatment of energy-loss straggling in the ETRAN algorithm. The defect was corrected (Seltzer, 1988), and point kernels to replace the earlier tables, for energies from 20 keV to 20 MeV, were calculated (Seltzer, 1991). From a large study of beta-particle dosimetry, Cross et al. (1992a; 1992b; 19924 used the ACCEPT code to calculate point kernels in an infinite water medium for electrons with energies from 0.01 to 10 MeV, integrating these over beta spectra to obtain radial dose distributions for a large number of beta-emitting radionuclides. In addition, these investigations took into explicit account the effects of the airlwater interface in calculations for (1) the on-axis dose from large-area sources, and (2) the dose averaged over a 1 cm2circular area from on-axis point sources. Pollanen and Toivonen (1994; 1995)describe a semi-analytical model for application to spherical fuel particles, based on point kernels from the Monte Carlo calculations of Cross et al. (1992a) in conjunction with a self-absorption correction within the source volume. The effects of air-backscatter on the dose from thin large-area beta-particle sources a t the airlwater interface were also investigated by Faw (1992) using CYLTRAN calculations. Other applications of these codes to beta-particle dosimetry problems include the ETRAN calculations by Berger and Seltzer (1982) for 1 to 60 MeV electrons

3.1 MODELS AND CALCULATIONS

/

21

normally incident on water phantoms; the recent systematic ETRAN calculations by Seltzer (1993)of dose in water from electrons incident with energies from 0.05 to 10 MeV and angles from 0 to 89 degrees; and the SANDYL calculations by Cross et al. (1991) for the dose in water from normally incident electrons and beta particles.

3.1.3.2 Electron Gamma Shower. The EGS code system (Ford and Nelson, 1978),a generalization of an early high-energy shower calculation, provided a general-purpose electron-photon Monte Carlo code for kinetic energies from a few thousand giga-electron volt down to 0.1 MeV for photons and 1 MeV for electrons. Further revisions resulted in EGS4 (Bielajew and Rogers, 1987; Nelson and Rogers, 1988; Nelson et al., 1985) in whlch the lower energy limits were extended down to 1 keV. The EGS code was used by Kwok et al. (1987)to simulate effects they measured in the beta dose distribution for a polystyrene (tissue substitute)/aluminum (bone substitute) interface; reasonably good agreement was found. Simpkin and Mackie (1990) used EGS4 to calculate point kernels in an infinite water medium for electrons with energies of 0.05, 0.1, 0.5, 1, 2 and 3 MeV, and for eight radionuclides, noting the small discrepancies with Berger's (1973)results. In an application to hot-particle dosimetry, Busche et al. (1991) used EGS4 to calculate the dose from pointsources of %o, 89Sr and lUPr a t various depths averaged over a specified area. Unfortunately, they replaced the continuous beta spectra with a monoenergetic electron having an energy corresponding to the average energy of the spectrum, so that their conclusions are only semi-quantitative, In a development somewhat similar to that for MCNP4, an EGSbased treatment of electron transport has been added to the MCNP code (Ferrari et al., 1992; Guaraldi et al., 1990). This version of the code, called MCNPE-BO, has been used by Gualdrini et al., (1994) in systematic dose calculations for external beta irradiation. They find that their results compare rather well with those from MCNP4, EGS3, and an earlier version of ETRAN. Other EGS work on dose distributions pertinent to beta-particle dosimetry include Rogers' (1984)extensive calculations for 100 keV to 20 GeV electrons normallyincident on ICRU-tissue phantoms, and the recent systematic calculations of dose from external electron irradiation by Hirayama (1994) and Ma (1995). 3.1.3.3 Other Monte Carlo Codes. Other Monte Carlo calculations used in electron penetration and dosimetry studies a r e based on methods that are often equivalent to those of ETRANIITS or of EGS. Patau (1991) has employed Monte Carlo techniques, essentially

22

1

3. DOSIMETRY OF HOT PARTICLES

similar to those used in ETRAN, to calculate dose distributions from hot particles. Rohloff and Heinzelmann (1986) report on Monte Carlo calculations of absorbed dose from 21 beta-emitting radionuclides, both for point and large-area sources with and without backscattering from the air. Grosswendt's PTB/BG code has been used to calculate a number of radiation protection quantities, most recently the fluence-to-absorbed-dose conversion coefficients for normally incident electrons (Grosswendt, 1994) and as a function of incident angle (Grosswendt, 1993; Grosswendt and Chartier, 1994). In contrast to "condensed-history" Monte Carlo calculations based on multiple-scattering models, single-scattering Monte Carlo methods track the electrons between each individual scattering event. Although such single-scattering electron Monte Carlo models are used mainly in low-energy and track-structure calculations, the single-scattering Monte Carlo code OREC (Hamm et al., 19851,developed for electron transport calculations in liquid water, has been applied to beta-particle dosimetry problems (Crawford et al., 1991; Turner et al., 1988). Caswell and Seltzer (1994) pointed out that the OREC depth-dose distribution from 800 keV electrons normally incident on a water slab target (Turner et al., 1988) appears to be in error, possibly due to the use of defective elastic-scattering cross sections. This appears to have been corrected by Crawford et al. (1991) who used the same elastic-scattering cross sections on which ETRAN/ITS is c.urrently based.

3.1.4 The VARSKlN Code The VARSKIN code was developed to provide estimates of the absorbed dose from hot particles, and, a s noted above, has been adopted by the NRC for skin-dose calculations in support of their regulatory functions. The original version of the code (Traub et al., 1987) assumed a n infinitely thin disk source directly on the surface of the skin, and performed the spatial integrations over Berger's (1971) electron point kernels for the beta spectrum of interest in order to estimate the radial distribution of absorbed-dose rate a t the specified depth. The radial distribution was integrated to obtain the absorbed dose averaged over an area of 1cm2as well as other desired areas. The point kernels were generated for the radionuclide using an auxiliary code called SADDE (Reeceet al., 1989). The more recent version, VARSKIN MOD2 (Durham, 1991; Durham and Bell, 1992; Durham et al., 1991), extends the calculation to include threedimensional beta-particle sources, an evaluation of the effect of layers of protective clothing and of an air gap between the source and

3.1 MODELS AND CALCULATIONS

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23

skin surface. There is also a limited treatment of the contribution to the dose from gamma rays emitted by the radionuclide. Selfabsorption of the beta particles in the extended source and in any intervening layers is described through a simple scaling of the water point kernels to the assumed density of these materials (i.e., other materials such as those comprising the source, air, clothing, etc., are assumed to be water but with the density of the actual material). Such a n approximation ignores differences in electron scattering and slowing down in the various materials. The gamma-ray dose, averaged over a circular area of 1 cm2, is estimated for sufficiently small source sizes based on the point-source model of Lantz and Lambert (1990). This model includes a treatment of the transition to electron equilibrium but ignores the dose build-up by scattered photons a t large depths. The dose from gamma rays can be particularly important for 60Co,because the short range of the beta particles from 60Cooften can be exceeded by the thickness of protective clothing, leaving the gamma rays as the major contributor to the absorbed dose a t depths of interest. The corrections for non-equilibrium have been shown by Durham and Lantz (1991) to be important for 60Co, particularly a t the "regulatory" depth of 7 mg ~ m - ~ .

3.1.5 New Point-Kernel-Based Calculations For the purposes of this Report, new methods of calculation were developed a t the National Institute of Standards and Technology (NIST).8Theintention was to retain the efficiency of the point-kernelintegration approach, to provide improved accuracy through the inclusion of energy-loss straggling, and to offer some independent verification of VARSKIN results. For purposes of identification, this new calculation will be referred to as NISTKIN. To include estimates of the absorbed dose from photon emission, a parallel point-kernelintegration routine for photons was developed for the NISTKIN calculations. For both electrons and photons, numerical integrations over assumed source volumes are performed using an adaptive quadrature routine (Genz and Malik, 1980). The methods used in the calculations are briefly outlined below.

3.1.5.1 Beta Particles. The calculations are based on the use of monoenergetic electron point kernels of Seltzer (1991) obtained from ETRAN Monte Carlo calculations, which include t h e effects of BSeltzer, S.M. (1996). Personal communication (National Institute of Standards and Technology, Gaithersburg, Maryland).

24

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3. DOSIMETRY OF HOT PARTICLES

electron energy-loss straggling. The point kernels for the radionuclides are obtained by integration over beta spectra generated with the LOGFT program (Grove and Martin, 1971) in conjunction with the Evaluated Nuclear Structure Data File from the National Nuclear Data Center, Brookhaven National Laboratory (BNL). The program and data used were current in the mid-19809, are still expected to be reliable, and are reasonably consistent with the earlier data in NCRP Report No. 58 (NCRP, 1985a). Some pertinent emission data, assumed for the calculations performed for this work, are summarized in Tables 3.la and 3.:Lb. To illustrate the initial quantities available from various calculations, Figure 3.1 compares the basic point kernels for the beta particles from a point source of 90Y in water as reported by a number of authors. On close inspection TABLE3. l a -Assumed electron emission data for hot-particle calculations. Line emission data pertain to conversion and Auger electrons. Line Emission

Continuous Beta Spectra Nuclide

Em (MeV)

E., (MeV)

Probability (dis-')

Co-60 Sr-90 Y-90 Sr-90N-90 Zr-95 Nb-95 Nb-95m Zr-95/Nb-95 Ru-106 Rh-106 Ru-106tRh-106 Ce-144 Pr-144 Ce-144/Pr-144 Tm-170

0.3179 0.546 2.2792 2.2792 1.1231 0.1597 1.1603 1.1603 0.0394 3.541 3.541 0.3182 2.996 2.996 0.968

0.0958 0.1958 0.9326 0.5642 0.1169 0.0433 0.3909 0.0667 0.0100 1.4151 0.7126 0.0821 1.2086 0.6454 0.3153

0.99925 0.49994 0.49998 0.99992 0.31371 0.68019 0.00032 0.99422 0.5 0.5 1.0 0.49999 0.50001 1.0 0.99854

(E)nm,~ (E)emi~ (MeV dis-') (MeV dis-')

0.0957 0.5642

0.0663

0.0009"

0.7126 0.6454 0.3148

0.003gb 0.0145'

"Assumed line spectrum (energylkev, probabilityldisintegration): 14, 0.00061; 15.8, 0.00021; 216.5, 0.00331; 232.5, 0.00067; 235.9, 0.00013. bAssumed line spectrum (energykev, probability/disintegration): 26.8, 0.00540; 34, 0.00485; 38, 0.01210; 91.7, 0.02755; 126.7, 0.00475. 'Assumed line spectrum (energylkev, probabilityldisintegration): 8.92, 0.065; 10, 0.049; 22.9, 0.0453; 74.5, 0.064; 75.8, 0.059; 82.1, 0.0303; 84, 0.0081.

3.1 MODELS AND CALCULATIONS

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25

TABLE3.lb-Assumed photon (gamma or x-ray) emission data for hot-particle calculations. Nuclide

Energy (keV)

hobability (dis-')

one can see that the results from recent Monte Carlo calculations (ETRAN, ACCEPT and EGS), which include the effects of energyloss straggling, generally show smaller absorbed doses close to the source and larger absorbed doses a t the greater distances when compared with the results of Cross (1967a; 196%) and Berger (1971) done in the CSDA.g Loevinger's empirical result is also included for comparison. In application of the electron point kernels to the more complicated geometry of hot-particle calculations, the assumption of simple density scaling of the distances through relevant material, as used in VARSKIN, was retained.

3.1.5.2 Photons. This calculation uses a set of photon absorbeddose build-up factors for a point-isotropic source in water obtained from ETRAN Monte Carlo calculations for energies from 2 MeV down 91t should be noted that Cross et al. (1992b) altered his results from ACCEPT calculations in order to force the absorbed dose at r = 0 to be equal to that given by the unrestricted collision stopping power. This artifact forces his results at small radius to mimic those from the earlier CSDA calculations, but is inconsistent with the full treatment of the transport of primary and secondary electrons included in the ACCEPT calculations.

26

/

3. DOSIMETRY OF HOT PARTICLES

1 ETRAN

-------

ACCEPT Berger (1 971) Cross (1 967) Loevinger (1 956)

Fig. 3.1. Scaled form of the distribution of absorbed dose in an infinite water medium a s a function of the distance ( r ) from a 9 point-isotropic emitter. The results fiom various authors are plotted such that the areas under the curves are unity. Distributions based on Monte Carlo calculations are indicated by the name of the code: ETRAN from Seltzer (1991), EGS4 from Simpkin and Mackie (1990), and ACCEPT from Cross et al. (1992b).

to about 5 keV and for distances out to eight mean-free paths; buildup factors for greater distances were obtained by extrapolation. Assumed photon emission data used for the calculations are given in Table 3.lb. Distances are calculated in terms of the mean-free paths in all relevant materials before applying the dose build-up factors in water. The calculation of the absorbed dose from photons takes into account the transition to conditions of electron equilibrium,I0 based on transition curves obtained also h m the Monte Carlo calculations for the point-isotropic source in water. Simple density scaling of the distances through the various materials is used in conjunction with the transition curve. l0This transition is due to the net migration away from the point source of the energy transferred to secondary electrons and eventually deposited in the medium. This occurs over a distance associated with the secondarg electron range, beyond which the assumption of electron equilibrium applies for the energies considered here.

3.1 MODELS AND CALCULATIONS

3.1.6

1

27

Comparisons for Pertinent Hot-Particle Geometries

Monte Carlo calculations were done to provide results for direct comparison with the point-kernel-integration calculations for threedimensional hot particles. The test cases included Y3rPOY in "fueln particles (assumed to be comprised of UOz,with density 11g cm-9 and the beta particles from 60Coin hot particles of cobalt-rich wearresistant alloy ("Stellite@"with an assumed composition of 1.1percent carbon, 1.5 percent silicon, 30 percent chromium, 1percent iron, 59.4 percent cobalt, 1 percent nickel, 1.5 percent molybdenum, and 4.5 percent tungsten, by weight, and density 8 g ~ m - ~Hot ) . particles were assumed to be spheres, uniformly emitting throughout their volume, with diameters of 10, 100 and 1,000 p.m. The spheres were assumed to be imbedded in an infinite water medium. This assumed spherical symmetry greatly simplifies the Monte Carlo calculations, reducing the problem to that of calculating the absorbed dose in water as a function of a single spatial variable, the radial distance from the particle surface. The Monte Carlo calculations were done with the ACCEPT code (Version 3), based on a sample of one million histories of emitted beta-particles, using the same beta-particle emission data and spectra as used for the NISTKIN calculations. The VARSKIN MOD2 code was modified slightly to treat also the imbedded sphere, retaining emission data and spectra incorporated into that code. Results are compared in Figure 3.2. The inclusion of energy-loss straggling in the point-kernel calculations improves the agreement with the Monte Carlo results, most obviously in the tail of the absorbed-dose distribution. As the size of the source volume increases, the increasing discrepancies indicate the shortcomings of the assumption inherent in both of these point-kernel approaches of the hot particle being simply high-density water. Absorbed-dose rates due to beta particles emitted in spherical and cylindrical hot particles of the same diameters are compared in Table 3.2, using results from NISTKIN calculations. The cylinder heights have been chosen to be one-tenth of the diameter in an effort to approximate the flatter shape of typical hot particles. The dose rates are for points a t the depth in water along the axis of the cylinder or a t the corresponding radial distance from the sphere. Differences are noticeable even for hot particles of small dimension, and can be quite large (e.g.,an order of magnitude) for the large particles. Based both on the perception of its more realistic shape and on the finding of significantly higher dose rates, the cylinder with a diarneter-toheight ratio of 10:1, directly on the skin (water), was judged suitable for the remainder of the calculations to give reasonably conservative estimates.

28

1

3. DOSIMETRY OF HOT PARTICLES 60

Co in stellite spheres (13-only)

Monte Carlo

-

-

-

Present WorK

Radial Distance in Water from Sphere Surface, r, crn

'OS~

lgOyUO, spheres

1

lo'

Monte Carlo

---

Present Work

Radial Distance in Water from Sphere Surface, r, cm

Fig. 3.2. Scaled form of the radial distribution of absorbed dose in an infinite water medium from uniformly emitting spheres of diameter 3.0 Fm. The distribution, given as a function of the distance ( r ) from the sphere surface, is plotted such that the areas under the curves are equal to the average energy (MeV) deposited by the beta particles per disintegration. The assumed composition of the "Stellite@"hot particle is given in the text.

3.1 MODELS AND CALCULATIONS

1

29

TABLE3.2 -Dose rate in water from uniformly emitting sources, assumed to be either spheres or cylinders. The dose rate (given in units of Gy h-I MBq-I) is for a point at a distance from the source surface and for cylinclers along the source axis. Beta Particles from 60Coin "Stellite@" (density 8 g cm-9

Distance (pn)

10 Fm Diameter

Sphere

Cylinder"

100 Fm Diameter

1,000 Fm Diameter

Sphere

Cylinder"

Sphere

Cylinder"

569 339 176 6.80 0.295

3,609 2,009 96 1 35.8 1.96

2.25 1.69 1.13 0.0876 0.0042

19.5 15.3 10.8 1.08 0.0619

Beta Particles from @"SrBOy in "Fuel"(density 11 g cm-9

Distance (km)

10 ~ r n Diameter

Sphere

Cylinder"

100 ~m Diameter

Sphere

Cylindef

1,000 p,m Diameter

Sphere

Cylinder"

"Height of the cylinder is one-tenth of its diameter. The absorbed-dose rates calculated by VARSKIN MOD2 and by NISTKIN are compared for cylindrical hot particles of various diameters in Table 3.3 for the beta particles from 60Coin "Stellite@,"and in Table 3.4 for 90SrPOYin "fuel."" The agreement in these examples is generally within about 15percent, and often better. The differences likely reflect the use of different numerical procedures as well as different point kernels. "The composition is actually irrelevant in both beta-particle calculations, which depend only on the assumed density.

/

30

3.

DOSIMETRY OF HOT PARTICLES

TABLE3.3-Comparison of beta-particle dose rates in water calculated with VARSKIN and with NZSTKIN, for uniformly emitting cylindrical sources directly on the skin." Dose Rates Averaged over 1cm2 Cylinder Dimensions (height x diameter) Depth (pm)

1 x 10 pm

VARSKIN

NISTKIN

10 x 100 pm VARSKIN

NISTKIN

100 x 1,000 pm VARSKIN

NISTKIN

Dose Rates Averaged over 1.1mm8 Cylinder Dimensions (height x diameter) Depth (pm)

1 x 10 pm

VARSKIN

NISTKIN

10 x 100 pm VARSKIN

NISTKIN

100 x 1,000 pm VARSKIN

NISTKIN

"Resultsare given for dose rates, in units of Gy h-' MBq-', averaged over circular areas of 1cm2and 1.1 mm2 centered on and perpendicular to the source axis. Cylinder dimensions are given as height times diameter. Source: 60Cobetas in "Stellite@"(density 8 g ~ m - ~ ) . Table 3.5 lists calculated absorbed-dose rates for the 60Cogammaray emission from "Stellite@"hot particles. VARSKIN MOD2 gives absorbed dose averaged only over an area of 1 cm2, and applies its results for a point emitter to all hot particles of suitably small dimension. The NISTKIN calculations are much more general, taking into account the effects of size, shape and composition of source and absorbers on the self-absorption and attenuation of the photons, but are also subject to limiting assumptions on whlch they are based.

3.1 MODELS AND CALCULATIONS

1

31

TABLE3.4-Comparison of beta-particle dose rates in water calculated with VARSKIN and with NZSTKIN, for uniformly emitting cylindrical sources directly on the skin." Dose Rates Averaged over 1 cma Cylinder Dimensions (height x diameters) Depth (pm)

1x

VARSKIN

10 +m

10 x 100 +m

100 x 1,000 pm

NISTKIN

VARSKIN

NISTKIN

VARSKIN

3.23 2.31 2.06 1.79 1.50 1.03 0.723 0.347 0.108 0.00093

2.92 2.17 1.95 1.71 1.45 1.01 0.714 0.351 0.112 0.00032

2.70 2.04 1.83 1.61 1.37 0.962 0.684 0.339 0.106 0.00087

1.19 1.03 0.970 0.895 0.797 0.619 0.484 0.276 0.0859 0.00011

NISTKIN

Dose Rates Averaged over 1.1 mm2 Cylinder Dimensions (height x diameters) Depth (pm)

1

X

VARSKIN

10 +m NISTKIN

10 x 100 +m VARSKIN

NISTKIN

100 X 1,000 pm VARSKIN

NISTKIN

"esults are given for dose rates (in units of Gy h-I MBq-I) averaged over circular areas of 1cm2 and 1.1 rnm2 centered on and perpendicular to the source axis. Cylinder dimensions are given as height times diameter. Source: gOSrPOYin ''fuel" (density 11 g ~ m - ~ ) .

1

32

3. DOSIMETRY OF HOT PARTICLES

TABLE3.5-Comparison of gamma-ray dose rates in water calculated with VARSKIN and with NZSTKIN, for uniformly emitting cylindrical sources directly on the skin." Dose Rates Averaged over 1 c m 2 Depth (~m)

VARSKIN (all)b

NISTKIN 1 x 10 ~ r n

10 x 100 km

100 X 1,000 ~ r n

Dose Rates Averaged over 1.1 mm2 Depth (Fm)

16 50 70 100 150 300 500 2,000 20,000

NISTKIN VARSKIN

1 x 10 p,m

-

0.529 0.483 0.462 0.435 0.396 0.308 0.230 0.0613 8.28 X lo-'

-

-

10 x 100 p,m

0.845 0.662 0.597 0.535 0.460 0.335 0.242 0.0619 8.28 X

100 x 1,000 Frn

1.80 1.31 1.15 0.958 0.759 0.466 0.302 0.0646 7.96 x lo-'

"Results are given for dose rates (in units of Gy h-I MBq-') averaged over circular areas of 1 cm2 and 1.1 mm2 centered on and perpendicular to the source axis. Cylinder dimensions are given a s height times diameter. Source: BOCogamma rays in "Stellite@"(density 8 g c m - 9 bVARSKINcalculates only the point-source gamma dose and will apply the result only to sources that are smaller than 1,000pm in their largest dimension.

The differences in the results from the two calculations of gamma absorbed-dose rates appear to be due mainly to the use of different transition curves to describe the approach to electron equilibrium. The NISTKIN point kernels are more accurate than those used in VARSKIN, but the application of any such point kernels to the

3.2 HOT-PARTICLE MEASUREMENTS

/

33

multi-material geometries of interest here require some relaxation of desired accuracy in the final result. Moreover, in practice, there are significant uncertainties associated with source specification (shape, composition, radionuclide mix),irradiation geometry (sourceorientation, proximity to skin, shielding by clothing), and duration of exposure that affect calculations of the absorbed dose from hot particles, uncertainties that probably overshadow the typically 10to 20 percent improvements that might be realized by using the NISTKIN methods. In view of these considerations, continued use of VARSKIN (which is a self-contained and fairly robust system) would seem adequate for routine skin dose estimates. Consideration might be given to incorporating the improvements outlined in this Report in a future version of VARSKIN or some similar code. I n order to provide dose information for consideration in the remainder of this Report, systematic calculations with NISTKIN were made for the radionuclides listed in Table 3.1, assuming hot particles to be cylinders with a diameter-to-height ratio of 10:1, and considering diameters of 10, 30, 100, 300, 1,000 and 3,000 km.12 Cobalt-60 was assumed to be emitted from "Stellite@" (density 8 g cm-9, the others from "fuel" (density 11g cm-9, with the addition of 95ZrPNb also from cladding material ("zircaloy," assumed composition of 0.125 percent oxygen, 0.1 percent chromium, 0.135 percent iron, 0.055 percent nickel, 98.135 percent zirconium, and 1.45 percent tin, by weight, and density 6.6 g cm-9. The cylinders were assumed to be in contact with the tissue phantom (water) and surrounded on the other surfaces by either air13 (on-skin scenario) or water (imbedded-in-tissue scenario). A nominal specific activity of 370 GBq g-I (10 Ci g-l) was assumed for each source.

3.2 Hot-Particle Measurements

The measurement of the absorbed dose to tissue from hot particles mainly involves refinements to established dosimetry techniques t h a t surmount t h e difficulties associated with t h e large dose gradients near these sources. Unlike most circumstances where 12Thecylindrical shape and the diameter to height ratio was selected because this geometry is a more reasonable approximation of actual hot particles than simple spherical geometry but is still a reasonably tradable geometry for which to make calculations. The diameters encompass the range of sizes for hot particles. 13Note that the underlying approach in these calculations does not account for possible airlwater backscattering effects, which, however, are partially mitigated by the assumption of a dense three-dimensional source region.

34

1

3. DOSIMETRY OF HOT PARTICLES

measurements can be made a t a distance from the source and thereby avoid having large dose gradients within the sensitive volume of the instrument, hot-particle exposures usually involve direct contact with the source. Another complication with hot-particle measurements is the current NRC requirement that the dose be averaged ) regulatory over a specific area of skin (1cm2a t a depth of 70 ~ mfor purposes. The following sections include descriptions of some successful measurement techniques that have been applied in laboratory and field situations to determine doses under these d i f f i d t circumstances. These techniques generally treat the hot-particle geometry as a point source on (or near) a flat tissue-air boundary.

3.2.1

Laboratory Measurements

The laboratory measurements include techniques that involve complex instrumentation or calculations not easily performed in the field. Although used primarily for research and standardization, the laboratory techniques are applied to the evaluation of exposure to hot particles when analysis beyond the initial field assessment is required. 3.2.1.1 Radiochromic Dye Films. Of the laboratory measurement methods, radiochromic dye films (Saylor et ad., 1988), show the most promise for becoming a standard technique for evaluating t h e absorbed dose from hot particles. Recent efforts a t NIST have resulted in a reliable a n d versatile technique for determining absorbed-dose hstributions (McWilliams et al., 1992; Soares and McLaughlin, 1993;Soares et al., 1991). Similar work has been carried out elsewhere (Darley et al., 1991). Once the distributions are known, hot-particle doses can be averaged over various areas and tissue depths. The radiochromic dye films are manufactured in sheets that consist of a few layers of dye in micrometer thicknesses contained in tissue equivalent materials that provide a thin (<1 pm) protective cover and a thick (about 100 pm) backing material. The optical density of the dye changes in proportion to the delivered dose over a 10 to 1,000 Gy dose range. When used to evaluate the dose gradients around hot particles, a scanning laser densitometer is able to resolve areas of some tens of micrometer in dimension and able to measure the optical density across the irradiated film surface in increments of a few micrometer. For each tissue depth evaluated, a series of dye films is exposed, with each film being irradiated for a different time period in order

3.2 HOT-PARTICLE MEASUREMENTS

1

35

to define the dose profile a t various radial distances off-center.14As with all of the measurement techniques, a desired measurement depth is achieved by introducing appropriate absorbers between the hot particle and the films. After irradiation, the films are scanned with the laser densitometer and the optical density a t each rectangular coordinate is stored in computer data files. Mathematical algorithms are used to convert the density information in rectangular coordinates to absorbed-dose rate versus radial distance from the centerline of the particle. The absorbed-dose rate versus radial distance is fitted with polynomial equations that can be used to calculate average absorbed-dose rate over any area of interest. By performing the analysis a t various absorber thicknesses, the dose-rate profile versus tissue depth can be established. Sources of uncertainty associated with radiochromic dye measurements include systematic and random variations in the data and calibrations, uncertainty introduced by the mathematical fitting processes, variations in the dye thickness, and a slight energy dependance of the response (Soares and McLaughlin, 1993).Inter-comparisons also indicate that using different scanning systems may contribute to the uncertainty (Darley et al., 1991; Kaurin et al., 1997a). 3.2.1.2 Extrapolation Chamber. The extrapolation chamber was one of the first instruments applied to hot-particle dose measurements (Forbes, 1969). Conceived by Failla (1939), the extrapolation chamber is considered a reference class instrument for determining the absorbed-dose rate to an infinitesimal mass. Ionization current is measured in a n incrementally decreasing air mass and extrapolated to a hypothetical air mass of zero. Most extrapolation chamber designs accomplish this by creating a cylindrical active volume between a thin entrance foil and a moveable, thick collecting electrode.15 Under uniform irradiation conditions, there is a linear relationship between the ionization current and the air volume, the slope of which is converted to an absorbed-dose rate through well defined methods (NCRP, 1991). When measuring the dose rate near hot particles, additional uncertainties arise because the measurement data exhibit a pronounced curvature due to the gradient in t h e absorbed-dose rate near the source. If not accounted for, this curvature can impact the results, especially when the dose rate from highenergy beta-emitting radionuclides (gOSrPOY) is being averaged over a n area <0.8 cm2 (Darley et al., 1991). In these situations, the 14Aseries of dye films is required to assess doses in the useful range of 10 to 1,000Gy. I5The thickness of the entrance foil determines the minimum depth at which dose can be measured with an extrapolation chamber.

36

/

3. DOSIMETRY OF HOT PARTICLES

curvature can be accounted for by using polynomial equations (Darley et al., 1991). Normally, when averaging over a 1cm2 area, the curvature can be minimized by using the smallest possible plate separations (Kaurin et al., 1997a; McWilliams et al., 1992). While not as versatile as the radiochromic dye films, different size collecting electrodes can be installed in an extrapolation chamber to average the dose rate over different areas. The application of extrapolation chambers is also restricted to sources that produce a sufficiently large ionization current in the active volume. For instance, when measuring over a 1 cm2area, a dose rate of at least 3 pGy s-' is normally required for a reliable measurement.

3.2.1.3 Exoelectron Dosimeters. Exoelectron dosimeters with extremely thin sensitive volumes can be useful in hot-particle dose evaluations (Merwin et al., 1989).Exoelectron dosimeters have beryllium oxide crystals, which trap excited electrons upon exposure to ionizing radiation (in a manner similar to thermoluminescent dosimeters). When the beryllium oxide crystals are subsequently heated, the trapped electrons emitted from a thin surface layer (<0.1 mm) are detected with standard gas-flow detectors (Merwin et al., 1989). Calibrations performed in known radiation fields are used to obtain the absorbed dose to the 0.23 cm2sensitive area of the detector. The average dose to other sized areas is determined by means of either geometry correction factors or techniques of calculation such as VARSKIN MOD2 (Kaurin et al., 1997a). 3.2.1.4 Thermoluminescent Dosimeters. Properly configured, thermolurninescent dosimeters can be used to evaluate hot-particle doses. A commercial extremity dosimeter that uses a thin layer of lithium fluoride powder to measure dose a t a depth of approximately 7 mg ~ m has - ~been applied to hot-particle skin dose assessments (Kaurin et al., 1997a; McWilliams et al., 1992). Like the exoelectron dosimeter, this dosimeter measures average dose over a fixed area (0.29 cm2) and, therefore, requires the application of a geometry correction factor in order to estimate the average dose to other areas. An additional correction factor to account for the finite phosphor thickness is needed for the accurate determination of dose from lowenergy beta-emitting radionuclides (Kaurin et at., 1997a).I6 3.2.2

Field Measurements

The field measurement techniques used a t nuclear facilities to evaluate hot-particle doses tend to be rapid, simple, reasonably I6Forexample the correction factor is approximately 16 percent for 60Co.

3.2 HOT-PARTICLE MEASUREMENTS

1

37

accurate methods that are acceptable to regulatory agencies. Only when a more thorough dose assessment is required are the more complex techniques described in Section 3.2.1 employed. In order to comply with current regulations, hot-particle dose is normally determined as the average over a 1cm2area a t a skin depth of 70 pm. 3.2.2.1 Survey Instrument Dose Assessments. Survey instruments are usually used for detection of hot particles in the field. When the instrument response exceeds a predetermined level, attempts are made to collect the particle in order to analyze it sufficiently to calculate a dose to assign to the exposed individual (Flood, 1988). If collection attempts fail, the survey instrument response is the only information available for the dose assessment. Recent testing indicates that the beta response of commonly used ion chamber survey instruments can be easily and accurately correlated to the dose a t 70 pm depth in tissue averaged over 1cm2 for hot particles with beta energies (E,,,) ranging from 0.32 to 1 MeV (Kaurin et al., 1997a; McWilliams et al., 1992). In some instances, a survey instrument measurement has advantages over the techniques of calculation described below because it is does not rely on assumptions about things such as the quantity of non-gamma-emitting radionuclides present. In addition to dose assessment, survey instruments are used with absorbers to estimate the beta energy of the particle. In situations where a single gamma radionuclide is present, ion chamber survey instruments can be used to quantify the activity present (Lantz and Steward, 1988).

Calculation ofDose Based on Particle Characteristics. Dose determination by calculation (after measurements are completed) requires, as a minimum, knowledge of the activity and isotopic composition of the particle and the time of exposure. For more refined analysis, additional information can be included such as the particle dimensions, the distance between the particle and the skin surface, and the thickness of any intervening material (e.g., clothing). Gamma-emitting radionuclides in hot particles are determined by gamma spectroscopy analysis and the presence of non-gammaemitting radionuclides is usually determined by applying known isotopic ratios." The particle dimensions can be determined with laboratory instruments such as an electron microscope (Menvin et al., 1989). Once the information about the hot particle is obtained, dose can be calculated. Due to its general acceptance by the NRC and because

3.2.2.2

17These isotopic ratios may be based on representative radiochemical analyses of facility contamination samples or on the age of the fuel.

38

1

3. DOSIMETRY OF HOT PARTICLES

it is simple to use, the VARSKIN code described in Section 3.1.4 is the most common method for hot-particle skin dose calculations in the United States nuclear power industry. In addition to the limitations described in Section 3.1.4, the methods of calculation have additional uncertainties related to determining the quantity of non-gamma-emitting radionuclides present and the use of simple geometric shapes (sphere, disc, cylinder, etc.) to represent the actual particle shape.

4. Biology and Radiation

Response of Skin Including the Ear The skin provides an external covering to the body surface, including the external ear. One major function of the skin is to provide a physical barrier to protect the body against the hazards of the environment, controlling fluid or electrolyte loss in climates that vary considerably from cold to hot and from dry to humid. Opportunistic infections may result when this barrier is broken and healing may be delayed. The skin also has an important role in thermoregulation. Cooling can be achieved by dissipating heat via the surface blood vessels or by the evaporation of fluid secreted onto the surface of the skin by specialized structures. A layer of subcutaneous fat acts as an insulator for retention of heat. The skin has important sensory functions, it senses the external environment and mediates physical and chemical communications. The area of the skin is 1.8 m2for the standard 70 kg man (ICRP, 1975).There are major variations in the surface contours of the skin with body site such that creases and folds and the tight adherence of clothing may make it more likely to be exposed, for a period of time, from a hot particle. This and variations in skin thickness with site may influence the skin's response to hot-particle exposure, but as yet no definitive information exists.

4.1. Structure and Function of Skin and Ear

The skin is composed of a series of layers, which can be broadly grouped into two structures. The outermost layers are' referred to collectively as the epidermis, which is derived from the embryonic ectoderm. The deeper layer, the dermis, is derived from the embryonic mesenchyme. The dermis is infiltrated with specialized structures formed by an infolding of the epidermis, which are collectively

40

1

BIOLOGY AND RADLATION RESPONSE OF SKIN

4.

referred to as the skin appendages (Figure 4.1). A detailed description of the structure and functions of the skin is found in ICRP Publication 59 (ICRP, 1991b) and thus only a brief review is given here as it relates to the risk from hot-particle exposure. Factors that might relate to more generalized radiation exposure of the skin are not reviewed. 4.1.1

The Epihrmis

In human skin, the epidermis is divided into a number of clearly defined layers. The outermost layer, t h e s t r a t u m corneum, is '

-

Fig. 4.1. Photomicrograph of human skin showing its organization into distinct layers: The epidermis (1) with the distinct undulations of the basal layer "rete pegs." The papillary dermis (2) with loosely arranged collagen fibers and a well developed papillary vascular network, and the much thicker reticular dermis (3)with its thick structural collagen bundles. The bulbs of hair follicles impinge on the subcutaneous fatty layer (4) (ICRP,1991b).

4.1. STRUCTURE AND FUNCTION OF SKIN AND EAR

1

41

composed of flattened dead cells, which provide a waterproof covering. In most body sites, the stratum corneum consists of 15 to 20 layers of dead cells (Potten et al., 1983) and comprises about 25 percent of the total epidermal thickness (Holbrook and Odland, 1974). In areas such as the palms of the hand and soles of the feet, the stratum corneum is considerably thicker. Beneath the stratum corneum is a layer of transitional cells, the stratum granulosum, lying between the nonviable and the deeper viable cell layers of the epidermis. Its cells, which are arranged in four to five layers, are characterized by the presence of dense cytoplasmic granules. Cells of this region become progressively flattened, they lose their cytoplasmic organelles and eventually the cell nucleus degenerates as they come closer to the stratum corneum. The viable cell layers of the epidermis are composed mainly of the stratum spinosum, which overlies a single layer of cells and is frequently referred to as the basal layer. The cells of the stratum spinosum are rich in cell-to-cell contacts, desmosomes, which bind the different cell layers firmly together. Cells in this layer are predominantly postmitotic, although cells adjacent to the basal layer are seen in division or have been found to incorporate a specific precursor of DNA (3H-thymidine).Many of the studies of cell labeling have been conducted in the pig since the organization of the thick epidermis in this species has many similarities with that of humans (Montagna and Yun, 1964; Weinstein, 1965). The skin of humans and pigs differ in many important respects from that of rodents, which have a much thinner epidermis. In a study ofhuman epidermis (Penneys et al., 1970), it was found that 32 percent of labeled nuclei were in a suprabasal position. This was higher than in the pig, where approximately 18 percent of labeled cells were in the first suprabasal layer and two percent in higher layers (Morris and Hopewell, 1985; 1987), but similar to the guinea pig where 33 percent of labeled cells occurred suprabasally (Yamaguchi and Tabachnick, 1972). The precise kinetic relationship between the proliferating cells of the basal and suprabasal layers is not fully understood. The basal layer, which is separated from the dermis by a basement membrane, is considerably undulated and in many regions distinct ridges can be seen, which have been referred t o as "rete pegs." The thickness and structure of these ridges are said to be comparable in man and pig. In a study in the pig, approximately 75 "rete pegs" intersected the projection of a line 1 cm in length a t the dermal/ epidermal interface (Archambeau and Bennett, 1984). Estimates of the cell-cycle time for the basal cells of the normal epidermis have come from a number of sources. On the basis of the time elapsed between the first and second peak in a fractional labeled mitosis

42

1

4.

BIOLOGY AND RADIATION RESPONSE OF SKIN

(FLM) curve, obtained from,in vitro studies, a value of 59 h was proposed (Chopra and Flaxman, 1974). Values of between 50 and 137 h were reported using flow cytometry (Bauer and de Grood, 1975; Bauer et al., 1980). However, because of the difficulties of applying the different experimental cell kinetic techniques to man, many of these estimates are thought to be less reliable than those obtained from studies in laboratory animals. Thus, in view of the general morphological similarities between the epidermis of man and that of the pig, and since subsequent use will be made of results from pig skin to estimate the deterministic risk from hot particles, the cell proliferation kinetic data for this species are given below. The basal cell density in four to seven-month-old pigs of the Large White strain, is of the order of 140 to 150 cells mm-I of basement membrane, comparable to that of adult humans (Potten, 1975; Schell et al., 1977). The results of an extensive study using the FLM technique (Morris and Hopewell, 1987)have provided times and standard errors (SE) for the length of the DNA synthesis phase (Ts),the total duration of mitosis (TM)and that of the gap (TG)between these two phases of the cell cycle. These values are 11.6 +- 2.9 hand 8.5 t 4.1 h for Ts and TG + TM,respectively. These values were not significantly different from those obtained from the FLM curve of Weinstein and Frost (1969) for human epidermis, as is also the case for the total transit time in the pig, which is 30 d (Weinstein, 1965). These results in the pig were also comparable with those obtained using other cell kinetic methods in this species (Archambeau and Bennett, 1984). Two methods of determining the cell production rate (Morris and Hopewell, 1987; Morris et al., 1987) produced values of between 5.8 and 8.1 cells per 1,000 basal cells per hour, comparable with the range for man, as were the calculated values of the turnover time (TT)of 118to 173 h (Epstein and Maibach, 1965).Thus the cell kinetic parameters of the pig and man would appear to be comparable. There was no marked evidence for any distinct diurnal variation in the kinetic parameters in the pig (Morris et al., 1987), nor have there been for man although there have been conflicting reports in the literature (Camplejohn et al., 1984; Gelfant et al., 1982). There are considerable variations in the thickness of epidermis in h u m a n s with respect to body site a n d this could influence t h e response of the skin on different sites to hot-particle exposures, particularly for low-energy beta-particle emissions. Measured values for the thickness of the epidermis is in the range of 20 to 1,400 pm (Konishi and Yoshizawa, 1985; Whitton and Everall, 1973). The average thickness for the head, trunk, upper arm, and leg was 40 Fm. A mean thickness of 400 p,m was obtained for the palm of the hand and the sole of the foot, the thickest sites on the body. The remaining

4.1. STRUCTURE AND FUNCTION OF SKIN AND EAR

1

43

body sites have an average thickness of approximately 80 km (Table 4.1). However, the epidermis also includes the hair follicles which extend past the normal depth of the basal cells layer deep into the dermal layer. The basal layer, continuous with the rest of the epidermis, surrounds each hair follicle and extends down into the dermis to a reported depth of from 1,500 to 5,000 Frn (Healy, 1971;Krebs, 1967).

TABLE4.1-Variations in epidermal thicknesses for adults, aged 26 to 30 y.a Epidermal Thickness (km) Skin Site

Thigh: medial lateral posterior Leg: medial lateral posterior Arm: medial lateral Forearm: back front Finger Abdomen, anterior Thorax, anterior Axilla Back Pubis Sole Face Forehead Cheek Neck Eyelid Palm

Females

Males

50-71 39-78 37-91

18-55 45-63 35-60

38-55 55-78 47-80

35-113 39-56 39-59

37-52 41-71

34-43 40-54

49-65 34-65 420-673 34-49 39-62 43-44 49-92 42-48 940-1,377 52

53-55 39-61 384-539 34-46 25-47 51 45-61 43 850-1,094

-b -b

61-102

-b

85-123 46-122

"FromICRP Publication 23 (ICRP, 1975). bNocorresponding values for females provided. 'Gender not specified.

-b 30-50" 500-650"

44 4.1.2

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

The Dermis

The layer of tissue immediately below the epidermis, the dermis, is composed largely of a complex network of collagen fibers, which make up approximately 75 percent of the tissue in terms of dry weight. The main cellular components include fibroblasts, vascular and lymphatic endothelial cells, smooth muscle cells (forming part of the walls of larger blood vessels), and nerve cell processes. Structurally the dermis can be separated into two distinct layers; the superficial papillary dermis, which is comparable in thickness to the epidermis, and the deeper and considerably thicker reticular dermis. These two layers of the dermis vary considerably in both their structure and function. The papillary dermis contains loosely arranged delicate collagen fibers interwoven with elastic fibers. The region is metabolically active and is very well vascularized. Its primary function is thermoregulation, since it is estimated that approximately 90 percent of the total blood flow is non-nutritive (Goetz, 1949).The maintenance of the metabolic requirements of the basal cell layer is an important additional function. The reticular dermis is the primary structural and mechanical component of the skin. It is densely fibrous, but with fewer fibroblasts, blood vessels, and ground substance than the papillary dermis. The vascular density in the papillary dermis is 12 to 14times higher than the deeper layer (Youngand Hopewell, 1980). Elastic fibers are also found throughout the reticular dermis. The thickness of the dermis in man varies from approximately 1to 3 mm (Freedman et al., 1968; Ordman and Gillman, 1966; Sejrsen, 1967). The skin of the back is one of the thickest sites, i.e., 2.5 mm, and i n general, sites on the t r u n k a r e thicker t h a n on t h e limbs (Table 4.2).Although no detailed measurements exist, the skin lining the external auditory meatus is very thin and adheres closely to both the underlying cartilaginous and osseous sections of the meatus. It also covers the outer layer of the tympanic membrane (the ear drum). A significant reduction in skin thickness has been reported (Tan et al., 1982) with age in adults of both sexes. In the majority of skin sites, the ratio of the dermal to epidermal thickness is in the range 10:l to 13:l (Rose et al., 1977).

4.1.3

The Skin Appendages

None of the skin appendages, which include hair follicles, sebaceous glands, eccrine (sweat) glands, apocrine glands and, in the case of the ear, the numerous ceruminous glands (which secrete the

4.1.

STRUCTURE AND FUNCTION OF SKIN AND EAR

1

45

TABLE4.2 -Variation in skin thickness with body site as assessed by pulsed ultrasound." Skin Site

Mean Thickness

+ 1 SDb (mm)

Forearm: flexor extensor Upper arm: flexor extensor Leg: medial lateral Thigh: medial lateral Chest Back

Abdomen "From Tan et al. (1982). bMean of measurements made on a number of individuals. ear-wax, and are akin to sweat glands in the sense that their ducts open directly on the skin surface) would appear to have any major role in the response of the skin to radiation. This is particularly true of exposure from hot particles since such a small area of skin is irradiated. The structure of these appendages was discussed in ICRP Publication 59 (ICRP, 1991b) and will not be discussed here. 4.1.4

The Ear-Anatomical Structure and Function

The organ of hearing can be divided into three distinct parts, the external ear, the middle ear or tympanum, and the internal ear or labyrinth. The external ear consists of an expanded portion, the pinna, which collects vibrations of the air, which are conducted via the auditory canal to the tympanum. The tympanic membrane acts as the interface with the middle ear and is covered, along with the other components of the external ear, by a continuous layer of skin. The pinna's irregular concave shape, the concha, is produced by the folds of its fibro-cartilaginous elements with associated ligaments and muscles. The auditory canal extends in an "S"shape from the base of the concha to the tympanic membrane, a length of approximately 24 mm. It forms a n oval canal with the greatest diameter in the vertical direction a t the base of the concha but in the horizontal

46

4.

BIOLOGY AND RADIATION RESPONSE OF SKIN

direction a t the tympanum end. The tympanic membrane is positioned obliquely such that the floor of the auditory canal is longer than the roof (Figure 4.2). The support for the auditory canal is approximately one-third cartilaginous and two-thirds osseous. At the point of junction of the osseous and cartilaginous portions, the canal has a sharp bend. This and the presence of a few short stiff hairs a t the entrance to the external orifice serve to prevent the entry of objects such a s insects and dust particles. The secretions of the ceruminous glands also serve to catch any small particles that may find their way into the auditory canal and prevent these from reaching the tympanic membrane where their presence could cause irritation. In any event, just in front of the membrane is a well marked depression, situated on the floor of the canal, which is bounded by a prominent ridge. In the uncommon event of hot particles penetrating deeply into the canal they would become lodged in this depression rather than on the tympanic membrane.

Pinna T ,ympanc i

membrane Tensor tympant

Exter~ auditc canal

i?ii glCarillage of

Osseous of aud~torycanal

7

the external auditory canal ,

-

tube

Fig. 4.2. Sectional diagrammatic representation of the ear, which shows the external ear consisting of the pinna and the external auditory canal. The tympanic membrane acts as an interface between the external ear and the middle ear. The middle ear contains the malleus, incus and stapes bone which connect to the inner ear. Of the inner ear (labyrinth),only the superior semi-circular canal, one of three such canals responsible for balance, is illustrated. The others are embedded in bone.

4.2 RADIATION RESPONSE O F SKIN

47

The middle ear is an irregularly shaped cavity in bony tissue. It is filled with air and is connected to the naso-pharynx by the eustachian tube. The cavity between the tympanic membrane and the labyrinth or inner ear is transversed by a moveable chain of three bones; malleus, incus and stapes. The cavity has a maximum diameter of approximately 15 mm. The mucosal lining of the middle ear cavity also covers the tympanic membrane making it a tri-layered structure with a middle fibrous layer sandwiched between the mucosal and cutaneous surfaces. The inner ear is the essential part of the organ for hearing, responsible for the ultimate distribution to the auditory nerve. The whole structure is imbedded in bone. It is in two parts, the 2.5 mm diameter, semi-circular canals, which are fluid filled and responsible for balance, and the complex cochlear structure, which interprets the air vibrations transmitted from the external ear. Its structure resembles a common snail-shell and in this conical form it measures 5 mm from base to apex, the base being approximately 9 mm in diameter.

4.2 Radiation Response of Skin

The skin has been found to exhibit both stochastic and deterministic responses to ionizing radiation. Stochastic changes are by definition probabilistic and t h e endpoint usually referred to i s the induction of cancer. The skin exhibits a broad spectrum of deterministic responses, which are predictable based on knowledge of the physical exposure conditions and the area of skin irradiated. 4.2.1

Deterministic Effects

There have been numerous experimental and clinical investigations into the effects of ionizing radiation on the skin. In the majority of these studies, x or gamma rays were used and the investigators were primarily interested in resolving problems such a s dosefractionation effects and volume-related changes as they relate to radiation treatment for cancer. Although these studies are not of direct relevance to radiological protection, they do provide information relating to the mechanisms of radiation-induced damage to the skin, when significant areas of the skin are exposed. They also provide a sound biological explanation as to why radiation responses may be modified after exposure to hot particles. In these latter situations, energy deposition is very localized either in terms of skin surface area andlor with depth in the skin.

48

/

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

4.2.1.1 Large-FieldIrradiation -Biological Responses. Following the irradiation of more than about 1cm2of skin surface with single doses of x or gamma rays, several distinct waves of radiation response may be seen, depending on the dose. The pathophysiological mechanisms leading to the development of these changes are now established to various degrees. An early erythematous reaction is well documented in patients receiving therapy, occurring within a few hours of doses of 2 2 Gy, common individual doses used in fractionated radiotherapy treab ments. The response may represent an immediate inflammatory reaction due to the activation of proteolytic enzymes (Jolles and Harrison, 1965). An increase in capillary permeability was found to be dose-related in a rabbit model for doses up to approximately 8 Gy (Jolles, 1972). An epithelial reaction is the most extensively documented and best understood of the different phases of radiation-induced damage to the skin. The target cell population is the basal cells of the epidermis. The associated main erythematous reaction represents a secondary inflammatory response due to the development of epidermal hypoplasia. The severity of clinical response associated with an epithelial reaction depends on the radiation dose. The responses are identified as erythema, dry desquamation, moist desquamation, or secondary ulceration. Secondary ulceration also develops in the case of very high doses where there is a progressive loss of dermal as well as epithelial elements of the skin resulting in slow healing of the moist desquamation. Within a few days of irradiation, a marked fall in the mitotic index of basal cells can be detected. There is a comparable fall in the 3H-thymidinelabeling index of these cells, suggesting that all cellcycle progression has been arrested. The number of degenerate cells were increased but not markedly (Morris and Hopewell, 1988).However, even if cells that are not reproductively viable after irradiation do not die, but merely mature and migrate a t the normal rate, then, in the absence of cell divisions, denudation of the basal layer would still result in a time-course approximately equivalent to the normal total turnover-time of the unirradiated epidermis. Thus, it would appear that it is the natural migration, differentiation, and loss of cells from the basal layer that accounts for most of the declme in the basal cell density with time after irradiation. The magnitude of the observed clinical response depends on the maximum level of cell depletion in the basal layer. The timing of the maximum observable clinical response in man and in dflerent animal models depends on the specific turnovertime of basal cells. For example, in the skin of the flank of the Large

4.2

RADIATION RESPONSE OF SKIN

1

49

White pig, the rate of cell loss from the basal layer was 2.6 + 0.2 percent per day (Morris and Hopewell, 1988); in the Yorkshire pig, it was approximately four percent per day (Archambeau et al., 1979). The programmed rate of cell loss has been shown to be independent of the radiation doses used in the various studies. The first appearance of spotty moist desquamation after sufficiently high doses, a t 33.2 -t 1.1 d in the Large White pig (Hopewell and van den Aardweg, 1988) and 17 to 21 d in the Yorkshire pig (Archambeau et al., 1968) was consistent with their respective rate of cell loss from the basal layer of 2.6 and 4 percent per day. In guinea pigs and mice, cells were lost a t faster rates of 5 to 6 percent per day, and 8.3 percent per day, respectively (Potten et al., 1983). Moist desquamation develops earlier in both these species, than in the pig or human. The peak of the main erythematous reaction in human skin, after a single dose of 12.5 Gy, was slightly longer than 30 d (Field et al., 1976). At doses just below the threshold for moist desquamation only, a graded level of erythema will be seen or a transient phase of dry desquamation over the same time scale. The latter represents an atypical thickening of the stratum corneum. The eventual repopulation of the basal layer following x-ray doses just above or just below the threshold for moist desquamation in the pig is predominantly by the proliferation of surviving clonogenic cells from within the irradiated area. Colonies of cells, originating from surviving clonogenic cells, can be recognized in histological sections as regions of the basal layer with a relatively normal basal cell density (Morris and Hopewell, 1988). Labeling with 3H-thymidine demonstrates that 40 to 50 percent of cells in these regenerating cell colonies are in the DNA synthesis phase of the cell cycle, suggesting a very high proliferation rate. The identification and counting of labeled clusters of cells from whole epithelial preparations of the skin of mice (Al-Barwari and Potten, 1976) or in histological sections in the pig (Archambeau et al., 1979) have been used as a means of assessing the radiosensitivity of clonogenic cells within the basal layer. Using this micro-colony assay, the dose (Do)required to reduce the number of clonogenic cells to 37 percent of their former value was established. The Do value was in the range of 1 to 3.5 Gy. Assessment of the increase in the number of labeled cells per cluster, as a function of time after irradiation, suggests a turnover time of approximately 25 h for the regenerating clonogenic cells of the skin of mice (Al-Barwari and Potten, 1976), as compared with 16 to 25 h for the pig (Archambeau et al., 1979; Morris and Hopewell, 1988) and 24 to 26 h for man (Dutreix et al., 1971). The latter study in man was based on clinical measurements of the growth of macro-colonies of epithelial cells in areas

50

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

of moist desquamation in patients that had received fractionated radiotherapy. An additional important finding arising from the investigations involving the use of the micro-colony assay was that a high proportion of the micro-colonies was associated with hair follicle canals (Potten and Al-Barwari, 1985), i.e., approximately 50 percent after 8 Gy and 70 to 80 percent afier 20 Gy. A similar conclusion was reached on the basis of histological studies in pig skin after x irradiation (Morris and Hopewell, 1989). Evidence for a two- to three-fold increase in the mitotic index ofthe cells of the basal layer, within the canal ofhair follicles, by the 20th day after irradiation provide further evidence for the important role played by these cells in the recovery of the epidermis after irradiation (Osanov et al., 1976). These findings have important implications for large-field irradiation with beta rays, since basal cells from withln the canal of hair follicles will be spared in exposures involvingintermediate-energy beta-emitting radionuclides. Following doses in excess of that usually associated with a high probability of developing moist desquamation, the area of irradiated skin is completely denuded of surviving clonogenic epithelial cells. In this situation healing of moist desquamation can only occur as a result of the division and migration of viable cells from the edges of the irradiated area. The stimulus for such ingrowths is unknown but may be initiated at approximately the same time and by a similar mechanism to that responsible for the initiation of divisions in reproductively viable clonogenic cells within the irradiated area, as seen after lower doses. However, the rate of migration of epithelial cells a t 1mm in 6 to 7 d, as estimated from wound healing studies in the pig (Winter, 1972), would only have a significant effect on the acute epithelial rahation-response of skin when relatively small areas of skin are exposed, such as is the case for hot particles. When larger areas of skin are irradiated with high doses and all the clonogenic cells within that area are sterilized, cell migration from the edges of the field will be relatively ineffective. Secondary ulceration, involving the loss of dermal tissue, may develop in such situations as a consequence of tissue dehydration, infection and trauma. Healing is then by a process of field contraction and fibrous tissue formation, as with any excision wound in skin. A late phase of erythema, identified by a distinct dusky or mauve ischemic coloration, is well characterized in the pig after irradiation with single or fractionated doses involving a small number of large doseslfraction of x rays (Archambeau et al., 1985; Hopewell et al., 1988). This was referred to as the midterm reaction in the early studies by Fowler et al. (1963; 1965). The distinct bluish coloration of the skin varies in its severity with dose. The reaction is associated

4.2 RADIATION RESPONSE OF SKIN

/

51

with edema and the probability of the development of necrosis increases with increasing dose above a threshold dose for necrosis of approximately 18 Gy of x rays. The latency for the development of necrosis was 10 to 16 weeks in the Large White pig (Hopewell and van den Aardweg, 1988), slightly shorter in the Yorkshire pig (Archambeau e t al., 19681, and approximately 10 weeks in man (Barabanova and Osanov, 1990). The development of the late phase of dusky/mauve erythema and of dermal necrosis is preceded by the loss of endothelial cells, a reduction in the capillary density and a n increased separation of the remaining endothelial cell nuclei, as assessed in the Yorkshire pig (Archambeau et al., 1985). At 12 weeks after the irradiation of the skin of Large White pigs, a dose-related reduction in dermal blood flow has been reported (Moustafa and Hopewell, 1979). The presence of edema and impaired lymphatic clearance (Mortimer et al., 1991) might also contribute to a collapse of the vasculature. However, the occlusion of end arterioles, by proliferating, viable, endothelial cells, has been reported and is likely to be another contributory factor (Hopewell, 1983). Vessels a t the level of the deep dermal plexus, between the dermis and the fatty layer, appear to be an important target population for the development of dermal necrosis (Hopewell, 1986).

Late skin changes occurring r 2 6 weeks after irradiation are characterized by a thinning of dermal tissue, telangiectasia, and late necrosis. Dermal thinning has been well documented in pig skin (Hopewell et al., 1979; 1989) and is recognized clinically as subcutaneous induration (Gauwerky and Langheim, 1978), although in the past it may have been erroneously referred to as subcutaneous fibrosis. After single doses of beta radiation from 22.5 mm diameter 90Sr/90Yplaques, dermal thinning in pig skin develops in two distinct phases; the first phase was seen to develop between 14 and 20 weeks, with a later phase after 52 weeks (Rezvani et al., 1994). Comparable phases of development of dermal thinning have also been seen after x-ray irradiation (Baker et al., 1989). It is probable that the pathogenesis of the first phase of dermal thinning is similar to that already proposed for the development of ischemic dermal necrosis after high doses. Alternatively, fibroblasts have been proposed as potential target cells (Withers et al., 1980). However, the time course for the loss of fibroblasts is later than that for endothelial cells (Hamlet and Hopewell, 1988). The underlying pathogenesis of the second phase of dermal thinning in pig skin is less certain. The degeneration of smooth muscle cells in the wall of small arterioles and their replacement by hyaline tissue has been reported in skin and other tissues a t these late times

52

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

(Hopewell et al., 1989). An additional observation, in the pig skin, was the appearance of histological change in blood vessels characteristic of telangiectasia. Telangiectasia is a well documented late change in human skin after radiotherapy and is rarely seen earlier than 52 weeks. It then increases in both incidence and severity for up to at least 10 y after irradiation. The rate of progression of telangiectasia is dose-related (Turesson and Notter, 1986). Late necrosis of the skin is usually precipitated by trauma in atrophic dermal tissue. These late necrotic ulcers are slow to heal as the function of the vasculature may be markedly impaired. Surgical intervention is frequently required in non-healing ulcers. 4.2.1.2 Dose- and Field-Size Effects Relationships. Based on clinical experience with orthovoltage x rays, several authors (e.g., Ellis, 1942; Paterson, 1948) have proposed doses for human skin that are associated with acceptable skin changes depending on the area of skin irradiated, i.e., safe "tolerance" doses. It was suggested that the "tolerancen dose should be decreased as the size of the treatment field is increased. The term "clinical tolerance" was not clearly defined but it was stated that this must not be confused with biologically "isoeffediven doses (Ellis, 1942). However, confusion was introduced when these clinically derived "tolerance" doses were considered to be biolo~cal"isoeffective" doses by authors developing mathematical formulae for area- and volume-effect relationships for the skin (e.g., von Essen, 1969).The consequences associated with the misinterpretation of clinical data for the skin are discussed elsewhere (Hopewell, 1997). In a n extensive study of the effects of irradiation on the response of pig skin (Hopewell, 1990; 1991), circular areas of 5 to 40 mm diameter, were irradiated with 90Sr/90ybeta rays. ED, values (i.e., 50 percent incidence of clinically detectable effects) plus their SE were derived for moist desquamation from curves relating the percent incidence of that response with the radiation dose (Figure 4.3). The doses were represented by the central axis dose, a t 16 pm depth, averaged over an area of 1.1 mm2.EDs0values were found to decline markedly, from about 70 Gy for a 5 mm diameter source to about 27 Gy for a 222.5 mm diameter source (Table 4.3). The apparent loss of a field-size-related effect for larger fields was taken to represent the situation where the migration of viable cells from the edges of the irradiated area failed to have a significant influence on the observed response. It is perhaps of significance that the dose-effect curves obtained for the 5, 11 and 15 rnrn diameter sources (Figure 4.3) had significantly shallower slopes than those for the two large sources. This implies a greater heterogenicity in the cell populations

4.2

RADIATION RESPONSE OF SKIN

53

Skin Surface Dose (Gy)

Fig. 4.3. Dose-related changes in the percentage incidence of skin sites showing moist desquamation after irradiation by sources that simulate hot particles and from somewhat larger sources (Hopewell, 1991): 90Sr/90Y (@ 40 mm, 0 22.5 mm, A 15 mm, A 11 mm, w 5 mm diameter) or 'I0Tm (0 19 mm; 0 9 mm, 6 5 mm diameter). Error bars indicate r SE on ED50 values. The beta-particle energy data are given in Table 3 . l a of this Report.

irradiated with the smaller sources. This might reflect a differential stimulus for cell migration with change in dose. The threshold doses reported in these studies for moist desquarnation were similar to those observed by Moritz and Henriques (1952) and George and Bustad (1966) after the irradiation of pig skin. The irradiation of skin with 170Tm (Em, = 0.97 MeV) required much higher skin surface doses than 90Sr/9"Y(Em, = 2.28 MeV) to produce the same degree of response in the skin (Table 4.3). This change in dose required for the same response is thought to be associated with those basal cells situated in the canal of hair follicles, more of which survive irradiation by the shorter-ranged beta particles from 17Tmthan survive irradiation from 90Sr/9"Y.For irradiation by 170Tm,the repopulation of the injured area by such cells would tend to predominate over repopulation by cell migration from the edges of an irradiated area. This would also be expected to reduce the significance of the migration of cells from outside the irradiated area in determining the response of areas of decreasing size. A significantly reduced field-size effect in pig skin after irradiation with 170Trn

54

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

TABLE4.3-Variation in EDSOvalues (2SE) for moist desquamation and late dermal thinning in pig skin after irradiation with sources of either gOSrISOY or I7OTm of varying diameter." ED,, 2 SE for isoeffect (Gy)

Nuclide

Source Diameter (mm)

Late Damage Moist Desquamation

~ 2 0 % ~

~30%~

"From Hopewell (1991). bIndicatesthe ED, values for skin sites showing either a 220 or 230 percent reduction in relative dermal thickness. Doses are averaged over 1.1 mm2 measured at 16 K r n depth. sources of 5 to 19 rnm diameter, as compared with 90Sr/gOyirradiation (Figure 4.3), is consistent with this hypothesis. For irradiations by the intermediate and higher energy betaemitting radionuclides, dermal thinning, and possibly telangiectasia may prove to be the cosmetically unacceptable late normal tissue changes. Measurements of dermal thickness a t 2 y after the irradiation of pig skin showed that there was a dose-related incidence of irradiated sites showing si&icant dermal thinning, i.e., a reduction in dermal thickness of 20 percent or more (Figure 4.4). This effect was seen even after doses that did not result in the development of moist desquamation as part of the acute skin reaction (Table 4.3). Dose-effect relationships for late skin damage in humans are available but only from studies on patients receiving fractionated radiotherapy treatments. Examination of the dose-related incidence of clinically evident late atrophy in large fields would suggest that the total dose, given in 30 fractions, that was associated with a 50 percent incidence of clinically detectable effect (EDso)was approximately 69 Gy (Reinhold et al., 1989). An EDSoof approximately 68 Gy was obtained for another measurement of late skin damage in pig skin, i.e., a linear contraction of irradiated skin fields of 12.5 percent or more a t 26 to 52 weeks after irradiation with the same dosefractionation schedule (Hopewell et al., 1979).

4.2

RADIATION RESPONSE O F SKIN

1

55

Dose (Gy) Dose-related changes in the incidence of skin sites on the pig irradiated with acute single doses from 90Sr/90Y(-) or '7@Tm (- - -) plaques of different source diameters showing a 2 2 0 percent reduction in relative dermal thickness a t 104 weeks after irradiation (90Sr/90Y:A 40 mm; 0 22.5 mm; and 5 mm; 17"m: H 19 mm and A 9 mm). Error bars indicate + SE on ED, values (reproduced from Hopewell, 1991). The beta-particle energy data are given in Table 3.la of this Report.

Fig. 4.4.

Assuming the applicability of the linear quadratic18(LQ) model of cell survival and a n alphabeta ratio of 3 Gy for late damage to the skin, the equivalent single dose, based on these data, would be about 17 Gy. For late telangiectasia in human skin, the ED50 for a moderate severity of telangiectasia at 5 y was approximately 65 Gy for total fractionated doses given as 2 Gy per fraction, five fractions per week (Turesson and Notter, 1986). 4.2.1.3

Summary of Large Field Irradiation.

1. The radiation responses of concern for radiological protection, following exposure to areas of skin >1 cm2, are early moist desquamation and late dermal thinning. Late dermal thinning

'The LQ model relates the fractional survival of clonogenic cells (SF) in irradiated tissues with the radiation dose ( D ) such that S F = Exp[ -(d + PD2)1.

56

2.

3.

4.

5.

6.

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

due to dermal necrosis may occur as a consequence of exposure to higher doses, although a secondary loss of dermal tissue (secondary ulceration) may also occur if the healing of early moist desquamation is delayed. Dermal injury heals by contraction of the damaged site with tissue scarring. Early moist desquamation results from the radiation-induced inhibition of proliferation in cells of the basal layer of the epidermis. The time of appearance of moist desquamation is dependent on the total turnover time of the epidermis and is independent of the magnitude of the radiation dose. The severity of moist desquamation is dependent on the radiation dose and the energy of the radiation. Nonuniform radiation exposure of basal cells in the canal of hair follicles from intermediateenergy beta rays allows rapid healing of moist desquamation compared with more uniform exposures with depth in tissue. Dermal thinning develops in two phases. The first is between 14 and 20 weeks after irradiation, the second is after 52 weeks, a period after which telangiectasia may also develop. Both phases of dermal thinning may have a vascular-mediated pathogenesis. The ischemic dusky or mauve appearance of the skin after 12 to 16 weeks, prior to the onset of dermal necrosis following high doses, is consistent with this view, for the initial phase of dermal thinning. For acute radiation exposures, si&icant late dermal thinning, reduction in dermal thickness, defined as 20 percent or more, is of greater significance for dose h i t a t i o n . It is seen after doses not associated with the development of early moist desquamation. The EDso for 2 2 0 percent dermal thinning following acute exposure to 90Sr/90Ybeta rays is approximately 12 Gy. This increases to approximately 40 Gy for intermediate energy beta rays (e.g., 170Tm).

4.2.1.4 Hot-Particles Biological Reactions. When areas of skin are exposed to radiation from hot particles, only a small volume of tissue is irradiated, even if high-energy beta-emitting radionuclides are involved. This has a pronounced effect on the tissue reactions to radiation exposure. The well-characterized limiting reaction of moist desquamation, which follows wide field exposures in radiotherapy and major radiation accidents and whose time scale of development i s predictable and dependent on the cell proliferation and differentiation characteristic of a particular species, is not characteristic of hot-particle exposure. It is likely that the migration of viable epithelial cells from the edges of a n irrahation site quickly compensates for any loss of cells when a very small area of the epidermis

4.2 RADIATION RESPONSE OF SKIN

1

57

is irradiated by a hot particle. The reactions observed of relevance to radiological protection are those produced by the death of cells in different layers in the skin a t interphase (Hopewell, 1986). The level or depth in the skin (epithelial and/or dermal) a t which cells are killed in interphase will depend on the total radiation dose and/or the energy of the beta emissions. Radiation doses below those needed for killing cells in interphase may be associated with a transient erythema. The nature of the cell killing will result in the very early appearance of a clinically observable change, namely an open lesion and/or a scab, usually within one to three weeks ofirradiation. Therefore, these changes usually occur earlier than the time scale associated with the appearance of moist desquamation following uniform irradiation of a large field. These very early-appearing lesions, occurring as a result of the killing of cells in interphase, would occur in large fields if doses are escalated sufficiently. However, these very early occurring lesions would never be considered to be the dose limiting lesion in radiological protection, since moist desquamation and other dose limiting lesions would develop after much lower doses to large fields. Dosimetry considerations are important in approaching the problem of the likely biological effects of hot particles and in establishing a workable dose limit. Doses measured over a small area (i.e., 1.1mm2is frequently used) a t various depths, as might be applicable to the target cells involved, have fundamental biological significance. However, such measurements are not simple to carry out and could be difficult to apply in all situations. This aspect will be lscussed later when consideration is given to the question of dose limitation. High- a n d intermediate-energy beta-particle emitting radionuclides. Experimental investigations with hot particles emittmg high- (Em 21.5 MeV ) and intermediate-energy beta partxles (0.5 MeV < Em, < 1.5 MeV) have been undertaken using applicatorheld sources or mimpheres to simulate exposure of the skin to hot particles. These have included the use of 170Trn - E,, = 0.97 MeV (Baum et al., 1992; Hopewell, 1991; Kaurin et al., 1997b); 90Sr/90Y Em, = 2.28 MeV (Hopewell, 1991; Reece et al., 1993) and fissioned 236U - Em, = 2.25 MeV (Dean and Langharn, 1969; Dean et al., 1970; Forbes, 1969; Hensley et al., 1965; Kaurin et al., 1997b). A few investigations have also been undertaken using 3 mm diameter sources of '44Ce/144Pr - Em, = 3 MeV (Reece et al., 1993). Most studies, including some of the exhaustive ones, have been performed on the skin of pigs. However, a few very limited evaluations have been undertaken on the skin of the backs of the monkey, Macaca speciosa (Dean et al., 1970; Hensley et al., 1965) and on the 4.2.1.4.1

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4. BIOLOGY AND RADIATION RESPONSE OF SKIN

inner forearm of a single human volunteer (Dean and Langham, 1969; Dean et al., 1970). Information from such limited studies on species other than pig cannot be used to provide truly quantitative data to indicate a possible threshold dose, but can act in a qualitative way as a cross-correlation with the more extensive results from pigs. The detrimental lesion that may develop a s a consequence of exposure to the above high- and intermediate-energy sources has been termed "acute ulceration." The full lesion usually develops within one to three weeks of irradiation (Hopewell, 1986). It may first appear as an open sore or as a lesion covered by a pigmented or lightly colored scab (Baum et al., 1993; Kaurin et at., 1997b). Scabs may form rapidly over open sores. Prior to the development of an ulcer, small pale areas or areas of coloration with a bluish tinge can be detected, sometimes as a raised area, indicative ofblisterhig (Hopewell, 1996; Reece et al., 1993). Forbes and Mikhail (1969) referred to a 'Bull's eye" phenomenon, as a description of these early changes. The 'Bull's eye" effect was verified with a pig with pigmented skin irradiated with I7OTm sources (Baum et al., 1993; Kaurin et al., 1997b). However, Forbes (1969) did not recognize that the response of skin to hot-particle exposure was over a time scale that was different from t h a t reported for moist desquamation in larger fields because the research to indicate such had not yet been performed. Thus, reports t h a t moist desquamation was associated with the development of ulcers or bull's-eye phenomena reflects a misunderstanding of the underlying mechanisms involved. The time of onset and duration of ulceration on skin sites in the pig irradiated with hot particles of 90Sr/9'Tand 170Tm(Hopewell, 1986) are given in Table 4.4. Comparable data for 3 mm diameter sources of both 90Sr/90Yand 144Ce/1441?r are given in Figures 4.5 and 4.6 (Reece et al., 1993). In these figures, the latency time and the time to healing are given for individual irradiated sites. Two and three sites were irradiated a t each dose level and the originally quoted doses were averaged over 1 cm2 a t 50 pm depth in tissue. These doses have been converted to a central axis dose, averaged over 1.1 mm2 a t 16 pm depth, using the VARSKIN code (Durham and Bell, 1992), in order to make comparisons with the results of Hopewell (1986). All the doses used in these studies with the 3 mm diameter sources were in excess of the -EDs0 for a 2 mm diameter BOSr/gOysource of 290 Gy (Table 4.4). The lesions were correspondingly more severe, all persisting for a much longer time than the period up to 3.5 weeks observed in the studies with smaller sources of 90Sr/9'T(Table 4.4). These studies with small sources did not distinguish between open sores (open ulcers) and those covered by a scab or scaly skin. However, the finding of ulceration, open or

TABLE4.4-Time of onset of acute ulceration and its duration (in weeks) in skin sites irradiated with beta rays from hot particles."

Nuclide

Sr-90N-90 Tm-170

Source Diameter (mm)

2 1 2

1 0.5 0.1

Tissue Breakdown -EDS;

(GY) 205 400 250 350 300 300

Tissue Breakdown -ED,,"

Onset

-1.5-3.0 -1.0-1.5 -1.5-2.5 -3.5-4.5 -2.0-3.0 -1.5-2.5

Duration

(GY)

-3.0-4.5 -2.0-2.5 -3.0 -1.5-2.5 -2.0-3.0 -3.0-4.0

290 770 440 550 580 400

Onset

-2.0-3.5 -0.5-1.0 -1.5-2.5 -1.5-2.5 -1.5-2.5 -1.0-2.0

Duration

-2.0-3.5 -1.5-3.0 -2.0 -2.5-3.0 -2.0-3.0 -3.0-4.0

9 a t a from Hopewell (1986) with the application of the dosimetry correction as described by Charles (1991). Doses were those measured a t 16 p,m depth averaged over 1.1 mm2.

g$ Z

rn

v

O

z

rn

M

8

60

1

4.

;I

BIOLOGY AND RADIATION RESPONSE OF SKIN

A

I

I

12

16

I

20

Time (weeks) Fig. 4.5. Time-related progression of lesions in individual skin sites irradiated with different doses of beta rays from a 3 mm diameter 90Sr190Y source. Doses are those at the center line measured at 16 km depth averaged over 1.1 mmz (0 open ulcer; I I I scab; x x x palpable or visible scar) (redrawn from Reece et al., 1993).

covered with a scab, in all sites is consistent with previous findings. The long duration of ulceration in the studies by Reece et al. (1993), sometimes for as long as 18 weeks (unhealed after 20 weeks), may reflect the very high doses used andlor the use of a 3 mm diameter source as compared with sources of 2 mm or less diameter, or the presence of infection. A combination of factors may have been involved. The reported appearance of a few late occurring open ulcers after four weeks or more (Figures 4.5 and 4.6) may reflect the fact t h a t red and white-centered blisters were not included on their graphical representation. However, Kaurin et al. (1997b) also noted a few later appearing lesions, if the observation period was extended to 10 weeks. The biological nature and significance of the limited number of later occurring ulcers has not been assessed. The present increased understanding of the effects of hot-particle exposure of the skin indicates that the terminology used in some of the much earlier investigations needs to be viewed with caution. This applies particularly in those studies in which only a limited

4.2 RADIATION RESPONSE O F SKIN

1

61

1

I

I

I

I

I

0

4

8

12

16

20

Time (weeks) Fig. 4.6. Time-related progression of lesion in individual skin sites irradiated with different doses of beta rays from a 3 mm diameter '"Ce/144Pr source. Doses are those at the center line measured at 16 km depth averaged over 1.1 mm2 ( 0 open ulcer; I I I scab; I / / scaly; or x x x palpable or visible scar) (redrawn from Reece et al., 1993).

dose range was used and when few sites were exposed. It is likely that terminology was adopted from earlier experimental experience using large field exposures or more specificallyfrom studies of radiotherapy cases. In retrospect, this is clearly inappropriate. For example, terms such as shallow dry desquamation involving monkey skin, or dry desquamation of a single site on human skin (Dean and Langham, 1969; Dean et al., 1970; Hensley et al., 1965) might, in reality, have represented a dry scab over an ulcer. It is somewhat surprising, given the difficulties and uncertainties associated with the identification of ulceration of the skin after hotparticle exposure and also to what depth in the skin damage may develop, that there have been limited histological investigations in which biopsies have been taken a t different times after irradiation in order to obtain a better understanding of these types of skin lesion (Hopewell, 1986; 1996; Kaurin et al., 1997b). These were conducted

62

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after the irradiation of skin sites with a dose of 770 Gy from a 1 mm diameter 90Sr/90ysource (Hopewell, 1996) or with 550 Gy from a 1mm diameter I7OTrnsource (Hopewell, 1986). The doses used were consistent with an approximate 90 percent incidence of ulceration (Hopewell, 1991). These doses were measured at 16 pm depth averaged over 1.1 mm2. Evidence for the death and loss of cell nuclei in the papillary dermis and the superficial reticular dermis was seen The area in which nuclei were at 5 d after irradiation with 90Sr/90y. lost was clearly demarcated and any remaining nuclei in the affected area appeared pyknotic. The affected area appeared to be avascular due to the loss of endothelial cells in addition to fibroblasts. The overlying, very palely staining, epidermis was much thinner but still intact. At intervals from 10 to 17 d after irradiation, the still intact epidermis had separated from the nonviable dermal tissue. Macroscopically this was identified as blistering of the skin, as reported by others (Reece et al., 1993).The blister space frequently contained neutrophils and red blood cells. The junction between the nonviable and the still viable dermal tissue was demarcated by a zone of inflammatory cells. The eventual loss of the epidermis covering the blister represented open ulceration (an open sore). This ulcer is often covered rapidly by a scab, although scabs tend to separate and are frequently lost as tissue is processed for histology. It should be restated that this sequence of changes, occurring after irradiation with high- and intermediate-energy beta emissions from hot particles, is distinctly different from that described by others after large field irradiation with lower doses, which leads to the development of dry or moist desquamation, and again emphasizes the need to adopt a separate terminology. Following 170Tmirradiation with a 1 mm diameter particle, changes similar to those observed following 90Sr/90Yirradiation were seen, but only the papillary dermis was affected, resulting in a shallower ulcer (Hopewell, 1986). This might reflect the lower dose used for the investigations, 550 Gy as compared with 770 Gy for 90Sr/90Y or the difference in the construction of the two sources. The 1mm diameter 90Sr/90ysource was partly collimated (Hopewell et al., 1993). I t consisted of a glass bead sealed in a stainless steel tube; the resulting radiation field was conical in shape. The 170Tmsource was planar. Late dermal atrophy may also develop after exposure to intermediate or high-energy beta rays from hot particles at doses below those causing acute ulceration. This may amount to a 20 to 30 percent reduction in dermal thickness over a small area aRer 100 Gy (dose averaged over 1.1mm2a t 16 pm depth) for particles of 90Sr/90Y,1to

4.2 RADIATION RESPONSE OF SKIN

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63

2 mm in diameter. These lesions have the appearance of a small dimple 1to 2 y after irradiation (Hopewell, 1991). Low-energy beta-particle emitting radionuclides. Only a very limited number of investigations have been conducted following irradiations with hot particles containing only low-energy betaemitting radionuclides (Em, s 0.5 MeV). AU of these studies have been conducted on the skin of the pig. The sources used included the beta-ray emitting radionuclides 17% - Em, = 0.47 MeV (Kaurin et al., 1997b), 46Ca- Em, = 0.26 MeV (Reece et al., 1992; 1994) and 147Pm- Em = 0.225 MeV (Hopewell, 1986) and the mixed gamma and beta-emitting radionuclides 60Co(Reece et al., 1992; Hopewell 1996), and 4 6 S(Kaurin ~ et al., 1997b), see Table 4.5. Cobalt-60 is the main radionuclide in activated Stellitem, which constitutes a major part of the hot-particle problem in commercial nuclear power plants. Sources used have varied in diameter from 200 to 3,000 Fm (3 mm). For the studies with 147Prn,a 15 mm diameter plaque source was used with a 5 pm titanium window. In order to simulate exposure to a hot particle, a screen with a central aperture of 2 mm diameter was placed in front of the larger source. The screen was constructed from 120 pm thick aluminum and 120 pm thick melinex. The lesion seen after 147Pm-irradiation,which was initially reported to have the appearance of moist desquamation (Peel et al., 1984), developed after 17 to 21 d following a dose associated with a 45 percent incidence of the response from the 2 mm dameter field. The lesion healed quickly (3 to 7 d) within a time scale that was shorter than that normally associated with the first appearance of moist desquamation in large fields exposed to higher energy radiations (i.e., approximately 33 d in pig skin). All other researchers report the preponderance of early occurring lesions using hot particles with low-energy beta emissions. Investigations involving irradiation with either 3 rnm diameter @To or *Ca sources (Reece et al., 1992; 1994), although very limited in the number of sites irradiated a t doses consistent with those required to produce skin changes, did 4.2.1.4.2

TABLE4.5 -Energy characteristics of two radionuclides that emit both gamma and low-energy beta radiation. Characteristic

Co-60

Sc-46

Maximum beta-particle energy (MeV) Gamma-ray energies (MeV)

0.32 1.173 1.332

0.36 0.889 1.12

Half-life

5.3 y

83.8 d

64

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4. BIOLOGY AND RADIATION RESPONSE OF SKIN

illustrate the general pattern of response. Following irradiation with 45Ca,a number of lesions, initially described as scaly (Reece et al., 1992), and subsequently described as scabs (Reece et al., 1994),were observed after approximately 7 to 14 d and these persisted for about 7 d (Figure 4.7). Some later appearing lesions were also observed in this series, one such lesion subsequently leading to permanent tissue scarring. Because of the way data were presented in these studies, it was not possible to determine if scabs were preceded by lesions referred to as red or white blisters. After 60Coirradiation (Figure 4.8), the majority of early appearing lesions were classed as open sores lasting for approximately 14 d. Open sores closed to leave scabs, some of which tended to persist and frequently resulted in tissue scarring. A careful comparison of the skin reactions to two sources with a similar beta energy, but with one having a gamma-ray component, was not possible because so few sites were irradiated. However, tended to produce more severe reactions for a comparable dose. In a more extensive study, involving irradiation with 200 Fm diameter 60Coparticles (Hopewell, 1996), groups of 12 sites were irradiated a t the three dose levels of 480, 995 and 1,490 Gy (dose averaged over 1.1 mm2 a t 16 Frn depth). The time-course for the appearance of open lesions, subsequently covered by a dry scab, is

Time after Irradiation (weeks)

Fig. 4.7. Time-related expression of damage to individual skin sites after irradiation from a 3 mm diameter 45Casource. Doses have been converted to those averaged over 1.1 mm2 at 16 pm depth. Lesions were initially described a s scaly (-), more recently a s scabs. Only one of these lesions left a scar when fully healed (- - -) (redrawn from Reece et al., 1992; 1994).

4.2 RADIATION RESPONSE OF SKIN

1

65

Time after Irradiation (weeks) Fig. 4.8. Time-related expression of damage to individual skin sites aRer irradiation from a 3 mm diameter60Cosome. Doses have been convertedto those averaged over 1.1 mm2at 16 p n depth. Lesions may have initially appeared as an open sore (- * -) or as scaly skin, more recently as scabs (- ). Healing frequently left scars (- - -) (redrawn from Reece et al., 1992; 1994).

illustrated in Figure 4.9. Open lesion developed from 7 to 18 d after irradiation; all skin sites had healed by day 36. When skin is exposed to radiation from low-energy beta-emitting radionuclides, there is a large reduction in dose with depth in tissue. After exposure to 147Pm, the skin surface dose is approximately 50 percent higher than the dose measured a t 16 km depth (Charles, 1991). The maximum reduction in dose across the epidermis may be as high as 80 percent, but this obviously depends on the thickness of the epidermis a t a particular skin site. Thus cells in the upper viable layers of the epidermis will receive significantly higher doses than will cells in the basal layer of the epidermis and the papillary dermis. The undulations in the depth of the basal layer, due to rete ridges, will produce a considerable variation in the dose to the basal layer. Although some limited histological investigations have been undertaken (Kaurin et al., 1997b),there are no published investigations into the pathogenesis of lesions of the skin resulting from irradiation with hot particles containing low-energy beta-emitting radionuclides. The most relevant studies appear to be those involving irradiation with a 15 mm diameter 14Tmplaque (Hopewell, 1986). After doses consistent with a high incidence of an early appearing

66

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

I I

0

10

I

I

I

20

30

40

I

Time after Irradiation (days) Fig. 4.9. Time-related expression of damage to individual skin sites after irradiation from a 200 krn diameter s°Cosource. Doses are measured as the average over 1.1 mm2 at 16 krn depth. Lesions initially appeared as a small open sore area (- *- and later were covered by a dry scab prior to healing (-1 (Hopewell, 1996). lesion, pyknosis was noted in the cells of the upper viable layers of the epidermis within 3 d of irradiation. This caused a n inflammatory reaction, initially in the upper viable layers of the epidermis, but by 9 to 10 d afier irradiation there was a total disruption of the epidermis. This disrupted epidermis was covered by a dried serum exudate (scab) (Hopewell, 1996). However, possibly due to the relatively lower radiation doses to stem cells in the basal layer, repopulation of the epidermis was rapid and the epidermis had a normal appearance a t 18 to 24 d after irradiation. No late atrophic changes were obsemed in the skin after irradiation with '47Prn(Hamlet et al., 1986). There was also no visual or histological evidence of scar tissue formation after l4'Prn irradiation. The appearance of scars after irradiation with 3 mm diameter 60Co sources (Reece et al., 1992; 1994)may reflect the gamma contribution to the total radiation dose a t deeper layers within the dermis from this particular type of source. 4.2.1.5 Effect of Beta-Ray Energy or Biological Response. The differences in the biological response of skin to irradiation from hot particles with emissions of intermediate- and high-energy beta particles, as compared with low-energy beta particles have been described above. Because different target cell populations may be involved for

4.2 RADIATION RESPONSE O F SKIN

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67

these two types of sources, initially it might be appropriate to consider dose-effect relationships for these two different situations separately. This could ultimately lead to the establishment of dose limits that might truly reflect the biological responses of the skin, and these dose limits could be defined a t a specified depth in the skin appropriate for the biological responses that develop. 4.2.1.5.1

High- and intermediate-energy beta-emitting radionuelides. Previous recommendations for exposure to hot particles on the skin (NCRP, 1989) relied heavily on the results of studies by Forbes (1969). In these studies, the skin of pigs was exposed to high-energy beta rays from small, fissioned 295UC2 microspheres with diameters of 150 and 300 pm. Dose rates from the microspheres were high, such that point doses in the range 2,400 to 74,000 Gy (at 100 pm depth) could be given in 2 to 3 h. All exposures were large enough to produce ulcers, which were reported to vary in diameter from 0.5 to 8 mm. Ulcer diameter was defined by the authors as being the diameter of either the denuded, oozing sore or the scab that filled the denuded space. As in other studies conducted over this same time period, the lesions were initially and, in retrospect, incorrectly described as exhibiting moist desquamation. The initial area of damage, termed moist desquamation, was said to gradually spread out to form an ulcer, which reached a maximum size after two to four weeks. Moreover, areas exhibiting what was termed moist desquamation or a dry scab frequently surrounded areas of ulceration, as a ring 2 to 3 cm wide (Charles, 1991). In terms of modern terminology and the present understanding of pathophysiological mechanisms involved, the true ulcer diameter may have been consistently larger than reported. Healing was associated with tissue scarring. This was usually completed by 12 weeks after irradiation. In these studies, only 19 sites were irradiated with fissioned 235UCz on pig skin. A range of doses was used with no duplicate exposures a t any specific dose. Thus it was not possible to determine doseeffect relationships, in terms of the incidence of a specified event, in the conventional way. It should be stated that the study was initiated as part of a nuclear propulsion program. Support for the k i m a l experiments was ended prematurely when the nuclear rocket propulsion project was stopped. In order to obtain an approximate threshold for ulceration from this type of data, it was considered appropriate to plot the diameter of the ulcers produced against the total number of beta particles emerging from the microsphere during the period of exposure and not in terms of the originally reported point doses a t 100 pm depth

68

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BIOLOGY AND RADIATION RESPONSE OF SKIN

in tissue (NCRP, 1989). Plotted in this way (Figure 4.10) a straight line could be fitted on a semi-logarithmic plot. The least squares analysis indicated an intercept on the abscissa a t 3 x 101° beta particles, i-e., an ulcer with zero diameter. It was noted in the course of the analysis that an emission of 3.14 x 101° beta particles to a single site produced a n ulcer 0.5 mm in diameter; emissions of 3.4 x 101° or greater (point dose a t 100 pm depth of 2,610 Gy or greater) were said to be required to produce ulcers in monkey skin. Beta-particle emissions of 2 x 101° to 3.2 x 101° produced areas of "dry" desquamation, 3 to 4 m m diameter, in the monkey (Dean and Langham, 1969, Dean et al., 1970), i.e.,point doses in the range from approximately 1,600 to 2,500 Gy (at 100 pm depth). Even point doses as low as 521 and 540 Gy to single sites in the monkey and in a human produced what was termed shallow dry desquamation or dry desquamation, respectively. Again it needs to be stated that these terms are now considered inappropriate mechanistically to describe reactions from hot particles and may have represented scabs covering small ulcers. It should also be recognized that there will be variation in response for the same or similar doses of irradiation in different sites. In

. 10 l o

10"

. .

,

. .. lot2

I 013

Beta Particles Emitted from Source

Fig. 4.10. Dose related changes in the diameter of ulcers after irradiation with either 150 p,m ( 0 ) or 300 km (@) diameter microspheres of fissioned n5UC2.The radiation dose is represented by the number of beta particles emitted from the source over the exposure period (log scale) [adapted from NCRP Report No. 106(NCRP, 1989)on the basis of data from Forbes (196911.

4.2 RADIATION RESPONSE O F SKIN

1

69

the d a t a of Forbes (1969), beta-particle emissions in the range 6.25 x 101° to 8.65 x 101° resulted in a four-fold variation in ulcer diameter (16 fold difference in area), a n effect not likely to be linked just to the radiation dose. In conclusion, with respect to a possible threshold dose, results based on individual sites that may or may not elicit a specific reaction must be viewed with considerable caution. Since the publication of NCRP Report No. 106 (NCRP, 1989), the results of Forbes (1969) have been reviewed by several authors (Baum and Kaurin, 1991; Baum et al., 1992; Charles, 1991). These subsequent investigations point to uncertainties in the linear regression analysis that had been noted in NCRP Report No. 106 (NCRP, 1989) as not statistically rigorous. When ulcer diameter was plotted against beta particles emitted from the microspheres on a linearlinear plot, both Baum and Kaurin (1991) and Charles (1991) noted that the curve was biphasic with the results for small and large microspheres appearing to fall into two distinct groups (see Figure 4.11). Analysis using the 150 pm diameter microsphere yields an intercept of (0.5 1.7) x 101° or (1.9 & 1.4) x 101° beta particles, depending on whether total beta emission or ulcer size was taken a s t h e independent variable (Charles, 1991). Based on total

+

Number of Beta Particles (x l o J 2 ) Fig. 4.11. Dose-related changes in the diameter of ulcers after irradiation with either 150 pm ( 0 ) or 300 pm ( 0 ) diameter microspheres of 235UCz. The radiation dose is represented by the total number of beta particles emitted from the sources over the exposure period (linear scale) (redrawn from Baum et al., 1992).

70

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BIOLOGY AND RADIATION RESPONSE OF SKIN

beta-particle emission, the intercept for the 300 p+mdiameter microspheres was ( - 2 ? 0.3) x 1012beta particles. These results clearly demonstrate the difficulties encountered in derivinga threshold from these data, since the uncertainties encompass zero dose (Baum and Kaurin, 1991). An alternative analysis of the data of Forbes (1969) resulted in a correlation that yielded common results for the two sizes of microsphere of fissioned n6UC2(Baum et al., 1992). However, the criteria proposed by Baum et al. (1992) were not generally applicable to other hot-particle source energies. The criteria predicted that a considerably increased threshold would be required for sources with an Em, of <1 MeV. The similarities in the response of pig skin to hot particles (Em, = 2.27 of 170Tm(Em, = 0.97 MeV), as compared with YOSr/gOy MeV), clearly do not provide support for this suggestion. An alternative approach, and one adopted by the ICRP (1991b) in its attempts to provide dose limits for the skin, was to assess the dose-related incidence of acute ulceration. At the time of publication of the ICRP document, in addition to the Forbes data, only the results of Hopewell et al. (1986) with a revision of the dosimetry (Charles, 1991) were available. This involved exposures from 90Sr/9"Ysources of 1 and 2 rnrn diameter and 170Tmsources of 0.1, 0.5, 1 and 2 mm diameter. These data had been available a t the time that NCRP Report No. 106 (NCRP, 1989) was published, but effects of various source geometries and the use of source holders prevented converting the measured doses (averaged over 1.1mm2 at 16 pm depth) into the number of beta-particle emissions with confidence, as was done for the other studies with microspheres (NCRP, 1989). However, a comparison of the various sets of data based on dose averaged over 1.1 mm2 at 16 Fm depth confirmed the similarity of the various sets of results in terms of the doses greater than the EDlooassociated with ulceration in pig and monkey skin, i.e., >700 Gy (ICRP, 1991b; NCRP, 1989). The dose-related incidence of acute ulceration in the earlier studies used by ICRP (199:Lb) are shown in Figure 4.12. This shows no significant differences in the radiation response of pig skin to 170Trn sources of differing diameters. The dose effect curve for a 1 mm diameter 90Sr/90Y source was parallel to those for the I7OTm sources. The dose effect curve for a 2 mm diameter 90Sr/90Y source, was significantly steeper. This might reflect the difference in construction of the 1 and 2 mm 90Sr/9"Ysources (Hopewell, 1991). The ED50 values for the different sized sources are shown in Table 4.6. At low levels of incidence of ulceration, i.e., the EDlolevel, the response to all the small sources was similar (Hopewell et al., 1993).

1

4.2 RADIATION RESPONSE OF SKIN

I

I

I

I

20

40

60

100

-

I

200

71

I

I

I

I

400

600

1000

2000

Skin Surface Dose (Gy) Fig. 4.12. Dose-related changes in the percentage incidence of skin sites showing acute necrosis/ulceration aRer irradiation from hot particles of 90Sr/9"Y(D 2 mm or 0 1mm diameter) or 170Tm(A 2 mm, 1 mm, 0.5 mm, or 0.1 mm diameter). Error bars indicate 2 SE on EDmvalues. The solid lines are for goSr/gOy,the dashed lines are for "OTm (data from Hopewell, 1991).

+

TABLE 4.6- Variation in values (+_ SE) for acute ulceration and late dermal thinning in pig skin after irradiation with sources of either 90Sr/90Y or 1 7 0 T n of varying diameter. -

p-

EDSok SE for Isoeffect (Gy) Late Damage

Source Diameter

Nuclide

(mm)

Acute Ulceration

~ 2 0 % ~

230%=

"Indicates the dose-related incidence of skin sites showing either 220 or 230 percent reduction in relative dermal thickness. Doses are averaged over 1.1 mm2 measured a t 16 pm depth (Hopewell et al., 1993).

72

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4. BIOLOGY AND RADIATION RESPONSE OF SKIN

Over the period associated with the preparation of this Report, studies have been conducted a t BNL using a n approximately 0.5 mm diameter l7O'I'm source, and these data have been published recently (Kaurin et al., 199713). Included amongst these investigations were studies on pigs approximately 16 to 17 weeks of age, similar to those used in the original studies (Hopewell et al., 1986). Multiple sites were exposed to single doses in the range 183 to 599 Gy (dose averaged over 1.1 mm2 a t 16 pm depth). Based on original data provided to the NCRP for this specific group of anim a l ~ ,an ' ~ EDjovalue was 240 ? 22. This could be equated to a dose of approximately 5 Gy averaged over 1cm2a t 70 pm depth. For this same set of animals, ulcer or scab diameters were also measured and the results expressed in terms of ulcer diameter against dose. Linear regression analysis, and extrapolation back to an ulcer of zero size produced a range of estimated threshold doses of approximately 0.89 to 5.6 Gy averaged over 1cm2 a t 70 pm depth for five different 170Tmirradiations (Kaurin et al., 199%). The original dose-related incidence data from the BNL study, as provided to the NCRP, has enabled a detailed comparison to be made between these new data and the earlier results for l7OTrn (Hopewell et al., 1986) using probit analysis. The results of this comparison are given in Table 4.7. In this Table, the results &om Oxford are first given a t the EDs0and EDlolevel of effect, based on the assumption that the dose effect curves for the various sized sources used were parallel (see Figure 4.12). This was justified on a statistical basis and the results based on the parallel fits to the dose effect curves and are those quoted in ICRP Publication 59 (ICRP, 1991b). In addition, for the purpose of this Report, each data set has now been evaluated separately and ED,, EDlo,ED6and EDl doses quoted. It can be seen from the separate evaluations of the Oxford and BNL data that similar dose-effect relationships were obtained for the different sized sources, except perhaps for the irradiation with the 0.5 mm source in Oxford where a trend towards higher doses was observed. However, in view of the similarities, the results obtained with the different sized sources in Oxford have been combined, as have the Oxford and BNL findings (Table 4.8). The similarities in the response between the two data sets are remarkable and suggest doses of 110 and 56 Gy for the 10 and 1 percent incidence of ulceration, respectively. Doses were averaged over 1.1mm2and assessed a t 16 bm depth. These equate to 2.2 and 1.2 Gy when averaged over "Kaurin, D.G. (1996). Personal communication (Nashville, Tennessee). A more refined analysis of the data, which was subsequently published, led to somewhat different values of ED50and dose (Kaurin et al., 1997b).

4.2

RADIATION RESPONSE OF SKIN

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TABLE4.7-lsoeffective doses (Gyp for acute ulceration of skin after hot-particle irradiation with l7OT7n source of differing diameter. Source Size (mm)

Oxford Effect Level

Separate Evaluation

BNLb Parallel Dose Effects

Separate Evaluation

"All doses a r e expressed a s t h e dose (Gy) averaged over 1.1 mm2 a t 16 pm depth. bKaurin, D.G. (1996). Personal communication (Nashville, Tennessee). A more refined analysis of the data, which was subsequently published, led to somewhat different values of ED,, and dose (Kaurin et al., 1997b).

TABLE4.8 -Isoeffective dose (Gyp for acute ulceration in pig skin after irradiation with sources of 170Trn designed to simulate exposure to hot particles. Effect Level

ED60 ED10 ED, ED1

Oxford Datab (all sources)

BNL Datab" (0.5 mm)

All Data Combinedb

262 (235-290) 111 (88-131) 87 (65-106) 55 (38-71)

240 (197-276) 109 (66-144) 87 (48-121) 58 (26-88)

253 (231-275) 110 (90-128) 87 (68-104) 56 (40-70)

"The doses quoted for the different levels of effect are those averaged over 1.1 mm2 measured a t 16 p,m depth. bValues quoted in parenthesis for the Oxford and BNL data and all data combined represent the 95 percent confidence interval. 'Kaurin, D.G. (1996). Personal communication (Nashville, Tennessee). A more refined analysis of the data, which was subsequently published, led to somewhat different values of EDSoand dose (Kaurin et al., 1997b).

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4.

BIOLOGY AND RADIATION RESPONSE OF SKIN

1 cma at 70 p.m depth for the EDloand ED,, respectively. The EDlo for higher energy beta rays from 90Sr/90Yand 235U sources were higher at approximately 5 and 8.5 Gy, respectively (Hopewell, 1991;Kaurin et al., 1997b). The threshold dose quoted in ICRP Publication 59 (ICRP, 1991b) was 1 Gy averaged over 1 cm2at 100 to 150 p,m depth in dermal tissue, for damage seen in association with acute ulceration. Late thinning of the dermis was also assessed a t 104 weeks after both 90Sr/90Yand I7OTrnirradiation (Hopewell et al., 1993). Analysis was based on the dose related incidence of skin sites showing either a 220 percent or 230 percent reduction in dermal thickness: The latter would show as a significant dimple in the skin; the results for this effect are shown in Figure 4.13. As distinct from the early ulcerative response, marked effects of particle size were noted. The EDSOvalues for both a 220 and 2 3 0 percent dermal thinning were significantly less than those for acute ulceration after 90Sr/90Yirradiation. This was the case only for 170Tmafter irradiation with the 2 mm diameter source. For the small 170Trnsources, very high doses were required even to produce a 220 percent reduction in dermal thickness (Table 4.6). For "OTm doses associated with e l 0 percent

Dose (Gy)

Fig. 4.13. Dose-related changes in the percentage of skin sites showing the developmentof 230 percent dermal thinning 104 weeks after irradiation (O 2 mm or 0 1 mm diameter) or I7OTm with hot particles of gOSr/gOY (A 2 mm, 1 mm, 0.5 mm, or 0.1 rnm diameter). Error bars indicate 2 SE on EDm values (derived from Hopewell et al., 1993).

+

4.2 RADIATION RESPONSE O F SKIN

1

75

incidence of acute ulceration, dermal thinning of 230 percent a t 104 weeks was limited to <30 percent of sites except for the larger 2 mm diameter 90Sr/9"Y plaques. At a dose limit set to prevent acute ulceration from intermediate and high-energy beta rays, dermal thinning of the severity illustrated would not be a significant health issue.

4.2.1.5.2 Low-energy beta-emitting radionuclides. Until recently, the only data available for irradiation with low-energy beta-emitting radionuclides that showed the relationship between dose and the rapidly appearing response, termed acute epidermal necrosis because of its links to the interphase-related death of supra basal epithelial cells, were those for 147Pm(Hopewell, 1991). This had involved the irradiation of skin with a partly collimated beam, achieved by placing a 2 mm diameter cutout in front of a large, brass backed, 147Pmplaque source to simulate exposure to a hot particle. The EDb0and EDlodoses for such irradiations, based on a probit fit to data for the incidence of acute epidermal necrosis and dose plotted on a linear scale were 478 +_ 26 Gy and 340 +- 27 Gy, respectively (Charles, 1991; ICRP, 1991b). These represent the dose a t 16 pm depth averaged over 1.1mm2. Data for the 2 mm diameter cut-out were compared with the incidence data for larger cut-out diameters (Hopewell, 1991). Recently results have become available for irradiation with 200 pm diameter 6oCo-spheres(Hopewell, 1996) and with 400 X 400 pm (131 pm thick) source of 46Sc,referred to as a 60Cosurrogate (Kaurin et al., 1997b). However it is important to recognize the 70 pm diameter 'j"Co sources produce nearly as much dose a t 70 pm depth in tissue from photons as from beta particles, whereas the 4 6 Ssource ~ produced about four times as much beta dose as gamma dose a t that depth. The dose-related incidence of early lesions developing after G°Co-irradiationare shown in Figure 4.14. The EDSo(kSE) obtained was 1,070 f 220 Gy, with a n estimated EDlo of 540 Gy, doses measured a t 16 p,m depth and averaged over 1.1 mm2. Based on a VARSKIN MOD2 calculation, the corresponding doses averaged over 1cm2measured a t 70 pm depth would be 8.2 f 1.7 and 4.1 +- 0.9 Gy for the EDb0( +- SE) and EDlo( f SE), respectively. These values are not significantly different from those quoted by Kaurin et al. (1997b) for 4 6 S ~ the ; EDb0and EDlovalues (95 percent confidence limits) were 12 (8.8, 17) and 5.1 (2.7, 7.2) Gy, respectively. A re-analysis was performed in order to compare the earlier results obtained with a 2 mm diameter cut-out source of 147Pm(a pure, low-energy beta emitter) with the results from 'j"Coand "SC (mixed, low-energy, beta and gamma-emitting radionuclides). The ED60 and EDlodoses obtained for 147Pmwere converted to express the dose in

76

/

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

I

I

150

500

I

1000

2500

Dose (Gy)

Fig. 4.14. Dose-related incidence of early occurring lesion after irradiation of pig skin with 200 pm diameter 60Cohot particles. Twelve sites were exposed at each dose level. Error bars indicate 4 SE (Hopewell, 1996).

terms of that averaged over 1cm2a t 70 km depth. Measured depth dose data for 147Pm(Wells, 1988) and a measured conversion factor for average dose over 1 cm2 as compared with 1.1 rnm2 (Charles, 1991) were used. The results obtained were similar to those for the 0.8 Gy for the mixed irradiation sources, i.e., 6.2 ? 1.3 and 3.6 ED,, and ED,, ( + SE), respectively. In further studies (Kaurin et al., 1997b), another predominantly beta-emitting hot-particle-type source E175Yb(E,,, = 0.47 MeV)] was used. A similar ED, (95 percent confidence intervals) value of 6 (4.3, 9.7) Gy w a s o b t a i n e d . However t h e ED,, was lower, 1.3(0.89, 1.8) Gy. Studies with small sources of low-energy betaemitting radionuclides by Reece et al. (1994), which included 45Ca and 60Co,are difficult to evaluate because the investigations were less comprehensive with only a few sites being irradiated a t a specific dose level.

+

4.2.1.5.3 Hot particles off the skin. Dose-effect relationships for hot-particle effects considered so far have been for a fixed hot particle of high, intermediate or low energy on the skin surface. This is considered to be the worst case scenario for occupational exposure.

4.2 RADIATION RESPONSE OF SKIN

1

77

Very little information exists for the effects of hot particles some distance off the skin, to simulate hot particles attached to clothing. In studies to simulate this situation (Kaurin et al., 1997b), the effect of irradiation with 280 pm diameter fissioned 235UCz microspheres on the skin was compared with that off the skin. A 440 pm thick piece of denim cloth between the particles and the skin was used to simulate effects of clothing. The microspheres were in a fixed position on the cloth. The dose-related incidence of ulceration andlor scabs on pig skin following both modes of irradiation are shown in Figure 4.15. Dose has been expressed either as that averaged over 1.1mm2 a t 16 pm depth (Figure 4.15a) or as averaged over 1cm2a t 70 pm depth (Figure 4.15b). There are some uncertainties in the data because of the limited number of data points, particularly for the results of irradiation off the skin, where the response was greater than anticipated and most sites were irradiated with doses greater than the EDmfor ulceration. The four data points that show a zero percent incidence were for individual sites irradiated a t each dose (Figure 4.15a and 4.15b), as was the 100 percent incidence data point for off-skin exposure a t 15 Gy (Figure 4.15b). When dose was expressed as averaged over 1.1 mm2 a t 16 pm depth (Figure 4.15a) marked differences were found in the response of skin for irradiation off as compared with on the skin. The response was more marked with fissioned 235UCzmicrospheres off the skin. This is best illustrated by a comparison of the response to a dose of approximately 500 Gy where the incidence of scabs was 15 percent for a microsphere on the skin, rising to approximately 100 percent when placed off the skin a t a distance of 440 pm. The ED50 and ED,, values for the incidence of scabs are given in Table 4.9; the values for irradiation on the skin are significantly higher than those for irradiation off the skin. This difference is likely to be explained by the reduction in dose heterogenicity produced by raising the fissioned 23SUC2 microsphere off the skin, thus increasing the area of skin exposed. This has the effect of increasing the apparent size of the hot particle. In studies with gOSr/gOy the response to a source of 2 mm diameter was greater than that to a smaller 1mm diameter hot particle (Hopewell, 1991). ED,, values for acute ulceration from these two 90Sr/90ysources varied by a factor of two (Table 4.6) and healing was delayed as illustrated by the duration of tissue breakdown a t the approximate ED,, value (Table 4.4). More severe lesions were also seen after irradiation with fissioned 235UC2 microspheres off the skin as compared with those on the skin (Figure 4.16) even after comparable doses in terms of scab incidence. For doses in t h e range of t h e approximate EDm-EDloo,all scabs had healed by 65 d when the microspheres

/

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

Dose (1.1 rnm2 at 16 prn depth) Gy

Dose (1 cm2 at 70 prn depth) Gy Fig. 4.15. Dose-related changes in the percentage ofsites showing scabs in association with acute ulceration in pig skin irradiated with 280 p,m diameter microspheres of T J C 2 placed on the skin surface ( 0 ) or separated from the skin by a 440 p,m thick layer of denim cloth (0).Doses are expressed a s that averaged over 1.1mm2at 16 p,m depth (a)or over 1cm2a t 70 p,m (b). Error bars indicate 95 percent confidence interval (redrawn from Kaurin et al., 1997b).

1

4.2 RADLATION RESPONSE OF SKIN

79

TABLE 4.9-Isoeffect doses for the induction .of acute ulceration1 scabs in pig skin after irradiation with 280 p n diameter fissioned UsUCzmicrospheres either on or off the skin (separated 440 pm of denim cloth). -

Dose Expression (arealdepth)

1.1 mm2/16Frn 1 cm2/70pm

-

Isoeffective Dose (96%CI) (Gy) Source Position

EDso

EDlo

off-skin on-skin off-skin on-skin

138.0 (80.2,179) 659.0(573,1,098) 10.6 (6.2,13.8) 11.4 (9.9,19.0)

58.5 (11.7,93.6) 490.0 (330,565) 4.5 (0.9,7.2) 8.5 (5.7,9.8)

"oses are expressed either as averaged over 1.1 mrn2at 16 Frn depth or over 1 cm2at 70 pm depth (from Kaurin et al., 1997b). were placed on the skin, but for a comparable biologically effective dose range, the occasional lesion persisted with a scab being observed for more than 100 d where the microsphere was placed off skin. This difference persisted for doses above the ED,,. For irradiation with microspheres off the skin a number of sites remained unhealed after 144 d, when the study ended. No such persistent lesions were seen after irradiation with microspheres on the skin. This difference in the persistence of lesions is clearly illustrated when the dose is expressed as that averaged over 1cm2a t 70 Fm depth (Figure 4.16b). When the dose is expressed in this way, the dose related incidences of ulcerationlscabs were comparable for irradiation with fissioned 236UCz microspheres both on and off the skin (Figure 4.15b) with no significant difference in EDloor ED5()values (Table 4.9). No information exists for irradiation with hot particles at a greater distance off the skin either with a fixed hot particle or with movement of the particle relative to the skin surface, as is likely to occur if hot particles are attached to clothing. However, both factors are likely to produce more reduction in the heterogenicity of the dose distribution associated with radiation from a fixed hot particle in contact with the skin. 4.2.1.6 Summary of Deterministic Effects in Response of Skin to Hot-Particle Irradiation.

1. Even when high-energy beta-emitting radionuclides are involved, hot particles only irradiate a small volume of tissue. 2. The lesions of clinical significance,following hot-particle irradiation, develop as a consequence of the direct killing of target cells, either suprabasal epithelial cells, endothelial cells, or fibroblasts in interphase. The level in the skin at which cells

80

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

Dose (1.1 mm2 at 16 pm depth) Gy

rn

.-c -

80

20

60-

(51

c.

E F=

40

.. . . .

-

-

-0.

200

•

om

0

-* I

0

a

0. I

10

'

'

. ... 1 .

I

'

'

.'

100

.'..I

1000

Dose ( 1 cm2 at 70 ym depth) Gy Fig. 4.16. Dose-related changes in the time to healing of individual lesions on a single pig produced by the irradiation of the skin with microspheres (280 pm diameter) of 235UC2 placed on the skin (0)or separated fmm the (0) by 440 pm thick denim cloth. Some sites remained unhealed and covered by a scab aRer being present for 144 d (1). Doses were expressed as averaged over 1.1 mm2 at 16 pm depth or as averaged over 1 crn2 at 70 pm depth (*site healed after topical application of antibiotic ointment) (redrawn from Kaurin et al., 1997b).

4.2 RADIATION RESPONSE OF SKIN

1

81

are killed depends on the energy of the beta emitter, i.e., lowenergy beta rays (60Co,%c, 147Pm) can kill suprabasal epithelial cells; intermediate and high-energy beta rays (90Sr/90Y,236U, 170Tm)are required to kill dermal endothelial cells or fibroblasts. Radiation from mixed gamma- and beta-emitting hot particles may result in a more persistent lesion, compared with pure beta emitters, due to the higher radiation dose a t depth. 3. Lesions produced by low-energy beta emitters have been termed acute epidermal necrosis while those produced by intermediate or high-energy beta-emitting radionuclides have been termed acute ulceration. Lesions are frequently covered by scabs. 4. Cell death during interphase results in the early expression of clinical injury, a disruption of the continuous epidermal barrier, which normally occurs within <21 d. Moist desquamation, on the other hand, requires four to five weeks to develop after large field irradiation. 5. The differing underlying pathology for the mixed pattern of lesions resulting from hot-particle irradiation means that there is no single depth of biological mechanistic significance a t which dose can be assessed in order to establish a n ideal dose limit. A given incidence of a surface lesion, such as a scab, is not always biologically isoeffectiveZ0because different pathological events may have been involved in the development of the lesion. 6. For the small surface area of skin in which most energy is deposited, i.e., approximately 1.1mm2,the EDlo(dose to produce a 10 percent incidence of a lesion) was approximately 110 Gy for intermediate energy beta-emitting radionuclides; and in the range 340 to 540 Gy for low-energy beta-emitting radionuclides. These doses were measured a t depth of 16 p,m. 7. If these doses were expressed as the dose averaged over 1 cm2 at 70 p,m depth, a method of assessment with no biological mechanistic significance, the EDlo values were in the range from 1.3 to 2.2 Gy for intermediate energy beta-emitting radionuclides and in the range of 3.4 to 4.1 Gy for low-energy beta-emitting radionuclides. 8. Information about the effects of irradiation with hot particles off the skin, i.e., on clothing is very limited. Studies to simulate exposure where a microsphere of fissioned T J C zwas separated from the skin by a thin (440p,m) layer of clothing suggest that the effect is like that produced by a larger-sized hot particle, namely lower isoeffective doses, when dose is expressed over 201soeffediveis defined here as the same incidence of the same pathological lesion.

82

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

1.1mm2 a t 16 p n depth. This difference is not seen when dose is averaged over 1 em2 a t 70 pm depth. Lesions produced by a hot particle slightly off the skin are more severe, taking longer to heal than lesions from similar doses from hot particles on the skin.

4.2.2

Skin Cancer Risk from Ionizing Radiation

The stochastic risk of ionizing radiation to the skin was examined in NCRP Report No. 106 (NCRP, 1989). The ICRP also reviewed the risk of skin cancer induction by ionizing radiation a few years ago in Publication 59 (ICRP, 1991b). Much of the discussion of skin cancer risk below is a summary of findings in those reports. Nevertheless, additional data on skin cancer risk have been published since the time of these reports. I n particular, data on skin cancer incidence have been reported for the Japanese atomic-bomb survivors (Thompson et al., 1994), as well as a n update of the New York scalp ringworm irradiation study (Shore et al., 1992). A recent review of the epidemiologic literature on radiation carcinogenesis, including that of skin, can be found in UNSCEAR (1994). The principal stochastic risk associated with irradiation of the skin is non-melanoma skin cancer (NMSC), i.e., basal cell cancer (BCC) and squamous cell cancer (SCC) (Shore, 1990). If there is any risk for malignant melanoma, it would be important since melanoma has a much higher risk of lethality than non-melanoma skin cancers. However, reports concerning melanoma risk (Ron et al., 1991; Storm, 1988; Tucker et al., 1988) are still equivocal; in totality the evidence suggests that if there is any risk of malignant melanoma from radiation exposure, it must be very small. It is expected that the risk of skin cancer following irradiation of the skin by hot particles is less per unit of dose than when extended areas of skin are irradiated due to the small number of cells involved and the greater potential for cell killing from high doses. On the other hand, several studies of the radiation induction of skin cancer in rodents have shown a quadratic upward curvature, which would imply that large doses to a skin area might confer greater risk per unit dose than would smaller doses, as the Japanese atomic-bomb study also found for skin cancer induction (Thompson et al., 1994). Several studies have compared the effects of equivalent total doses either delivered uniformly to a relatively large skin area or delivered in a sieve pattern such that part of the skin area received high doses and part received little or none. Studies have shown that a sievepattern of skin irradiation confers less risk than a uniform pattern

4.2 RADIATION RESPONSE OF SKIN

1

83

for low-LET radiation (Albert et al., 1967; Charles et al., 1988; Williams et al., 1986) but not for high-LET radiation (Burns et al., 1972), and that the frequency of epidermal malignancies decreases a t very high skin doses (Papworth and Hulse, 1983). A more recent study (Lang et al., 1993), which involved implantation of irradiated natural uranium particles under the skin of mice, purported to contradict those conclusions. However, the experimental technique of implantation calls into question its applicability to hot particles on or near skin of humans. There are three main components to estimating the skin cancer risk from ionizing radiation: (1)develop an overall incidence risk coefficient for each risk model from existing studies, (2) project the incidence risks over a lifetime, and (3) determine the appropriate lethality fractions to transform estimates of excess incidence to excess mortality. The summary results reported in NCRP Report No. 106 (NCRP, 1989) and ICRP Publication 59 (ICRP, 1991b) will be used to estimate lifetime skin cancer incidence and mortality risks, rather than derive them anew. Skin Cancer Lethality. The lethality of NMSC is known to be low, although few reliable data are available to quantify the case fatality rate. SCC of the skin appear to have a lethality of about one percent, based on three studies, which have found 0.6, 0.7 and 1.4 percent case fatality rates (Dunn et al., 1965; Epstein et al., 1968; Giles et al., 1988). The case fatality rate for BCC is very low, perhaps on the order of 0.01 percent (Kopf, 1979; Paver et al., 1973; Weedon and Wall, 1975). The available stuhes of ionizing radiation and skin cancer suggest that radiation induces BCC about 10 to 20 times as frequently as SCC (Ron et al., 1991; Shore, 1990; Shore et al., 1984), although it should be noted that many of these studies involved irradiation specifically of the head and neck where it is known that BCC predominates (Scotto et al., 1983). Hence, to be more conservative, it was assumed that the BCC to SCC ratio is about 5:1, as it is for "spontaneous" skin cancers (anywhere on the body) in the general population (Scotto et al., 1983). With this assumption, the lethality of BCC and SCC combined would be about 0.2 percent (ICRP, 1991b).

4.2.2.1

Risk Modifying Factors. Since skin pigment protects which against the carcinogenic effects of ultraviolet radiation (UVR), is believed to be a promoter of radiation-induced skin cancer, one might anticipate lower skin cancer risk in darkly pigmented persons. The New York tinea capitis study found this to be true (Shoreet al., 1984) when radiation induced considerable skin cancer among whites but

4.2.2.2

84

1

4. BIOLOGY AND RADIATION RESPONSE OF SKIN

little among blacks. This is discussed in more detail in ICRP Publication 59 (ICRP, 1991b). Three studies have found that the magnitude of radiation-induced skin cancer risk varies inversely with age a t exposure, although only one was able to examine the entire age range (Ron et al., 1991; Shore et al., 1992; Thompson et al., 1994). However, since the age differential is presently not well quantified, and the age distribution is not well characterized for a number of the studies, this factor will not be taken into account here in assessing the risk. A few genetic conditions appear to confer susceptibility for radiationinduced skin cancer, notably the Nevoid Basal Cell Carcinoma Syndrome (Strong, 1977). There are suggestions, based on very limited evidence, that ataxia telangiectasia and retinoblastoma patients may be more susceptible to radiation-induced skin cancer (Shore, 1990). There is also a report suggesting that ionizing radiation and P W A (psoralen plus W A ) may be synergistic in skin cancer induction among psoriatic patients (Stern, 1989), although the history of multiple treatment modalities and the lack of verification in other P W A studies makes this uncertain. On the other hand, there is no evidence that other skin conditions such as xeroderma pigmentosum or albinism confer extra susceptibility for radiogenic skin cancer. In summary, because the diseases conferring susceptibility are very rare they would account for little skin cancer in an irradiated population. 4.2.2.3 Risk Coefficients for Radiation-Induced Skin Cancer. Two conclusions from the previous assessment are important in calculating risks: it is necessary to normalize the risk estimates for the amount of s h n exposed (which ranged from about 100 cm2 up to whole-body exposures), and the risk appears to be greater on chronically UVR-exposed skin (face, neck, arms) than on relatively UVRshielded skin (rest of body). This suggests that UVR is a promoter (or co-carcinogen) of skin cancer in cells initiated by ionizing radiation, which is in accord with experimental results (Fry et al., 1986). A number of radiation epidemiology studies have reported data on skin cancer incidence, and most have found an association between radiation and non-melanoma skin cancer. Eight studies of ionizing radiation exposure to UVR-exposed skin have the requisite information on dose and adequate population follow-up so they can be used in estimating risk, and six studies of UVR-shielded skin also meet these criteria. (The studies with whole-body exposure, the Japanese atomic-bomb study (Thompson et al., 1994), and the uranium miner study (Sevcova et al., 1984; 1989), were included among the studies of UVR-exposed skin.) The results of these studies of NMSC incidence

4.2

RADLATION RESPONSE OF SKM

1

85

in irradiated populations are shown in Table 4.10. For a fuller description of these studies and the risk calculations, see ICRP (1991b) and Shore (1990). Composite estimates of the excess relative per year of skin cancer were risk (ERR) and the absolute risk (AR) calculated based on these studies of UVR-exposed and UVR-shielded skin. The approximate inverse-variance weighted composite estimates of ERR are 61 percent per sievert for UVR-exposed skin and 1.4 percent per sievert for UVR-shielded skin. The AR estimates are 1.8 x (PY Sv)-I ~ m (i.e., - ~person-' y-' Sv-I ~ m - for ~ )UVR(PY Sv)-' ~ m for- UVR-shielded ~ skin. exposed skin and 3.9 x The NMSC risk estimate as applied to hot-particle exposures is subject to a number of uncertainties. These include underascertainment of NMSC, particularly in cancer registries; uncertainties in baseline rates of NMSC; uncertainties in the case fatality of NMSC (i.e., the percentage of persons with NMSC who die from it); uncertainties in skin doses in the studies used to derive the risk estimate; uncertainties in the shape of the dose-response curve for NMSC; uncertainties in the skin cancer potential from a hot particle compared to uniform skin irradiation; uncertainties in skin shielding from or exposure to ultraviolet exposure (e.g., scalp baldness, skin coloration, amount of clothing worn, amount of sun exposure sustained); uncertainty as to whether there is an additive or interactive association between ionizing and UVR exposure; uncertainty in how much age a t irradiation modifies the risk; and uncertainty in the appropriate lifetime risk extrapolation (i.e., according to an ERR or AR model). Some of these uncertainties will probably tend to average out within and between studies, but others will not. There is insuflicient information to estimate the magnitude of these uncertainties. Projection of Lifetime Risks of Radiation-Induced Skin Cancer. Protection of risk is required because follow-up data are not yet complete. Lifetime risk estimates were based on the ERR model, since that gives more conservative (i.e., larger) risk projections than the AR model. The updated risk estimates presented here are very similar to those reported a few years ago in NCRP Report No. 106 (NCRP, 1989) and ICRP Publication 59 (ICRP, 1991b), from which the ICRP derived its tissue weighting factor (wT)for skin. Specifically, the ICRP estimate and the present estimate of ERR per sievert were both 61 percent for UVR-exposed skin, and were 0.5 percent and 1.4 percent, respectively, for UVR-shielded skin. The ICRP and the present excess AR estimates (PY Sv)-' ~ m were - ~ 2.2 x and 1.8 x respectively, for UVR-exposed skin, while and 3.9 x for UVR-shielded skin. they were 1.3 X 4.2.2.4

86

1 4. BIOLOGY AND RADIATION RESPONSE OF SKIN

Mastitis (Hildreth and Shore, 1988d; Shore et al., 1986) Scalp ringworm, blacks (Shore et al., 1984; 1992) Warts (Veien et al., 1982)

2.6 5 -42

14110.7 = 1.3

12% (0, 38)

4.0 (0, 12.9)

311.03

=

2.9

38% (0, 119)

0.3 (0, 1.0)

01-0.2

=

0

0% (0, 25)

0 (0, 17)

Values preceded by "-" were estimated for this Report from the available information in the publications. bBased on an assumed RBE of 20 for alpha particles. 'Boice, J.D., Jr. (1988). Personal communication (National Cancer Institute, Bethesda, Maryland). dHildreth, N. and Shore, R. (1988). Personal communication (University of Rochester and New York University, New York).

t

88

1

4.

BIOLOGY AND RADIATION RESPONSE OF SKIN

The W T for skin of 0.01 (ICRP, 1991a) is still appropriate and will be applied to estimate stochastic effects from hot particles. The factor to convert from average dose to 10 cm2to average dose to the entire skin, is 10118,000 = 0.00056 since there are about 18,000 cm2 of skin in an adult. T h s can be viewed as a n area weighting factor. Thus the area-weighted effective dose for calculating stochastic risk is: 10 cm2 dose (Sv) x 0.00056 x 0.01 = 10 cm2dose x 5.6 X In other words, an average dose of 0.5 Sv to 10cm2of skin corresponds to an area-weighted effective dose of 2.8 x 10-%v. The ICRP (199la) and NCRP (1993) mortality risk estimate for whole-body exposure to workers is 4 x Sv-I. Thus the area-weighted effective dose of 2.8 x would have an estimated mortality risk of 4 x SV-I x 2.8 x 1 0 - 6 sv = 1.1 x 10-7

4.3 Radiation Response of Ear Direct human evidence of the effects of radiation on the ear can best be obtained from the study of radiotherapy patients. Radiotherapy for cancers of the nasopharynx, maxilla, base of the skull, posterior fossa, or brain stem is likely to result in sigmficant irradiation of the ear. Radiation therapy for carcinoma of the pinna, provides specific information on radiation effects on the external ear. In essence, the external ear, including the pinna, auditory canal, and the tympanum can be considered to be an extension of the skin in terms of their likely responses to radiation exposure. There have been few clinical studies specifically assessing the response of the skin in these sites, however, even high single doses of 60 to 70 Gy from low-dose rate (0.3 to 0.9 Gy h-I) interstitial lg21rtherapy, for the treatment of small tumors of the pinna, produced either no or only minor l a t e sequelae (Mazeron et al., 1986). The changes observed were pigmentation, telangiectasia and atrophy, identical to those observed in other skin sites. The changes affected 78 percent of patients treated, the remainder showing deformity as a result of tumor regression. It would seem reasonable to assume that no specific risk to the external ear from hot particles has to be considered and that the dose limitation recommended for less specialized skin areas can be applied. There would appear to have been only a single published report of a hot particle impinging on the external ear (Horan, 1966). This was a 70 ym diameter particle of aged fission products. Dosimetry information was limited, except t h a t the beta-ray exposure was reported to be in the order of "thousands of roentgen" to an extremely

limited area of the tympanic membrane. The field strength from the particle on its removal from the ear was reported to be approximately one roentgen per hour a t 3 cm. The particle was apparently introduced into the external auditory canal of a worker by a mild blast of air from a contaminated heat exchanger of a shutdown prototype propulsion reactor. The air blast would appear to have caused the particle to impinge on the tympanic membrane. Approximately a week later the worker reported problems with a draining ear; the condition was treated as an ear infection. Only 3 d later, after a radiation survey, approximately 10 d after the initial contamination, was the particle detected and removed. Acute ulceration of the tympanic membrane, over a time scale of approximately 7 d is consistent with that reported experimentally for skin after hot-particle irradiation. Acute ulceration, leading to perforation of the tympanic membrane is perhaps the most likely event that might result from hot-particle contamination of the external ear. Only a slight hearing loss would result in the affected ear if any associated inflammation was treated promptly. A 10 percent hearing loss was claimed in the reported case. A well recognized effect associated with the middle ear, observed in cancer patients undergoing radiotherapy for head and neck cancer, is a suddenly appearing earache. This may be explained by a serous effision in the middle ear due to a disturbance in ventilation and drainage caused by oedema of the mucous membrane of the pharynx and a partial or total obstruction of a n eustachian tube CYarnaguchi et al., 1990). Medical examination of patients will reveal mild to moderate hyperemia of the ear drum, with slight retraction of the tympanic membrane a t a n early stage and bulging a t a later stage. Perhaps between 50 to 60 percent of patients receiving 40 to 60 Gy, in 2 Gy fractions, develop ear symptoms during or shortly after completion of treatment (Borsanyi, 1962).This is termed radiation otitis media. However, the incidence of persistent otitis media is much lower a t 2 to 14 percent (Table 4.11).These chronic changes may cause conductive hearing loss. TABLE4.11-Incidence of persistent otitis media in human patients following radiation of the pharynx. Authors

CasedPopulation

Incidence (%)

Baker (1980) Urdaneta et al. (1976) Lee et al. (1992)

4/99 6/43 111457

4 14 2

90

/

4.

BIOLOGY AND RADIATION RESPONSE OF SKIN

Experimental studies involving observation on the middle ear are few in number. Local irradiation of the ear of guinea pigs with a single dose of 30 Gy produced early changes consistent with the development of acute otitis media (Ohashi et al., 1987; 1988). Immediately after irradiation they found a marked effusion in the tympanic cavity, degenerating ciliated epithelial cells and increased vascular permeability. In a more extensive study (Berg and Lindren, 1961), half-brain irradiations were conducted, including the ear, on rabbits. Acute single doses of 21,25 and 30 Gy were used and animals were killed after 1 y. After 30 Gy, fibrosis and other changes were present in the mucosal lining of the middle ear. The fibrosis was referred to a s being loose under an atrophic epithelium. The auditory ossicles were frequently involved in the fibrotic reaction. No histological lesions were detected in the middle ear after 21 Gy. Conductive hearing loss, as a result of the late rahonecrosis of one or more of the auditory ossicles has been described in radiotherapy patients (Elwany, 1985; Gyorkey and Pollock, 1960). I n the inner ear, the possibility of sensorineural hearing loss (SNHL) caused by damage to the cochlea andlor the auditory nerve has to be considered as distinct from the conductive hearing loss, which may originate from the other two regions of the ear. Knowledge as to post-irradiation SNHL is restricted to a few clinical studies and the data are somewhat contradictory as to the incidence, time of onset, the type and severity of the hearing loss. SNHL may develop many months or years after irradiation, when patients may have completed follow-up. A particular problem is a lack of pre- and postirrahation evaluation of changes in audiological function. These problems were outlined in a review of five studies that examined the sensitivity of the inner ear (Talmi et al., 1989). One study in which some of the problems were overcome involved 22 patients in which cochlear function was assessed before and after primary radiotherapy for carcinoma of the nasopharyngeal region (Grau et al., 1991). There was a n increase in the severity of hearing loss with fractionated doses of >45 Gy. The latent period was 12 months or more. Evidence for direct radiation damage to the semi-circular canals is very limited. In a study of 25 patients treated for head and neck cancer (Gabriele et al., 1992), in which the labyrinth had received fractionated irradiation resulting in total doses of 25 to 51 Gy, 11 showed abnormalities on electronystagmographic (ENG) examination. This was three to six months after completing radiotherapy. Patients in the group also complained of dizziness (three persons) or balance disturbances (two persons). However, there was no correlation between the clinical signs and ENG findings.

4.3 RADIATION RESPONSE OF EAR

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91

In animal studies (Berg and Lindren, 1961)labyrinthitis was seen in 3 of 10 rabbits irradiated with a single dose of 20 Gy. In none of these cases could an inflammatory origin be excluded and in two, the spread of infection from the middle ear was evident. No lesions of the labyrinth were apparent aRer 14 Gy. Simple geometric consideration would suggest that the changes observed in the middle and internal ear, as a consequence of radiotherapy treatment are unlikely to occur after exposure of the ear to radiation from a hot particle. Even in a situation where a particle impinges on the tympanic membrane, doses to the middle ear, and particularly to the inner ear, will be low due to distance and absorption in boney tissue. Doses needed to produce damage either to the mucous membranes of the pharynx, the cochlea, the auditory nerve or the semi-circular canals would not be expected to be achieved. The only effects are likely to result from a direct ulcerative perforation of the tympanic membrane. Secondary infection of the middle ear could produce some conductive hearing loss if this was untreated.

5. The Eye 5.1 Structure and Physiology

Of the organs thought to be a t risk from possible exposure to ionizing radiation from hot particles, the eye, by virtue of its location, functional importance, and the differential sensitivity of its tissues warrants special consideration. As shown in Figure 5.1, there are a number of media through which light must pass prior to reaching the photosensitive retina. Although the eye is highly vascularized, its two primary refractive tissues, the cornea and the lens, because they lack a blood supply,

a

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cornea

I

chamber

Posterior chamber

Fig. 5.1. A schematic (drawn to scale) of the human eye, including upper lid, illustrating the various tissues and associations described in the text.

5.1 STRUCTURE AND PHYSIOLOGY

1

93

are nutritionally dependent on the aqueous humor. The aqueous humor is actively transported from the ciliary body into the posterior chamber. An epithelium covering the ciliary body is the morphological site of the blood-aqueous barrier. The area behind the lens is occupied by the vitreous body, a substance of gel-like consistency due to its collagen and glycosaminoglycans content. The vitreous "pins" the retina to the back of the eye thus keeping it in close proximity to its major blood supply, the choriocapillaris, of the choroid. The eye includes the globe or eyeball and the adnexa (extraocular support structures critical to vision). Of the adnexal tissues, the most relevant to radiological concerns are the eyelids. The globe itself is histologically described as composed of layers or "coats." The outermost layer is the tunica fibrosa, a structure consistingprimarily of connective tissue defined by the cornea anteriorly and sclera (or white of the eye) posteriorly. The extraocular muscles are anchored in this tissue. The middle coat, the uvea, is a predominantly vascular structure limited by the iris anteriorly and the choroid posteriorly. The retina, or the neural portion of the eye, is the innermost of the three layers of the eye. The visual axis intercepts the retina at the fovea, which is the site of central vision. The retina is connected to the brain by the optic nerve which leaves the eye at the optic nerve head (papilla). Within the intraocular space, the lens is suspended by the zonule fibers, which are anchored to the ciliary body. Between the lens and retina the eyeball is filled with the vitreous. The anterior chamber, bordered by the back of the cornea, the iris and lens, contains aqueous humor.

6.1.1 Fibrous Tunic The outer coat of the eye, the fibrous tunic, includes the sclera and cornea. The sclera, a dense, tendon-like, connective tissue, provides a degree of rigidity to the globe. The sclera's basic structural components are wide bands of collagen fibrils. Between the collagen fibrils are elastic fibers, fibrocytes, and occasional melanocytes. The collagen fibrils of the sclera differ from those of the cornea in that they are larger, variable in diameter, and irregularly arranged. The cornea, approximately 0.5 mm thick, is primarily connective tissue (stroma) sandwiched between a stratified epithelium anteriorly and a monolayered endothelium (a lining epithelium) posteriorly

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5. THE EYE

(Figure 5.2). Because of its large collagen content, the stroma tends to swell and opacify if either covering cell population is damaged. The corneal epithelium is a mucous type (no keratin) with a cellular turnover of approximately 7 d in young adults (i.e., about a week is required for a post-mitotic cell in the basal layer to differentiate, migrate upwards, and desquamate). The corneal endothelium, consisting of a monolayer of non-mitotic cells, repairs injury by the spreading of surviving adjacent cells. Its finite cell number and location places it a t considerable risk to damage from external sources. The endothelial cells are second only to photoreceptors in metabolic activity and despite being only 2 to 3 pm thick in the adult, must actively transport all the nutritive requirements of the cornea.

5.1.2

Uvea

The middle layer of the eye is comprised of the iris anteriorly, the choroid posteriorly, and the ciliary body between. The iris is a loose connective tissue containing blood vessels, pigment cells, and muscles. It can be divided into a peripheral, or ciliary portion, and a central, or pupillary portion. The anterior border surface is nonepithelialized and composed of a loose connective tissue, which contains melanocytes (pigment cells). The color of the iris depends on the number and disposition of the melanocytes in this layer. The iris stroma contains blood vessels, nerves and melanocytes. Within the stroma is the sphincter muscle, which consists of muscle fibers derived from ectoderm and organized in a 1mm wide band around the pupillary margin, near the posterior iris surface. In the manner of a sphincter, its contraction constricts the pupil. The back of the iris consists of a bilayered epithelium. The layer bordering the iris stroma is heavily pigmented, being a continuation of the pigmented epithelium of the retina. I t is also myoepithelial, each cell containing contractile elements. The cells collectively form the dilator muscle. The outer epithelium, which faces the lens and posterior chamber, is an extension of the neural retina. It consists of heavily pigmented cuboidal cells. The choroid is the largest and most posterior portion of the uvea. The region lying immediately external to the retina is Bruch's membrane. It consists of the basal lamina of the retinal pigment epithelium and a thin connective tissue layer. The connective tissue contains elastic fibers and collagen fibers. The remainder of the choroid is primarily connective tissue in which a huge vasculature and many nerve fibers are embedded. The vascular elements include

5.1 STRUCTURE AND PHYSIOLOGY

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96

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THE EYE

the choriocapillaris, which forms a capillary network adjacent to the Bruch's membrane. The choroidal vasculature is responsible for the nutritional requirements of the outer two thirds of the retina. Collateral vasculature between the choriocapillaris and the arterioles and venules of the posterior ciliary vessels form a layer of medium-to-large sized vessels. The ciliary body is that portion of the uvea located between the iris and the choroid. Its outer side is adjacent to the sclera; the inner is covered by the extension of the retina and the pigment epithelium. It is composed of two distinct anatomical structures. The one closest to, and contiguous with, the iris is the pars plicata from which the ciliary processes arise. The ciliary processes are finger-like folds, which contain high numbers of highly fenestrated capillaries and large blood vessels. This rich vasculature supplies not only the ciliary body but provides the raw material for the aqueous humor and vitreous. The ciliary body is covered by a two-layered epithelium. The outer layer, the pigmented ciliary epithelium, is a continuation of the retinal pigment epithelium; the innermost, the non-pigmented ciliary epithelium, is a continuation of the neural retina. The nonpigmented epithelial layer of the ciliary body is characterized by tight junctions between the cells. The tight junctions collectively constitute the anatomical basis of the blood-aqueous barrier. The constituents of the aqueous humor must be actively transported into the posterior chamber (the space between the lens and iris). The aqueous humor then percolates beneath the pupillary margin into the anterior chamber. Aqueous humor exits the anterior chamber via the Canal of Schlemm, an endothelium-lined channel in the angle of the anterior chamber. (The angle is so-named because, in cross section, a triangular space is formed between the cornea, sclera and ciliary body.) The canal is separated from the anterior chamber by an endotheliumcovered connective tissue lacework, the trabecular meshwork.

5.1.3

Retina

The retina and the optic nerve are derivatives of the forebrain, and consequently their structure, physiology and pathology are much like that of the brain. The retina receives almost all of its nutrition from the retinal and choroidal capillaries. Because of its absolute dependence on the dual bIood supplies to sustain its high rate of metabolism (one of the highest of any tissue in the body), ischemia occurs if either source of nutrition is deficient. The result could be

5.1 STRUCTURE AND PHYSIOLOGY

1

97

the complete loss of retinal function. Any potential vascular damage is critical since the internal retinal vasculature is a non-anastomosing, endpoint blood supply (if a vessel is lost there is no provision for collaterals to supply new blood to that region). Grossly, the retina is a very thin transparent tissue that is connected to the choroid of the uveal tract by the pigment epithelium. However, there are no junction-like specializations to connect the two, which is why retinal detachment occurs between the photoreceptor layer and the pigment epithelium. Microscopically, the retina is divided into 10 well-defined histological layers outermost of which is the monolayered pigment epithelium. The retinal (inner) surfaces of the pigment epithelial cells are provided with microvilli, which surround the outer segments of the photoreceptor cells. Thus, a direct contact exists between the pigmented epithelial cells and photoreceptor cells (the outermost retinal neurons), although they are not joined by specialized membrane junctions. The pigment epithelium contains pigment granules, which absorb light. Pigmented epithelial cells also phagocytose the excess membrane sheath material from the photoreceptor cells and thus are involved in processing and recycling the Vitamin A that is bleached during normal vision. Each retinal pigmented epithelial cell ramifies with 30 to 45 photoreceptor cells. The signals generated by the photoreceptors are directed to the innermost layer of the retina, the ganglion cells, by way of bipolar neurons. In addition, there are two types of interneurons, the horizontal and the amacrine cells, whose function is to integrate (laterally) the impulses from the other neurons. The supporting framework of the retina is formed by glial cells (Muller cells). The nuclei of all the retinal cells reside in three strata: the outer nuclear layer (the nuclei of all photoreceptor cells); the inner nuclear layer (the nuclei of the bipolar, horizontal, amacrine and Muller cells); and the ganglion cell layer (the nuclei of the ganglion cells). Between the inner and outer nuclear layers is an exceedingly complex tangle of axons and dendrites of the photoreceptors, bipolar and horizontal cells, which make synaptic connections. Collectively, this area of the first synaptic connections is called the outer plexiform layer. Separating the inner nuclear and ganglion cell nuclei layers is another layer of complex synaptic connections between the axons and dendrites of the bipolar, ganglion and amacrine cells called the inner plexiform layer. The axons of the ganglion cells turn and course toward the optic disc, forming the nerve fiber layer. The space between the neurons is occupied by the processes of Muller cells. The en face topography of the retina is highly specialized. The photoreceptor layer consists of rods and cones except for an area near the central part of the retina, the fovea centralis or foveola, which

98

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5 . THE EYE

contains only cones. In this region the thickness of the retina is reduced to the thickness of the photoreceptor layers. The remaining layers, including those containing the internal retinal vessels, are absent. The macula is an oval depression about 5.5 mm in diameter. Its central region, the fovea, measures about 1.5 mm. Here the retina has less than one-half its usual thickness and contains the greatest concentration of the cone photoreceptors. The other layers of the retina are absent from this area; therefore, the photoreceptors are directly exposed to the incoming light without the scattering of the other inner layers that occurs elsewhere. Ganglion cells are abundant around the fovea, supplying the foveal cones with a one-to-one connection and thus providing for maximal resolution. The axons of the ganglion cells (the nerve fiber layer) are routed out of the retina a t the optic nerve or disc. The diameter of the disc is approximately 1.5 mm in the adult human eye. The optic disc is the area where all the ganglion cell axons meet, form bundles and turn 90 degrees to exit through the scleral aperture to the optic nerve. After leaving the globe, the nerve fibers are covered with myelin sheaths. The internal blood vessels of the retina enter and leave a t the optic disc (central artery and vein). The disc lacks all neural elements except the axons of the ganglion cells. Therefore, it has no perceptive function and is the blind spot of the eye.

5.1.4

Lens

The lens is a non-innervated, non-vascularized derivation of surface ectoderm (Figure 5.3). Nutritionally, the lens is totally dependent on the aqueous humor, a medium transported and produced by the ciliary body (pars plicata). A highly organized cytosystem composed entirely of epithelial cells, the lens is isolated from the rest of the eye (and the rest of the body) by a tremendously hypertrophied basal lamina called the capsule. The lens grows throughout life, albeit a t a decreasing rate with age. The cells responsible for this growth are arranged in a monolayer called the lens epithelium, which is located on the anterior side of the tissue (Worgul, 1982). Following a terminal cell division, the pre-equatorial cells of the germinative zone begin to undergo differentiation in the transitional zone and become internalized in the region known as the meridional rows. As the cells elongate into fibers, they eventually lose their nuclei. The mature lens fiber cell is anuclear and stretches from the anterior to the posterior sides of the lens. The abutments of the termini of these cells collectively

5.1 STRUCTURE AND PHYSIOLOGY Anterior

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99

Suture

Posterior ~ u i u r e Fig. 6.3. A diagram (not drawn to scale) of a sagittal section of the human lens illustrating the various cellular relationships in that tissue. The epithelial cell subpopulations reside in the central zone (CZ), germinatransitional zone (TZ), and the meridional rows (MR). Note tive zone (GZ), that by convention, the lens drawing is rotated 90 degrees to that which would be the case in situ (from Merriam and Worgul, 1983).

constitute the linear patterns called the sutures. Although anuclear and devoid of cytoplasmic organelles, the cells of the deepest region of the lens (the so-called lens nucleus) have patent membranes and are otherwise intact. The survival of the cells deep to the surface depends on a system of gap junctions between all the cells of the tissue. Thus, the lens can be appropriately described as a syncytium. In this way the deepest cells of the lens are in intimate contact with the most superficial cells and therefore can maintain their viability despite the absence of vasculature. The lens is completely enveloped by the lens capsule. A product of the lens epithelium, the capsule represents a barrier to anything larger than very small proteins. The zonular fibers are inserted in the lens capsule pre- and postequatorially. The other ends of the zonular fibers are anchored in the basal lamina covering the ciliary epithelium. This arrangement provides the means of altering the tension on the zonules by contraction or relaxation of the ciliary muscle. The tension is transmitted to the capsule and deforms the somewhat elastic lens, changing its convexity. The resulting change in refractive power is called accommodation. Vitreous The vitreous is a loose connective tissue that fills most of the eye. In an adult human its volume is 5 mL, making it the largest tissue 5.1.5

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of the eye. It provides a transparent, viscoelastic medium between the lens, ciliary body, and the retina. Its primary function is to "pin" the retina to the back of the eye. In the young adult human, about 30 percent of the vitreous is a viscous liquid, and 70 percent is a relatively rigid, transparent gel. During aging, the gel gradually collapses so that it occupies only half of the vitreous space. The gel vitreous is made of thin, mostly randomly-oriented, collagen filaments. The collagen filaments are anchored into the basal lamina of the retina, the ciliary body, and the lens. There are no blood vessels o r nerves in the vitreous, and there is only one layer of scattered phagocytic cells embedded in the outer margin of the gel in the vicinity of the retina and ciliary body.

5.1.6

Eyelids

Critical to the protection and the maintenance of the eye are the eyelids and conjunctiva. In cross section, the eyelids are layered structures consisting of (1)skin, (2) subcutaneous areola connective tissue, (3) muscle, (4) submuscular areola connective tissue, (5) a fibrous layer, and (6) conjunctiva. To accommodate its extensive mobility, the skin of the lids is one of the thinnest of the body being
6.2 THE EFFECTS OF LARGE RADIATION FIELDS ON THE EYE

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101

The conjunctiva, like all mucous membranes, consists of two layers, the epithelium and the substantial propria (stroma). The epithelium contains a population of goblet cells, which are differentiated and produce mucin. The junction between the sclera and cornea is called the limbus. Here the corneal epithelium makes its transition into the conjundival epithelium, where the wider stratified squamous epithelium contains scattered goblet cells. The epithelial cells of this region undergo a dynamic realignment of the spindle apparatus during mitosis resulting in a preferred orientation of the daughter cells during cytokinesis, a process thought to be involved with maintaining tissue organization.

5.2 The Effects of Large Radiation Fields on the Eye Ionizing radiation can result in damage to a variety of ocular tissues. Many of the effects may be secondary to altered nutrition, i.e., the result of primary effect on the vasculature of aqueous humor production. In the human, the blood-aqueous barrier is somewhat radioresistant, certainly requiring more than a single dose of 5 Gy and perhaps a s much as 20 Gy of fractionated doses of x rays to facilitate breakdown (Ellsworth, 1969; Merriam et al., 1972). However, when this occurs, the resulting altered intraocular environment can adversely affect the lens, cornea and intraocular pressure. If these effects persist, as can happen following fractionated doses of 30 to 40 Gy delivered in 3 to 4 d (Ellsworth, 1969), the situation can result in permanent visual disability. Except for direct effects on the lens, the major influence of r a h a tion on the eye is generally mediated by effects on the vasculature. As shown in Tables 5.1and 5.2, many radiopathies of the eye require relatively high single or fractionated doses and become apparent only after an extended latent period. The notable exception is the opacification of the lens known as cataract. The tables are a compilation of observations from a variety of studies. The latent period is the approximate onset time of the described effect a t the dose indicated. Many studies reflect irradiation with a range of high-dose r a t e fractionated irradiation protocols although a number were from lowdose rate plaque therapy. For the most part, the data on the superficial ocular tissues (cornea and conjunctiva) resulted from exposures to 10 to 15 kVp Grenz rays (HVL = 0.02 to 0.04 mm aluminum). While three primary tissues have received considerable attention (the cornea, the lens, and the retina), it is important to recognize

TABLE5.1 -The effects of large-field radiation on ocular tissues. \

Dose (Gy) Tissue

Effect

Latent Period

Punctate keratitis

Several weeks

Edema Mild ulceration Chronic ulceration Perforation Thinning Scarring Keratinization Vascularization Lipid infiltration Poor wound healing Atrophy Ulceration endophthalmitis Iritis Vascularization Atrophy Cataract

1-3 weeks Several weeks Several months 4-12 months Several months -1 Y -1 Y 1 ' Y 1 ' Y

Acute Exposure

10

Protracted Exposure

?'

References

30-5014-5 weeks

1, 2, 3, 4, 5

40-5012-3 weeks 30-4012-3 weeks 6015-6 weeks 6015-6 weeks 30-5013-5 weeks 6015-6 weeks 5014-5 weeks 5012-5 weeks 7015-7 weeks 180 200-300 20-50

2, 4, 6, 7, 8, 9

Cornea

Sclera Iris Lens

Several years 1-10 y Several days Several months 3' Y > l y (1-20)

-20

20 20

22

6015-6 weeks 43-8016-8 weeks 16-25 4.013 weeks-3 months 5.5/>3 months

10 7, 9 4, 11, 12, 13 13 7, 14 4, 7, 9 4, 7, 9, 13, 15, 16 11 4, 7, 11, 17 4, 1 8 19, 20, 21 2, 4, 9, 15, 16, 22, 23 10 4, 9, 11 10

3

Retina

Edema Vascular occlusion

Several weeks 6 months-8 y

25-50/3-5 weeks 25-50/3-5 weeks 25-50/3-5 weeks

Telangiectasis Hemorrhages Exudates Degeneration rods cones ganglion cells Atrophy 'Kinyoun et al. (1984) 2Lederman (1952) 3Mann and Watt (1958) Merriarn (1956) 5Pe~ers-Taylor et al. (1965) 6Anderson (1969) 'Blodi (1958) sGallardo and Weindenheim (1955) Merriarn (1955) 1°Merriamet al. (1972) l 1 Barron et al. (1970)

25-5013-5 weeks 30-5013-5 weeks

10, 24 1, 6, 14, 15, 23, 24, 25, 26, 27, 28, 29, 30 see vascular occlusion see vascular occlusion see vascular occlusion 31

20

>loo -300

50-8014-8 weeks I2Merriam and Focht (1957) Jiang et al. (1994) 14Parsonset al. (1983) 15Amoakuand Archer (1990) 16Lederman(1956) l7 Castrouiejo (1953) 18Jonesand Reese (1953) IgTalbot (1979) 20Tarrand Constable (1981) *'Van den Brenk (1968) QEllsworth (1969) l3

2PKincaidet al. (1988) 2 4 H o ~ a r(1966) d W h e e (1968) 26Forrest(1961) 27MacFauland Bedford (1970) 28Midenaet al. (1987) 29Milleret al. (1991) 30Tengrothand Rosengren (1969) 3 1 ~ ~ e(1962) 11 32Winteret al. (1958)

The cited studies in italics used continuous exposure regimens while the others employed fractionation protocols.

0 A

T ~ L 5.2-The E effwts of large-field radiation on the eyelids and conjunctiva.

\

Dose (GY) Latent

Tissue Lid skin

Lid tarsus Lid margin

Lacrimal gland Conjunctiva

Effect Erythema Pigmentation Depigrnentation Telangiectasis Moist desquamation Scarring Atrophy (thinning) Epilation (incomplete) Epilation (complete) Rounding Ectropion Entropion Atrophy Hyperemia Conjunctivitis Telangiectasis Keratinization Symblepharon

Period

2-4 weeks 2-3 weeks 6-12 months 2-5 y 2-8 weeks >6 months >6 months 1-2 weeks 2-5 weeks 6-12 months >l Y 1' Y >6 months Immediate 1-3 weeks 2-5 y

Acute Exposure

6 4-6

20

References

Exposure

ED5@-600P3 40-5014-5 weeks 30-5013-5 weeks 50-6015-6 weeks 80/3-8weeks 40-5014-5 weeks

10

20 >5

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Protracted

20-3012-3 weeks 40-5014-5 weeks 80-10011-4 d 80-10011-4 d 50-60/5-6 weeks -5014-5 weeks 30-50/3-5 weeks 35-100/5-10 weeks 80-10011-4 d

1,2 1 1, 3 1 1 1 1 1 1 1 1 1 4,5, 6 1 1

7, 8,9, 10, 11,12,13, 14, 15,16, 17 5, 14,15,16 1

4

3

5.2 THE EFFECTS OF LARGE RADIATION FIELDS ON THE

EYE

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105

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5. THE EYE

that a failure in systems other than the refractory media and the photosensitive tissues can result in the ultimate loss of ocular function. For example, the tear film, which keeps the cornea moist is an admixture of materials that arise from three distinct cell populations in the conjunctiva and the lid. Damage to any of these adnexal secretory tissues can in turn affect the tear film, which ultimately could cause the cornea to keratinize and opacify.

5.2.1

Eyelids

The external surfaces of the lids are vulnerable to changes that also might be found in any skin site of the body. Erythema, pigrnentation and epilation can occur a t relatively low doses (5 Gy), based on studies involving exposure to fractionated irradiation protocols that usually involved treatment five times a week over five to six weeks. The development of nonsymptomatic telangiectasis requires doses in excess of 50 Gy given conventionally as 25 fractions of 2 Gy. Ulceration, with subsequent tissue scarring, may result following total doses >80 Gy. Internal lid structures can be damaged from fractionated doses of 40 to 50 Gy. These include atrophy of the tarsi, obliteration of the lacrimal puncta (the outflow orifices of the tear film), rounding of the lid margin and thinning. Entropion or ectropion (turning of the lid in or out) can result from exposures to 80 to 100 Gy. Atrophy of the lacrimal gland has been described after a single dose as low as 20 Gy. Most studies suggest that 50 to 60 Gy, when delivered in fractions over extended time frames, are required before an effect on the lacrimals can be noted. This generally does not influence tear film production since the accessory lacrimals can provide the necessary secretion. The innermost lining of the lid, the conjunctiva, can become hyperemic a t doses of <5 Gy. The hyperemia is typically transient and of little consequence. This can be accompanied by conjunctivitis. Typically, conjunctivitis is usually seen after fractionated doses of the order of 50 Gy. A problem of potential negative impact is keratinization of the conjunctival epithelium, which can occur following fractionated doses of 50 to 100 Gy. Ordinarily, localized keratinization of the conjunctiva is, in and of itself, not a problem but it may cause atypical abrasion of the cornea secondarily producing a keratitis, or inflammation of the cornea. High doses of radiation can cause conjunctival epithelial cell denudation resulting in adhesion of the exposed conjunctiva, a condition known a s symblepharon. Secondarily, a symblepharon can produce adhesions to the globe and other lid deformities.

5.2 THE EFFECTS OF LARGE RADIATION FIELDS ON THE EYE

5.2.2

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Cornea

As illustrated in Table 5.1, protracted doses of 30 to 50 Gy to the cornea result in generally transient effects such as keratitis. Higher doses, however, can produce vision-impairing changes and eyeendangering effects such as corneal thinning, scarring and keratinization. Only after exposure to doses on the order of hundreds of gray in protracted regimens are scleral thnning and atrophy potential problems. It is at the site of the cornea where experimental hotparticle data are critically wanting. The experience with skin (Section 4) indicates that one can anticipate an effect of hot particles that differs biologically from that resulting from large-field exposure. It is possible that high-energy beta emissions from a hot particle could result in liquefaction of the stroma through the entire corneal thickness of 500 p,m. The ultimate response of the corneal stroma to a lesion of this sort, caused by a n intense radiation source, is unknown. The consequence could be a nonreparable breach of the eye, with a host of attendant sight-threatening complications. 5.2.3

Lens

In the human population, about 90 percent of all individuals over 65 y of age have some sort of lens opacity, although visual acuity may not be affected sufficiently to require surgical intervention. Furthermore, there is a reasonable certainty that everyone, if sufficiently long-lived, will develop compromised lens transparency (Cinotti and Patti, 1968). At least 50 percent, and perhaps as many as 75 percent, of these opacities are associated with cortical changes, i.e., changes associated with the superficial substance of the lens. The remainder are nuclear, i.e., they represent changes in the deeper portions of the lens. The latter cataracts are due to changes in the protein andlor deep membrane systems in the lens and are, for the most part, post-translational changes reflecting photochemical effects.The cortical changes, however, are frequently associated with an altered cellular morphology and may be due to an interference in the continued normal growth and differentiation of the tissue (Rothstein et al., 1982; Worgul et al., 1989). This can result from an altered intraocular state such as might occur following inflammation within the eye (uveitis), from a number of diseases (e.g., retinitis pigmentosa), from some drugs (steroids, chemotherapeutic drugs, etc.) or from an accumulated exposure to various physical agents such as ionizing and nonionizing radiation. The unique biology of the lens is the basis for its predominant pathology, i.e., cataract. The sole function of the lens is to refract

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incoming light onto the retina and its entire physiology and biology is geared towards that end. A failure in organization andlor metabolism results in opacification. Because the lens grows throughout life, there is considerable opportunity for errors in growth and differentiation. These errors are compounded by the confinement of the cells within the limiting capsule. Furthermore, because the lens depends on a rather extensive system of cellular communication, a failure in the cortex or the most superficial regions in the lens can cause the entire tissue to fail eventually. It is likely that this is the basis of the eventual complete opacification of the lens by a number of physical agents (including radiation) that have a primary effect in the most superficial cell populations, the lens epithelium. That ionizing radiation can produce cataracts is a fact well known by the ophthalmological and radiological community. Since the pathology occurs in a well defined cell population that is easily amenable to noninvasive examination, radiation cataract has been considered as a type of "biological dosimeter." In addition, the lens permits the assessment of biological damage in an integrated cytosystem i n vivo with a degree of reproducibility not otherwise readily available. Because cataract represents a debilitation that can eventually affect visual acuity, the pathology of radiation cataract also has considerable medical importance, particularly among those occupationally involved with radiation. The data on human radiation induced cataract are derived primarily from the studies of Merriam and Focht (1957; 1962).Those studies focused on the timedose relationships in the development of cataracts arising from radiotherapy (see Tables 5.3 and 5.4). Using these data, the ICRP (1991a) and the NCRP (1993) have determined that

TABLE5.3 -Minimum cataractogenic dose. Duration of Treatment

Dose (Gy)

Single 3 weeks to 3 months Over 3 months

2.0 4.0

Duration of Treatment

Dose (Gy)

Single 3 weeks to 3 months Over 3 months

5.5

2.0 10.0 10.5

5.2

THE EFFECTS OF LARGE RADIATION FIELDS ON THJ3 EYE

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an exposure of 0.15 Sv y-I to the eye should be the maximum allowed for occupational exposure. It should be emphasized that the data are presented as a function of treatment and time rather than in the context of current radiotherapy concepts, wherein the predominant criteria are dose per fraction. These data are the results of extrapolations of the curve in Figure 5.4 (from Merriarn and Focht, 1962). Because,in that study, the maximum duration of treatment was <1 y, there is some dissent regarding the propriety of the extrapolation, since it assumes that the slope is valid for more extended exposures. Also, it is not clear whether a low-dose, continuous exposure would affect lenticular transparency in a different manner than discontinuous, but individually larger, doses over that same period. Experimental data suggests that the effect would not be different for the lens (Brenner et al., 1996). Based on the Meniam and Focht findings, it is likely from the single dose data, and from the nearest data points available, that even the 150 mSv y - I exposure over 30 y will not constitute a cataractogenic load by itself, although the Merriam and Focht data suggest that if their threshold estimates are correct,

o- Slahonary cataract 0- Pmgressive cataract

01

1

10

100

Total Duration of Treatment in Days

Fig. 5.4. The results of a follow-up of radiotherapy patients where the eye doses for the cataract and non-cataractcases are plotted against overall treatment times. The numbers indicate several cases at one point. The vertical arrows are all progressive cataracts following doses higher than indicated but not precisely determined. The indeterminate cases are those in which the classification of stationary or progressive cataract could not be ascertained. Above the upper line, progressive cataracts were observed in all cases. Below the lower line, no cataracts of any type were observed (from Memam and Focht, 1962).

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little margin is left for additional exposure without the possibility of increased risk. If, as the data are beginning to intimate (see discussion by Worgul et al.,1996), there is no threshold for radiation cataract, then the 150 mSv y-' allowance is problematic. Historically, the response of the lens to radiation has been thought to be deterministic and given that the current risk guidelines from the NCRP and ICRP are based on this assumption, this Report deals with the phenomenon as such. However, as implied above, there are data that suggest otherwise. The first attempt a t true evaluation of the radiation dose response of the lens in humans used a limited population of radiotherapy patients (Merriam and Focht, 1957). Although relatively few low-dose exposures were available for comparison (the total population numbered under 300 with 34 cases receiving <2 Gy of x rays), that study suggested a 2 Sv threshold for cataract. In a recent re-analysis of a 17 y collation of data on the incidence of opacities characteristic of radiation damage, posterior subcapsular (PSC)cataracts, among 2,124 subjects in the Japanese atomic-bomb study, the authors applied nonthreshold models that were linear or linear-quadratic with dose, and models that assumed dose thresholds (Otake and Schull, 1990). They found a slightly better fit from a dose threshold model than from the nonthreshold models. However, the difference between the goodness of fits was small and far from statistically significant. In fact, the nonthreshold linear quadratic model provided an adequate fit @ = 0.18) to the data. I t is of interest that there was a suggested elevation of risk in their lowest dose group of 0.01 to 0.99 Gy, such that the relative risk (RR)was 2.1 @ = 0.08, 95 percent confidence interval 0.8 to 5.8). In the most recent report on the data analysis, lumping the significant opacities together with minor lens changes resulted in a better fit for a nonthreshold linear dose-response function t h a n for a threshold function. Somewhat weaker data that support arguments against a threshold (or at least one as high as the current risk estimates presume) are found in the Beaver Dam Eye Study (Klein et al., 1993), which related PSC cataract prevalence to radiation exposure from diagnostic CAT scans to the head region. The association should be interpreted cautiously since the diagnostic radiation history was based on self-reports, which are subject to recall bias. However, if valid, the data represent evidence that lens opacificationin humans can result from exposure to doses on the order of tenths of a gray. A nonthreshold relationship is also suggested by a recent study of a pediatric population in regions contaminated by the Chernobyl incident. Those individuals had a higher incidence of early lens

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changes (in this case, posterior, capsular, polychromatic sheen) than those who lived in unexposed regions (Day et al., 1995; Eller et al., 1993). Although dose levels were not available, dose estimates for the regions suggested that it was highly unlikely that the children in question received doses exceeding 0.1 to 0.2 Gy. A study of 114 adult patients residing in contaminated regions revealed a high incidence of early cataracts (Madekin, 1991). These individuals also were unlikely to have received doses even remotely approaching the Otake and Schull (1990) calculated threshold of 0.7 Sv. Until the question of whether radiation cataracts are truly deterministic is resolved, the possibility that they are not must be considered in recommending allowable exposure. This is important also from the cytopathological viewpoint. The cells at risk from ionizing radiation reside in the region of the epithelium known as the germinative zone (GZ in Figure 5.3). This zone is positioned immediately pre-equatorially placing it below the corneal-scleraljunction. A variety of studies has shown that these cells are the progenitors of the abnormal fiber cells that constitute the cataract (Merriarn and Worgul, 1983; Worgul and Rothstein, 1977). The damage is an expression of primary effect on the DNA of the epithelial cells, which later differentiate aberrantly when the progeny of the injured epithelial cells undergo fibergenesis (lens fiber cells formation) (Worgul et al., 1989). Thus the damage that is the basis for cataractogenesis is unquestionably stochastic, a fact that bolsters the position that radiation cataracts are not deterministic. Experimental findings show that the target cell population is positioned at the surface, near the equator of the lens, close to possible locations for particle sequestration in the orbital region (see Section 5.3). Recent experimental evidence has shown that a very small fraction of that cell population needs to suffer radiogenic damage in order to cause the cellular cascade leading to an effect on lens transparency. The data from heavy ion experiments utilizing fluence to control hit frequency suggest that irradiation of less than one percent of the epithelial cells can be cataractogenic (Worgul et al., 1993). However, the cataracts required a substantial fraction of the life span for development, and they were not considered clinically significant. In the case of a hot particle positioned external to the globe, the surface dose would have to be extraordinary to deliver enough dose to a sufficient number of the lens cells at risk to cause detectable cataracts within the remaining lifetime of the individual. Furthermore, experimental evidence (Leinfelder and Riley, 1956) has shown that partial exposure of the lens (e.g., one quadrant) to a given dose of radiation results in localized opacity, the density of which is less than that which would have developed had the whole

lens been irradiated. In the case of a hot particle, the dose would be so highly localized that even if a high enough dose could be delivered to the lens to cause an opacity, it likely would not be one that has a measurable effect on visual acuity. If a dose sufficient to affect the lens is encountered, the morbidity outcome would be minor compared to the potential damage that the more superficial tissues would suffer. Thus one must conclude that for hot particles, exposure to the surface tissues must be considered limiting.

5.2.4

Retina

Characteristic of nerve tissue, the retina is regarded as somewhat radiation resistant both functionally and structurally. Typically, effects are not noted unless relatively high doses are absorbed by the retina, and many of these are generally late effects that seem to be tied to a primary influence on the vasculature. Although doses as low as 30 Gy have been reported to cause retinal damage, there are few acute effects of ionizing radiation a t doses <50 Gy. However, above that level an immediate though transient retinal edema may occur. Micro-occlusive vascular disease, hemorrhagic complications resulting in retinitis or vitreous hemorrhage, and chorioretinal thinning are all possible sequelae of doses that exceed the fractionated 50 Gy dose level. Not infrequently, a papillitis (inflammation of the optic nerve) can be a consequence of exposure. This is consistent with dose levels suggested for tolerance of the central nervous system. Experience with radiotherapy suggests that doses in excess of 70 Gy given over several months will cause changes in the retina in about 85 percent of the patients. They may appear any time from 6 to 36 months post treatment although hemorrhages and exudates may appear as late as 5 y after therapy. The hemorrhages, which may be intraretinal or intravitreal, are generally viewed as secondary to retinal vessel occlusion. The overall clinical picture may mimic severe arterial sclerotic and hypertensive retinopathy. Severe hemorrhaging can result in intractable secondary glaucoma. In other cases, this can occur concomitant with retinitis proliferans resulting in retinal detachment. Salt and pepper pigmentation of the retinal pigment epithelium can also result from radiation exposure. Recent studies utilizing high-LET radiations indlcate that the early primary damage is first noted in the choroidal vasculature and is typified by thrombosis, which secondarily affects the photoreceptor layer causing receptor degeneration (Krebs et al., 1990).At the histological level, low-LET radiation effects are typified by hyaline degeneration of the vessel walls and localized area of occlusion. Neovascularization

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(telangiectasis) is often observed. Periodic petechial hemorrhaging of the affected vasculature can occur. The effects of ionizing radiation on the photoreceptors and retinal function are poorly documented in humans but have received some attention in experimental animals. Typically, an impairment in rod function can result from a dose of 20 Gy while cones and ganglion cells are much more resistant and can tolerate single doses of up to 300 Gy. Such high doses in the human would be expected to produce anterior ischemic optic neuropathy and posterior vascular occlusion in the optic nerve. In addition, optic atrophy secondary to ganglion cell degeneration could be anticipated. 5.3 Hot Particles and the Eye

While the likelihood of intraocular particle intrusion is vanishingly small in the intact (nontraumatized) eye due to the blood-aqueous and retinal barriers, a superficial localization of a hot particle may be important in risk considerations due to the relative dimensions and positions of the ocular components (Figure 5.5). One must consider, however, that the circular symmetry of the globe and its rotational capacity allows for a range of positions of the intraocular tissues from the facial surface. For example, while the anterior margin of the retina, the ora serrata, may be approximately 6 mm from the surface in the resting eye, an askance stare can bring it withln 2 mm. As this relates to hot particles, a relatively static inclusion can be the source of large area of exposure due to the potential for ocular motion beneath the source. A small particle nestled in a conjunctival fold might remain in place relative to its immediate environs, but would be in motion over a constantly moving globe, providing a lesser dose to a larger area adjacent to the conjunctiva. Predicting effects based on the experience with large-field radiation is inherently difficult due to the modulating influence that partial exposure might have on the overall response of the tissue. For example, irradiating only a portion of the lens has been shown (from shielding studies) to have a n overall ameliorating effect on the cataractogenicity of a given dose of radiation. While partial exposure of the ciliary body causes a breakdown of the blood aqueous barrier in half-shielded eyes, it is not clear whether or not a highly localized dose would produce a more regionalized effect or have any effect a t all. In any case, little experience is available from which to extrapolate the effect of irradiation from radionuclides in hot particles on the

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Fig. 5.5. A schematized, drawn to scale, rendering of the human eye in sagittal section. The relationship of the various components and their dimensions in millimeter are provided. Those values not situated between arrows are the thicknesses of the tissues in the regions indicated (Worgul, 1991).

eye. The region of irradiation is expected to be highly localized and constitute a near point source. The closest approximation to such a situation is the exposure to the eye from plaque therapy, in which case a flat (contoured) applicator is usually placed in proximity to the area to be treated. Experience with plaque therapy indicates that a source of relatively restricted size, near the sclera, could cause local thinning and even ulceration of the sclera. Another issue unique to the hot-particle situation is the number of possible scenarios associated with its localization. One is that the hot particle is lightly adherent to the conjunctival or corneal epithelium, in which case it might remain in place (float about in the tear film) or might even be removed from the ocular area by tear fluid elimination through the lacrimal puncta. The particle would then find itself in the nasal-lacrimal duct. Another possibility is that the particle is embedded in the tissue (nestled in a crypt or fold, or mechanically embedded in the epithelium by rubbing the eye), in which case it would remain in place. Finally, depending on whether

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the individual is a contact lens wearer, a particle may be embedded into a contact lens or caught beneath its rim. The nature of the contact lens (hard or soft contact lens, daily or extended wear) may play a role in the eventual fate of the particle. In terms of monitoring for an ocular localization, one might anticipate that a hot particle in the eye may evoke a foreign body response causing an irritation and heightened awareness of the individual to its presence. Unfortunately, it is impossible to predict if a particular particle of some dimension, or constitution, will, in fact, be noted by the individual. The lower limit of the size of a foreign body that can produce a sensation response is extremely variable. Furthermore, the response is greatly affected by the composition, shape and localization of the particle, as well as by individual variability, e.g., eye color, and whether or not the individual wears, or has worn, contact lenses. The size of an object that may be retained in regions of the adnexa, particularly the upper fornix of the conjunctiva, can be astounding. The literature is robust in this regard. Pieces of iron up to 2 cm2,as well as brass, wood and plastic of dimensions near that size, have been retained in the eye for periods as long as 22 y (see review by Duke-Elder, 1972). Thus it appears that it may be a mistake to suggest that the particle of some dimension may alert its host to its presence and one must presume that a hot particle in the eye can go unnoticed by the host and may be detectable only by its radiological properties. Doses that can be anticipated to produce minimally detectable changes or functional disabilities for the deterministic endpoints listed in Tables 5.1 and 5.2 are presented in Table 5.5. The doses are very conservative in the sense that they are believed to err in the direction of greater protection. These values are derived from studies with fractionated or chronic exposures to large field and plaque sources. There has been a t least one report of a hot particle being retained in or around the orbit. That event involved a hot particle finding its way into the conjunctival sac of a worker during annual maintenance in a reactor service pool a t the Olkiluoto Reactor in Finland (Tossavainen, 1990). The worker had no sensation of the presence of the particle, whch was discovered by routine radiological monitoring a t the plant exit. It is not clear how long the particle was sequestered although medical personnel assumed a period of 4 h. The diameter of the particle was approximately 150 p,m and contained 95Nb(10.7 kBq), 95Zr(7.8 kBq), 60Co(0.3 kBq), l17Sn (0.3 kBq), ll%n (0.2 kBq), 64Mn (0.1 kBq), believed to have come from fuel channels. Based on a 4 h exposure, a surface dose of 1Sv averaged over 1.4mm2was calculated for the conjunctiva. No "perceivable changes" were noted by the attending physician.

TABLE 5.5-Doses that may produce minimally detectable and clinically relevant ocular effects. Dose (Gyp Minimally Detectable Changes

Tissue Lid Conjunctiva Cornea Sclera Iris Lens Retina

Visually Debilitating

Changesb

Large Areac

1cmZd

Large Areac

1cmZd

6 5 30 15 16 2 25

2 2 2

40 35 30 200 16 5.5 25

6 6 6

-

e

-

-

-

"oses that define potential action levels. If these levels are reached, the patient should be monitored for possible damage to the tissues indicated. bThelowest dose that can possibly cause potentially severe (sight threatening) visual system problems. =Thedose levels chosen are based on the local doses for which large field, typically fractionated exposures have been reported to produce detectable changes. dTheaverage dose for a hot particle averaged over 1 cm2 at the distance (see Table 5.6) of the tissue relative to the particle. "The dashes indicate that, because of the distances involved, the doses necessary to produce effects in the tissues in question are so large that they would exceed the limiting dose for nearer tissues by an order of magnitude or more, a t even the "near" proximities (see Table 5.6).

Because of the scarcity of experience with periocular retention of hot particles, one approach for the purpose of developing guidelines for their occurrence is to consider a variety of possibilities involving characteristic radionuclides. For this purpose, 60Co,90Sr/90Y, 95ZrP6Nb,106R~/106Rh, 144Ce11MPr, and 17% are the radionuclides of choice (see Section 2). The potential scenarios include several particle diameters retained in three possible sites (Figure 5.6) for 8 h (a fullwork shift). The regions chosen in each circumstance are labeled in Figure 5.6. The site in Scenario 1, the corneal apex, is an unlikely location for a hot particle to lodge or remain for any length of time. Scenario 2, a position near the limbus, reflects a more likely location for a particle, particularly in the case of a contact lens wearer, or, if it is sequestered in one of the canthi. Of the three scenarios, longterm retention of a particle is most likely to occur as depicted in Scenario 3. Here a particle is trapped in the cul-de-sac of the conjunctival fornix. But here too, because of the motility of the subjacent

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Fig. 5.6. The anticipated scenarios for the localization of hot particles in the ocular region. The eye tissues, but not the dots meant to represent the particles, are drawn to scale.

globe, the position relative to some intraocular structures may be variable and, within certain limits, ever changing. Two potential outcomes are considered (Table 5.5). Both depend on the experience with large field ocular irradiation and are, while based on fractionated or protracted regimens, likely to be highly conservative and possibly not biologically achievable. One outcome addresses those doses that may produce minimally detectable, or subclinical, changes in the relevant tissues. The other outcome addresses those levels that have the potential to compromise the visual system. Table 5.6 illustrates the nearest portion of a given tissue at risk and its furthest distal location. When viewed in light of these possibilities, the data suggest that the sclera and retina are at essentially zero risk of damage from a 3.7 x lo6 Bq particle of the radionuclides considered and positioned in any of the sites as suggested in Figure 5.6 for 8 h or less. Because of the unknowns associated with partial or small field irradiation, the effect on the

TABLE5.6-Scenario dependent (Figure 5.6) nominal distances (in mm) of hot particles from various tissues a t risk. Scenario

Tissue

Near

Distal

Near

Distal

Near

Distal

Lid Conjunctiva Cornea Sclera Iris Lensa Retina

3.8 3.8 0.04 13.8 4.6 4.6 15.4

5.4 5.4 0.4 24.0 6.9 6.2 22.7

0.4 0.1 0.4 0.8 1.5 2.1 6.2

1.9 0.4 8.5 24.0 4.6 4.6 21.5

0.4 0.1 4.6 0.6 4.6 5.4 4.6

10.8 0.1 14.6 14.1 7.7 7.7 21.5

"In this case, the "lens" is considered the site of the germinative zone of the epithelium. lens is difficult to quantify, although there is little question that a cataract is a possible or even probable sequela, although that cataract would be of relatively little consequence. If one were to assume a 2 Gy acute dose threshold for cataracts, which is limiting for large-field exposures, the ocular radiopathy of most concern is a breaching of the cornea by an ulcer, which could be difficult to treat medically and might potentially compromise the entire eye. Therefore it is prudent to regard a corneal effect as limiting in the case of extraocular hot-particle exposure. The stochastic effects of radiation exposure in ocular tissues are not well known. While in the case of the lid skin there is no reason to expect the response to differ from that of skin elsewhere, the evidence for radiation-induced neoplastic disease in the eye is relatively sparse (Leff and Henkind, 1983; Montessori and North, 1972; Roarty et al., 1988; Sagerman et al., 1969; Schlernitzauer and Font, 1976) and is generally derived from experience in the treatment of retinoblastoma in children (Sagerman et al., 1969). There has been a suggestion of a link between low-level radiation and the incidence of retinoblastoma in children (Morris and Buckler, 1991; Morris et al., 1990; 1993). Those studies are somewhat problematic epidemiologically. But even if validated mechanistically, the effect of radiation on the developing retina in utero or in the germ line of the parent bears little relevance to the concerns of this Report. Because of the paucity of reports on adult susceptibility to ophthalmic carcinogenesis from exposure to radiation, and for the same rationales that apply to the far more likely skin lesions, one could conclude that the probability of radiation carcinogenesis in the ocular

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tissues is extremely low and the overwhelming concern for ocular morbidity should focus on deterministic and cataractogenic effects. As it relates to external hot-particle exposure specifically, cataractogenesis is not a likely outcome unless extremely high doses were delivered to the surface, which, in turn, would produce damage that could potentially be far more serious.

5.4 Conclusions Regarding the Eye Insufficient data, experimental or otherwise, exist to allow one to predict the outcome of a high dose delivered to a portion of the eye from an intense point source represented by a hot particle. However, it is reasonable to assume that within the limits provided for the skin, one should not expect that small-field effects would exceed the expectation of damage from the same dose delivered to a larger area of tissue. Based on the experimental experience with skin, the tissues potentially most problematic are the cornea and the region a t the corneal/scleral border. Because the cornea is only about 500 pm thick, a high-energy beta source producing a dose of 6 Gy could possibly cause corneal ulceration and liquefaction of the stroma, ultimately resulting in breaching of the eye. According to the data for skin effects (Section 4), although 5 Gy averaged over 1 cm2 a t 70 pm depth represents a n EDso for skin lesions, only a very small fraction of those lesions would extend to depth equivalent to corneal thickness. Non-transcorneal wounds would not be expected to produce other than very small imperfections in corneal topography, which would have little likelihood of influencing visual function or acuity. Considering the dose delivered by a hot particle to tissues in the various strata (see Table 5.5), and by using the convention applied to skin, it is apparent that the skin limit is not only relevant but appropriate for the eye, when it is clear that potential corneal damage is the limiting effect. Almost no data exist on ocular exposures to hot particles to be able to assess possible outcomes. To be conservative it must be recognized that a transcorneal lesion caused by hot-particle radiation may not repair as might a mechanical injury and that a permanent breaching of the globe may result. Clearly this area requires further investigation if exposure to the eye by hot particles is found to occur with significant frequency in nuclear facilities.

6. Respiratory Tract 6.1 Structure and Physiology

The respiratory system is a complex arrangement of organs and tissues whose primary function is the intake of oxygen and the elimination of carbon dioxide. The respiratory tract can be separated into two parts, based on gross anatomy and physiology: (1)the proximalconducting, nonrespiratory airways, which include the nose, pharynx, larynx, trachea, bronchi and nonalveolarized bronchioles; and (2) the distal respiratory region (i.e., respiratory bronchioles, alveolar ducts, and alveoli). Gas exchange between air and blood is restricted to the respiratory region. Key anatomical features of the respiratory tract are presented in Figures 6.1 and 6.2. More details on the structure and physiology of the respiratory tract than presented here can be found in recent publication~of the ICRP (1994) and NCRP (1997).

6.1.1 Nose The nose functions as an olfactory organ. The interior components of the nose warm, moisten, and filter incoming air and transport trapped particles from the nasal cavity. The nasal septum divides the nasal airway into two passages. Each passage extends from the nares (nostrils) to the nasopharynx. Inhaled air flows through the nares into the vestibule (the section just inside the nares before the main chamber of the nose). The nasal vestibule is surrounded primarily by cartilage, unlike the more distal (relative to the vestibule) main nasal chamber, which is surrounded by bone. After traversing the nasal vestibule, inhaled air passes through the narrowest part of the upper airway, the nasal valve, into the main chamber. The lumen of the main chamber is lined by highly vascularized and innervated mucous membranes, which are covered by a layer of mucus. The mucous layer, which contains entrapped particles, is moved by underlying cilia to the oropharynx where it is swallowed. Turbinates or conchae (bony structures lined by well-vascularized respiratory or olfactory mucosal tissue) project into the airway lumen from the lateral walls. The nasal turbinates (superior, middle and

6.1 STRUCTURE AND PHYSIOLOGY

Nose

I I I

1

121

, \

5

Alveolar Duct

Fig. 6.1. Anatomical features of the respiratory tract.

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6. RESPIRATORY TRACT

(

Turbinate Bones

Vestibule

Laryngopharynx

Fig. 6.2. Upper respiratory tract with the upper portion of the trachea and esophagus included. [Abbreviations: superior turbinate (ST), middle turbinate (MT),inferior turbinate (IT).]

inferior) increase the inner surface area of the nose, which is important in filtering, humidifying and warming the inspired air. The surface of the anterior nasal region is stratified, squamous epithelium. Three types of surface epithelia (stratified nonciliated transitional, pseudostratified columnar ciliated respiratory, and olfactory) are located in specific portions of the main nasal chamber. The epithelium is separated from the subepithelial connective tissue by a prominent basement lamina (ICRP, 1994).Numerous free cells are found beneath the epithelium and the region is richly vascularked. The vessels receive blood from branches of the ophthalmic, maxillary, palatine and facial arteries. The lymph drains into the skin that covers the external nose or into the upper deep cervical nodes. The nerves include branches of the trigeminal and olfactory cranial nerves.

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The paranasal sinuses may contribute to conditioning inspired air by acting as a n insulator and supplementing nasal secretions (ICRP, 1994).Narrow openings lead from the nasal cavities into the paranasal sinuses. The sinuses in the bones of the face protect the brain from blows to the front of the head.

6.1.2 Pharynx

The pharynx connects the nasal andlor oral airway with the laryngeal airway during breathing. The pharynx is a musculomembranous tube shaped somewhat like a funnel. It can be anatomically divided into nasal, oral and laryngeal regions. The pharynx lies just behind the nasal and oral cavities and extends part-way down the neck. The wall of the pharynx consists of striated muscle lined with a mucous membrane. The pharynx allows passage of air and food and provides a resonating chamber for speech sounds. The uppermost portion of the pharynx, the nasopharynx, is lined with a pseudostratified ciliated epithelium that contains goblet cells. The cilia move mucus with entrapped particles toward the esophagus. The middle portion of the pharynx is called the oropharynx; the lowest portion is called the laryngopharynx, which extends downward and becomes continuous with the esophagus and larynx. Both the oropharynx and laryngopharynx are GI and respiratory pathways. Blood is supplied to the pharynx by branches of the facial, maxillary and lingual arteries (ICRP, 1994). Lymph drains directly or indirectly into the deep cervical nodes. The nerve supply is mainly derived from the pharyngeal plexus.

6.1.3 Larynx

The larynx (or voice box) is a short cavity, which has a slit-like, variable-sized narrowing in its central portion. The narrowing is caused by two pairs of folds in the larynx walls. The lower folds are called vocal chords and the upper folds the false vocal chords. The larynx connects the pharynx with the trachea and functions as (1)a pathway for inhaled and exhaled air during breathing, (2) a valve in conjunction with the epiglottis (a muscular flap) to prevent swallowed food from entering the lower respiratory tract during eating and drinking, and (3) a tone-producing structure. The airway lumen in the larynx is lined mainly by pseudostratified ciliated epithelium, except for a small area on the vocal folds where it is stratified squamous epithelium. The ciliated epithelium of the larynx also warms,

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fdters and humidifies the air. A layer of mucus covers the laryngeal airway epithelia. The mucus is propelled by underlying cilia toward the oropharynx where it is swallowed into the esophagus. The larynx is a major resistive element to air flow and can cause an inspiratory air jet that leads to particle impaction on the wall of the trachea. It is surrounded anteriorly and laterally by the lobes of the thyroid gland. The main arteries associated with the larynx are the laryngeal branches of the superior and inferior thyroid arteries. Lymph vessels include the superior (above the vocal folds), which drain into the deep cervical lymph nodes near the bifurcation of the common carotid artery and the inferior (belowthe vocal folds). The nerves are derived from the internal and external branches of the superior laryngeal nerve, the recurrent laryngeal nerve, and the sympathetic nerves.

6.1.4

Trachea

The trachea is continuous with the larynx in the neck and extends into the thoracic cavity where it bifurcates to form the left and right main bronchi. The structure of the trachea airway is maintained during breathing because of numerous cartilaginous rings within its wall that prevent collapse during forceful inspiration. Its inner walls are covered with mucus supplied by goblet cells and mucous glands. The tracheal epithelium primarily consists of ciliated cells interspersed with goblet cells and ducts associated with glands that secrete mucus. The cilia propel mucus and deposited matter toward the larynx to be swallowed. The arteries associated with the trachea are mainly derived from the inferior thyroid arteries (ICRP, 1994). The lymphatics drain into the lymph nodes that accompany the trachea. The nerves that supply the trachea arise from the recurrent branch of the vagus nerve and from the sympathetic chain.

6.1.5

Bronchi and Bronchioles

The main bronchi branch into the lobar bronchi, then into segmental and subsegmental bronchi, and the conducting airways and eventually end a t the smallest of the conducting airways, the terminal bronchioles. The bronchial walls have an epithelial lining, a smooth muscle layer, and a connective tissue layer. In the large bronchi (for about the first 10 divisions), the connective tissue layers contain cartilage. The epithelial lining of the bronchi contains mucoussecreting goblet cells, ciliated cells, and lesser numbers of basal cells

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and other cell types (e.g., Clara cells). The larger airways are lined by high columnar, pseudostratified epithelium, which changes to columnar cuboidal epithelium in the bronchioles. Submucosal glands of the bronchial lining also produce mucus. The ciliated epithelial cells propel the mucus toward the trachea and pharynx, where it can be swallowed or expectorated by coughing. Foreign particles and micro-organisms that are not expelled by mucociliary clearance and coughing can be attacked by cellular components of the inflammatory response and by antibodies. Glands producing mucus are found only in the bronchi, and goblet cells are not found beyond the terminal bronchioles. Ciliated cells are more sparse, and smooth muscle and connective tissue layers are thinner toward the terminal bronchioles. The bronchi are supplied by pulmonary arteries (ICRP, 1994). Venules associated with the bronchi arise from capillaries of the pleura and interalveolar septa and portions of the alveolar duct. Bronchial vessels do not extend beyond the bronchial tree. The associated nerves mainly arise from the pulmonary plexus at the root of the lung. There are two main divisions of the lymphatics (one in the pleura, the other in the pulmonary tissue) that drain into the lymph nodes at the hilum (ICRP, 1994). 6.1.6 Gas Exchange Airways

The conducting airways terminate in gas-exchange airways. The gas-exchange airways are made up of respiratory bronchioles and alveolar ducts. The respiratory bronchioles have very thin walls, which consist of an epithelial layer devoid of cilia and goblet cells and have very little smooth muscle. Alveoli are the gas exchange units of the lung. They have thin walls and a somewhat spherical structure when distended. Two major types of epithelial cells are found in the alveolus: Type I and Type I1 alveolar cells. Type I cells provide structure and line most of the surface of the alveoli. Type I1 cells secrete surfactant (a lipoprotein mixture), which facilitates lung expansion. Like the bronchi, alveoli contain cellular components of the immune system. Alveolar macrophages ingest foreign material that reaches the alveolus and facilitates its removal by the lymphatics and mucociliary transport. The respiratory tract defense mechanisms are summarized in Table 6.1. 6.1.7 The Lymphatic System

Lymph vessels are a tree-like system of endothelium-lined tubes (ICRP, 1994). Unlike blood vessels, they do not form a circular system

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TABLE6.1-Mechanism of pulmonary defense. Structure or Substance

Defense Mechanism

Upper respiratory tract mucosa

Warms and humidifies the gas that enters the nose; traps and removes some foreign particles, micro-organisms, and noxious gases from inspired air

Nasal hair and turbinate

Filters and traps some foreign particles, microorganisms, and noxious gases from inspired air

Mucous film

Protects trachea and bronchi from injury; traps most foreign particles and micro-organisms that reach the lower airways

Cilia

Propel mucous blanket and entrapped particles toward the oropharynx, where the mucus can be swallowed or expectorated

Alveolar macrophage

Ingests and removes bacteria and other foreign material from the alveoli by phagocytosis

Irritant receptor in nares

When stimulated by a chemical or mechanical irritant, triggers a sneeze reflex, which can result in rapid removal of irritants from the nasal passage

Irritant receptor in the trachea and large airways

When stimulated by chemical or mechanical irritgnt, initiates a cough reflex, which can result in removal of the irritant from the lower airways

but carry their contents, called lymph, in only one direction, toward the base of the neck. Lymphatic vessels recover fluids that escape from blood capillaries and venules into the connective tissue spaces and return the fluids to the blood. The lymph vessels of the lungs originate in superficial (pleural) and in deep (bronchi, pulmonary arteries, and veins) plexuses (ICRP, 1994). In the large bronchi, the plexus consists of two networks: (1)submucosal and (2) peribronchial. In the small bronchi, there is only a single plexus, which extends to the bronchioles but does not reach the alveoli. There are no lymph vessels associated with the lungs beyond the alveolar ducts. Dense encapsulated collections of lymphocytes are called lymph nodes and lie across collecting lymphatic vessels and lymph percolates through them. The nodes filter lymph and serve as a station for transporting T- and B-lymphocytes and their immunological products. After an antigen has entered a lymph node, an immune reaction can occur. Antibodies produced by plasma cells leave the nodes via efferent lymphatics. Macrophages t h a t phagocytized

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particles can enter the lymphatics and be transported into lymph nodes (Harmsen et al., 1985; ICRP, 1994).

6.1.8 Mechanisms of Particle Deposition in the Respiratory Tract

There are several mechanisms by which inhaled particles may deposit in the respiratory tract. The five most important mechanisms are impaction, sedimentation, Brownian diffusion, interception, and electrostatic precipitation (Figure 6.3). The information that follows on particle deposition is largely based on a publication by Schlesinger (1989). Other pertinent references include ICRP (19941, NCRP (1997), and Schlesinger (1995).

Sedimentation

Impaction

Diffusion

Interception

Electrostatic

Fig. 6.3. Mechanisms of deposition of particles in the respiratory tract.

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6.1.8.1 Impaction. The impaction of an inhaled particle in the airway can lead to inertial deposition onto the airway surface. Deposition by impaction can occur when the particle momentum is too large for the particle to change directions in an area where there is a rapid change in the direction of the bulk airflow. For particles with diameters 20.5 pm, impaction is an important mechanism for deposition in the upper respiratory tract and in the tracheobronchial region. The probability of impaction increases as the air velocity, particle size, and particle density increase. Air velocity increases as breathing rate increases. For radioactive particles with aerodynamic equivalent diameters >10 pm, impaction in the nasopharyngeal region should be an important mode of deposition in that region. The aerodynamic equivalent diameter (also called aerodynamic diameter) is the diameter of a unit density sphere with the same terminal settling velocity under gravity as the particle considered. When the gravitational force on an airborne particle is properly matched by the forces due to air resistance and air buoyancy, the particle will fall a t a constant rate; this rate is the terminal settling velocity.

Sedimentation. Sedimentation represents deposition caused by gravity. For sedimentation to occur in an airway, the falling particle must interact with the airway wall. The probability of deposition by sedimentation increases as the particle size, particle density, and airway residence time increase. Airway residence time increases as breathing rate decreases. Respiratory tract deposition by sedimentation is important for particles with aerodynamic diameters 10.5 pm, which penetrate to the medium-sized to small bronchi and bronchioles where air velocity is relatively low. 6.1.8.2

Brownian Diffusion. For submicron-sizeparticles, Brownian dffusion is a major deposition mechanism in airways where the bulk flow is low or absent (e.g., bronchioles and alveoli). With Brownian diffusion, particles acquire a random motion because of their bombardment by surrounding air molecules; this motion can result in particle contact with an airway wall. The displacement sustained by a particle depends on a parameter called the diffusion coefficient, which is inversely related to the particle cross-sectional area. Deposition by Brownian diffusion is especially important for particles with diameters less than about 0.2 km. Particles in this size range may also deposit by diffusion in the upper respiratory tract, trachea, and larger bronchi. Deposition in the respiratory tract by Brownian diffusion is unimportant for relatively large particles. 6.1.8.3

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6.1.8.4 Interception. Particle deposition in the respiratory tract can occur when the edge of the particle contacts the airway wall. For elongated particles (e.g., fibers), interception is an important respiratory tract deposition mechanism. The probability of interception increases as the airway diameter decreases. 6.1.8.5

Electrically Charged Particles. Inhaled particles can be electrically charged and may exhibit enhanced regional deposition over what would be expected based on their size, shape and density. The enhanced deposition is due to image charges induced on the surface of the airway by the charged particles and/or repulsion of particles with like charges leading to increased migration toward the airway wall. For very low air concentrations of particles, only the former mechanism is likely to be important. Inhaled, uncharged particles with aerodynamic diameters >10 pm have a high probability of depositing in the nasopharyngeal region. An electrically charged particle with an aerodynamic diameter >10 pm would have an even higher probability of depositing in the nasopharyngeal region than an uncharged particle of the same size, shape and density. 6.1.9

Retention and Clearance of Deposited Particles

The information on retention and clearance that follows is largely based on publications by Cuddihy and Yeh (1988),Oberdorster (1988; 1991; 1993), Schlesinger (1989), and Snipes (1989). Retention is used here to describe the amount of material previously deposited in the respiratory tract (or a region or subregion therein) that is retained there a t a subsequent time (or times) of interest. Clearance is used here to represent the dynamic process whereby the deposited material is removed from the respiratory tract (or a region or subregion therein) (Bailey et al., 1991). For all regions of the respiratory tract, clearance can be described in terms of competing mechanical (mucociliary transport) and absorptive (dissolution/elution) processes (Cuddihy and Yeh, 1988). Mechanical clearance processes move deposited substances toward the oropharynx where they can be swallowed, or to the pulmonary lymph nodes. Absorptive processes lead to the transfer of substances from the respiratory tract and lymph nodes to the blood circulation. Absorption mainly occurs for substances that dissolve or elute from particle surfaces. These substances may react with tissue constituents and remain in the respiratory tract for a long time. Undissolved, free particles may pass into the blood and translocate to other organs or be excreted; this rarely occurs for particles larger than 0.1 pm in diameter.

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Particle solubility is influenced by surface-to-volume ratio and other particle surface characteristics (Snipes, 1989). The rates a t which dissolution and absorption occur are influenced by chemical composition of particles and by other factors. 6.1.9.1 Upper Respiratory Tract. Soluble particles can be cleared from the nasal passages by mucociliary transport. Some material from the particles can also be cleared by absorptive processes into the blood. Insoluble particles that deposit in the nasal passage clear mainly by mucociliary transport. The mucus generally flows toward the nasopharynx. Mucous flow rates in the nasal passage are nonuniform. Regional mucous velocities in healthy adult humans may range from <2 to >20 mm min-I. The most rapid flow occurs in the midportion of the nasal passages. The mean transport rate over the entire region is about 10 to 13 mm min-I. The epithelium in the most anterior part of the nasal passages does not contain cilia. The mucus flows slowly toward the entrance to the nose and is moved by traction associated with actions of more distal cilia. Particles depositing in the nonciliated anterior portion of the nasal passages may be cleared a t a rate of 1 to 2 mm h-'. Because clearance by the indicated mechanism may take up to 12 h, deposited particles are usually more rapidly removed by sneezing, wiping or nose blowing. In such cases, clearance may occur in under 30 min. These results indicate that a radioactive particle deposited in the upper respiratory tract would likely be cleared from the region within 1d after its deposition. Thus, when end-of-work-day monitoring is conducted for possible radioactive contamination of workers, a n inhaled hot particle that deposits in this region hours before monitoring could be cleared from the respiratory tract without its presence being noted. When such exposures are suspected, but not confirmed, possible respiratory tract deposition could be evaluated based on the concentration and size distribution of the particles in air and an estimate of the volume of air inspired. Insoluble particles that deposit in the oral passages are translocated to the GI tract by swallowing. In the NCRP (1997) respiratory tract model, clearance of particles from the oral passages is postulated to occur within 24 h. 6.1.9.2 Tracheobronchial Region. When soluble particles deposit in the tracheobronchial region, diffusion of material dissolved between cells and pinocytotic processes may lead to absorption into the blood (Oberdorster, 1988). Intact soluble particles may also be cleared mechanically by the mucociliary transport pathway.

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The mucociliary escalator is the main clearance pathway for insoluble particles in the tracheobronchial region. The escalator consists of the ciliated epithelium moving a mucous layer on top of it. This layer is composed of a sol phase of low viscosity (hypophase) in which the cilia beat, and an overlaying gel phase of high viscosity (epiphase) thought to be moved by ciliary motion towards the pharynx (Oberdorster, 1988). Clearance of particles depositing in the tracheobronchial region may also occur through phagocytosis (consumption) by airway macrophages, which are either alveolar macrophages moving up the mucociliary escalator or macrophages entering the airways by way of the bronchial and bronchiolar mucosa. Another clearance mechanism, which is less important, is penetration of insoluble particles of submicronic size through the epithelium (Oberdorster, 1993). Some free particles may traverse the epithelium, entering the peribronchial region. Coughlng can be a n efficient clearance mechanism, but clearance by this mode is likely to be limited to the upper generations of the conducting airways. The mucous transport rate varies in different areas of the tracheobronchial region. The mucus moves fastest in the trachea and becomes progressively slower in the more distal airways. Measured rates in the human trachea range from 4 to 10 mm min-' (Foster et al., 1980). In healthy nonsmokers, average tracheal mucous transport rates range from about 4 to 6 mm min-' (Foster et al., 1980; Leikauf et al., 1981; Yeates et al., 1975). For insoluble particles, the transport rate appears to be independent of particle shape, size and composition. The mean mucous velocity in the main bronchi is about 2 rnrn min-' (Foster et al., 1980). Medium size bronchi have an estimated mucous velocity of between about 0.2 and 1mm min-' (Schlesinger, 1989). For the most distal ciliated airways, the mucous velocity may be as low as 0.001 mm min-' (Cuddihy and Yeh, 1988; Yeates and Aspin 1978). In healthy, nonsmoking adults, about 90 percent of insoluble particles in the size range from 1to 10 pm, depositing on the tracheobronchid tree, will be cleared from 3 to 13 h after deposition, depending on the individual and particle size (Albert et al., 1973). Most of the particles are likely to be cleared within 48 h after deposition (Bailey et al., 1985). This suggests that a single radioactive particle that deposits in the tracheobronchial region would have a high probability of clearing the region within 48 h after being deposited. In some studies using laboratory animals, a small fraction of the inhaled particles has been shown to be retained in the nasal and tracheobronchial epithelium for several weeks after exposure.

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Cuddihy and Yeh (1988) summarized these studies and discussed possible mechanisms of prolonged retention. The mechanisms may include pinocytosis (fluid uptake by invagination and pinching off of the cell membrane) by epithelial cells, phagocytosis by macrophages with subsequent translocation into epithelial tissue, passive movement along normal fluid clearance pathways, and trapping in areas where clearance mechanisms have been damaged. Also, the displacement of particles into the mucous sol layer might contribute to longterm retention (Oberdorster, 1988). The bronchial surfaces are not homogeneous. Islands of nonciliated cells occur a t bifurcation regions, whereby the progress of mucous movement can be interrupted. Thus, bifurcations could be sites of retarded clearance of radioactive particles (Snipes, 1989).

6.1.9.3 Pulmonury Region. Clearance of particles from the pulmonary region appears to depend on their size, shape and composition (Cuddihy and Yeh, 1988). Deposited particles smaller than 1 p,m and down to molecular sizes can be found in almost all types of cells in this region. They can be taken into cells by phagocytosis or pinocytosis and can be cleared to the lymphatic vessels, tracheobronchial airways, or blood circulation. Larger particles are mainly taken up by phagocytic cells, then cleared to the tracheobronchial airways or lymph vessels. However, soluble material leaving the surface of radioactive particles can pass directly into the blood circulation. Clearance kinetics in the pulmonary region for insoluble particles are highly uncertain. Insoluble particles that deposit there generally remain much longer than those deposited in the conducting airways. For insoluble particles in healthy, nonsmoking humans, clearance has generally been observed to consist of two components; the first having a half-time on the order of days and a second on the order of hundreds of days. There is a large variation in clearance rates among different individuals. Should a long-lived radioactive particle deposit in the pulmonary region, it could irradiate lung tissue for hundreds of days. However, to do so, the particle must first be airborne, inspired and deposited in the pulmonary region.

6.2 Radiation Response 6.2.1 Deterministic Effects 6.2.1.1 Large Radiation Fields. A large radiation dose to a large area of the respiratory tract can lead to deterministic effects. The

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nature of the effect depends on the region of the respiratory tract considered and how t h e radiation dose is distributed over time. Whereas numerous publications deal with deterministic radiation effects in the lung (e.g., Coggle et al., 1986; Scott and Hahn, 1989; Travis, 1987), less has been published on such effects in the upper respiratory tract (nose, pharynx and larynx) and the trachea. When considering adverse deterministic reactions to radiation therapy, early (or acute) and late reactions refer to the time over which the specific deterministic effects evolve. Early reactions may be seen within a few days after large radiation doses and may subside within a few weeks after fust appearing (Tharnes et al., 1982). Late reactions may appear after several months following a brief, single exposure to external radiation and even later after the start of a fractionated external exposure (Thames et al., 1982) or protracted internal exposure from inhaled radionuclides (Scott and Hahn, 1989). The prevalence of deterministic effects in the respiratory tract depends strongly on absorbed dose, dose rate, linear energy transfer (or its microscopic correlate, lineal energy), fractionation scheme, and volume (or mass or area) of tissue irradiated. Deterministic effects in the respiratory tract are highly unlikely unless the radiation dose exceeds a dose-rate-dependent threshold (Scott a n d Hahn, 1989).

6.2.1.1.1 Large-field effects in upper respiratory tract a n d trachea. Mucosal cells in the upper respiratory tract, which proliferate rapidly, show the earliest radiation-related cell deaths, but can repopulate soon after exposure (Utley, 1987). Underlying bone and cartilage, which have a zero or slow proliferating rate, may show late reactions even though no early reactions may have been observed (Utley, 1987). The prevalence of the late reactions depends on dose, and the reactions may occur months to years after exposure. Because fibrocytes are abundant in submucosal connective tissue, a possible late radiation effect in the upper respiratory tract and trachea is fibrosis. Other possible effects in the upper respiratory tract include mucosal atrophy, vocal chord paralysis, severe (and possibly lethal) hemorrhaging (nose bleeding), swallowing dysfunction, and bone, cartilage and soft tissue necrosis (Rezvani et al., 1989; 1991; Wiernik et al., 1990). For the nose, severe mucosal atrophy was reported after 4.5 to 8 MeV photon therapy for nasopharyngeal carcinoma, based on a retrospective analysis of complications, data for 4,527 patients treated during 1976 to 1985 (Lee et al., 1992). Unconventional fractionation schedules were used because of severe resource limitations. Lee and colleagues reported repeated episodes of nose bleeding

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among some of 4,527 patients who exhibited markedly atrophic and telangiectatic (i.e., presence of dilated vessels) mucosa of the nasopharyngeal region, after total doses of 64 to 66 Gy from different fractionation schedules. Twenty-eight (0.6 percent) of the patients had repeated episodes of nose bleeding, and two (0.04 percent) died as a result of uncontrolled hemorrhage. Lee et al. (1992)cited another publication (Ballantyne, 1975)that reported a one percent incidence of lethal hemorrhaging related to radiation therapy for nasopharyngeal carcinoma. Mesic et al. (1981)reported pharyngeal wall necrosis and vocal chord paralysis to be complications of fractionated photon irrahation of the upper respiratory tract after total doses of 60 to 70 Gy. They also reported xerostomia (dry mucous membranes in the mouth) to be a complication, suggesting that dry mucous membranes in the nasopharyngeal region might also be a complication of irradiation. Soft tissue and bone necrosis were reported as complications of cancer therapy for nasopharyngeal carcinoma (Petrovich et al., 1982; Pryzant et al., 1992).Pryzant et al. also listed swallowing dysfunction as an upper respiratory tract complication and indicated that 2 out of 53 patients (i.e., four percent) receiving second courses of photon radiation therapy of 27.5 to 99 Gy died of swallowing dysfunction secondary to cranial nerve radiation neuropathy; the total cumulative dose ranged from 80 to 160 Gy. Radiation-induced deaths of large numbers of cells in the upper respiratory tract could lead to the following impairments in respiratory-tract function: (1)a reduced ability to transport deposited particles, due to the death of ciliated cells that propel the mucus; (2) a reduced ability to moisten inspired air due to dry mucous membranes; and (3) a reduced ability to detect odors, due to damaged olfactory nerves that reside in the lumen of the nasal chamber. Large radiation doses to the trachea could also lead to a reduced ability to transport deposited particles out of the trachea, and could cause cartilage necrosis and fibrosis. Large-field radiation doses required to induce the above effects have not been reported. 6.2.1.1.2 Large-field effects in lung. More than 40 different cell types are found in the lung, and most would be considered radioresistant (Coggle et al., 1986). However, because much of the tissue in the lung has limited regenerative capacity, the lung cannot tolerate very large radiation doses to large areas. Present knowledge about deterministic effects of large-field, external irradiation of the lung is derived mainly from radiation therapy experience (e.g., Coggle et al., 1986; Depledge et al., 1983; Hines, 1922; Pino Y Torres et al., 1982; Travis, 1987; Van Dyk et al., 1981)

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and from animal studies (e.g., Collis and Steel, 1982; Giri et al., 1985; Hill, 1983; Kurohara and Casarett, 1972; Michaelson and Schreiner, 1971; Travis and Down, 1981; Varekamp et al., 1986). Some additional knowledge has been gained from modeling studies (e.g., Scott and Hahn, 1989; Travis and Tucker, 1987). The lung has been found to be a major dose-limiting organ in radiation therapy for some primary tumors, including esophageal cancer and breast cancer; in therapy for Hodgkin's dsease; in therapy for occult metastases from distant primary tumors; and with forms of radiation therapy involving bone marrow transplantation. Animal studies have demonstrated that for fractionated exposure to external photons, doseresponse relationships for deterministic radiation effects in the lung are very steep, have a threshold, and depend on fraction size, on the total treatment time, and on the volume of tissue irradiated. Much of what is known about deterministic effects arising from inhaled radionuclides is derived from animal studies (e.g., Dagle and Sanders, 1984; Mauderly et al., 1973; 1980; McClellan et al., 1982; Scott and Hahn, 1989). The animal studies demonstrate relatively steep dose-response relationships for deterministic effects of irradiation of the lung with clear indications of dose thresholds (Scott and Hahn, 1989). They also demonstrate that the incidence and prevalence of specific deterministic effects depend on age, total dose, the dose distribution over time, and radiation quality. Radiation-induced injury to the lung can lead to a variety of functional impairments, including reduced compliance, vital capacity, and alveolar-capillary gas exchange efficiency (Mauderly et al., 1980; Scott et al., 1990). Significant deterministic radiation effects in t h e lung were described in a review by Coggle and colleagues (Coggle et al., 1986). The response of the lung in patients and in experimental animals is similar. The main reactions have been divided into two syndromes, which are not necessarily related: (1)radiation pneumonitis, which develops within about six months after brief exposure to photon doses greater than about 8 Gy; and (2) pulmonary fibrosis, which is delayed and may develop from about six months to years after exposure. Radiation pneumonitis from total irradiation of both lungs is usually fatal (Steinberg et al., 1993). The time course of development of the radiation pneumonitis and pulmonary fibrosis syndromes were reviewed by Coggle et al. (1986) and more recently by Benjamin et al. (1991). In their characterizations, the radiation pneumonitis syndrome is called a n acute syndrome, which is divided into three phases: (1)latent phase, (2) exudative phase, and (3) acute pneumonitis phase. The fibrosis syndrome represents a fourth phase of reaction development. The

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extent and timing of each phase is related to radiation dose and its temporal distribution. With fractionated or protracted exposure, a higher dose is required to induce radiation pneumonitis than is required with brief, single exposures. After a brief exposure, the latent phase generally lasts a t least three to four weeks during which there is little morphological evidence of injury noted with light microscopy; however, ultrastructural lesions may be seen (Benjamin et al., 1991). The exudative phase generally occurs three to eight weeks after a single, high-dose irradiation, and is characterized by protein-rich deposits in the alveoli, with evidence of alveolar epithelial and endothelial cell damage (Coggleet al., 1986). Doses on the order of 20 Gy may lead to death during the exudative phase, while lower doses may lead to death during the acute pneumonitis phase. The acute pneumonitis phase occurs two to six months after brief exposure (Coggle et al., 1986) but may occur from 2 to 19 months from the start of protracted exposure (Benjamin et al., 1991). Acute pneumonitis involves the accumulation of fluid (edema) in the air spaces and in the alveolar septa, and desquamative changes occur in epithelial and endothelial cells. Interstitial pneumonia occurs during the phase and is characterized by infiltration of the alveolar septa with lymphocytes, monocytes and neutrophils, and with fibrin, macrophages and neutrophils accumulating in the alveoli; also, alveolar Type I1 cells increase both in number and size (Benjamin et al., 1991). The fibrosis syndrome is a late, chronic phase that occurs 6 to 12 months onward, after brief exposure, and involves proliferation of septa1 and alveolar cells leading to reconstructional changes in septal, vascular and connective tissue elements. This process leads to an increase in interstitial fibrosis and capillary sclerosis that characterizes the late radiation fibrosis (Coggle et al., 1986). Vascular lesions represent another effect of irradiation of the lung (Benjamin et al., 1991). Similar lesions occur after external gamma or internal beta irradiation. The observed lesions include blood vessel inflammation (vasculitis) and fibrinoid necrosis, whch can involve both bronchial and pulmonary vessels. Progressive vascular inflammation can lead to fibrous accumulation around blood vessels and to narrowing of the lumen. Benjamin et al. (1991) indicate that these and other lesions can lead to pulmonary hypertension. Dose-response models have been developed for evaluating the mortality risk or morbidity risk associated with exposure of the lung to beta andlor gamma radiation (Scott and Hahn, 1989). The cited mortality model provides central-, upper- and lower-bound estimates of threshold doses for inducing acute pneumonitis-syndrome

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lethality when the entire lung is irradiated. These estimates are given in Table 6.2 and depend on average dose rate to the lung and on age. For persons over age 40, indicated threshold estimates should be divided by two. Corresponding threshold estimates for respiratory-functional morbidity associated with impaired respiratory function can be obtained by dividing threshold estimates for mortality by two (Scott and Hahn, 1989). Respiratory-functional morbidity is considered to occur if any three of the following radiation-induced effects are found in the lung (Filipy et al., 1988, 1989; Scott and Hahn, 1989; Scott et al., 1987): (1)a reduced volume, (2) a reduced compliance, (3) a nonuniform gas distribution, or (4) a reduced alveolar-capillary gas exchange efficiency. 6.2.1.2 Hot Particles. When a subregion of a given region of the respiratory tract (eg., subregion of the lung) is irradiated by a single radioactive particle, a larger threshold dose for a given level of functional impairment would be expected than is required when the total region (e.g., entire lung) is more uniformly irradiated (Scott et al., 1992). This claim is supported by animal data for respiratory functional effects of partial lung irradiation (Travis, 1987) and by clinical studies on the effects of partial organ irradiation (Cohen, 1982; Emami et al., 1991; Kutcher and Burman, 1989; Kutcher et al., 1991; Lawrence et al., 1992; Lyman, 1985; Lyman and Wolbarst, 1987; Molls et al., 1993). For example, clinical data indicate that serious

TABLE6.2-Acute pneumonitis-syndrome lethality thresholds for healthy young adults (age 40 or less) exposed to beta or gamma radiation or both (based on Scott and Hahn, 1989).9b1c Threshold Dose to Entire Lung (Gy) Dose Rate (Gyh-')

Lower Bound

Central Estimate

Upper Bound

"For individuals over age 40, indicated estimates should be divided by a n age-sensitivity factor of two. bTo obtain estimates of thresholds for respiratory-functional morbidity, threshold estimates for lethality should be divided by two. 'For alpha radiation, indicated thresholds should be reduced by an RBE of seven, with lower and upper bounds of 5 and 10, respectively (Scott, 1993).

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clinical symptoms may not arise if <20 percent of the lung is irradiated (Molls et al., 1993). For some functional endpoints, no impairment in function may be induced when a small subregional mass of tissue is irradiated by a hot particle. Whether a single moving (by mucociliary transport) hot particle (in respiratory size range) in the upper respiratory tract or trachea could produce a dose in excess of the threshold for deterministic radiobiological effects is currently unknown. Presently, there are no dosimetry models to evaluate radiation dose distribution from a single beta or betalgamma-emitting particle that deposits in the upper respiratory tract and moves along with t h e mucus. One possible local effect would be a decreased efficiency in mucociliary transport of trapped particles due to radiation-induced damage of ciliated cells. Some insights about whether hot-particle irradiation of the upper respiratory tract could lead to a reduction in the efficiency of mucociliary transport of deposited particles can be obtained by considering respiratory tract dosimetry models. The new NCRP (1997) and ICRP (1994) respiratory-tract dosimetry models are based on the implied assumption that regional (or subregional) mucociliary transport rates do not depend on regional (or subregional) radiation dose. While the ICRP model allows for particle sequestering in the upper respiratory tract, the probability of sequestration is very small and does not depend on the radiation dose to target tissue. With the ICRP model, a nonsequestered insoluble particle in the upper respiratory tract is about 2,000 times more likely than a sequestered insoluble particle in that region. Based on the ICRP respiratorytract dosimetry model, a single, insoluble hot particle in the region would be expected to be removed from the region by nose blowing or by translocation to the GI tract with a probability very close to one. Radioactive particles that deposit in the alveolar region of the respiratory tract can remain and irradiate the lung tissue for extended periods. However, as particle activity increases, so does aerodynamic size (see Figure 6.4) and radioactive particles with aerodynamic diameters >10 pm deposit, with high probability, in the upper respiratory tract where they are usually removed rather quickly from the respiratory tract. Particle deposition fractions (or efficiencies) for three regions of the respiratory tract (nasopharyngeal, tracheobronchial and pulmonary) are given in Figure 6.5 as a function of particle aerodynamic size. The deposition fractions represent average values expected when large numbers of monodisperse particles are inhaled. The fractions can be used to estimate regional deposition probability when a single particle is inhaled.

1

6.2 RADIATION RESPONSE

139

Relative Spectfk ~ c t l v i t y(%)

20

1

I

I

3

4

5

I

I

I

7 Activity In kBq

8

9

I

6

I 10

Fig. 6.4. Aerodynamic equivalent diameters (in micrometer) for activated spherical particles of cobalt-rich alloy as a hnction of particle radioactivity in kilo-becquerel a n d relative specific activity (dimensionless). Relative specific activity is evaluated a s a percentage of the assumed maximum specific activity of 1.85 x 1012Bq g-' for activated cobalt-rich alloy.

0.0001

; 1

I

I

I

I

2 4 8 16 Aerodynamic Diameter, Micrometers

I

32

Fig. 6.5. Regional deposition fractions (or efficiencies) for adults, for activated hot particles of cobalt-rich alloy, a s a function of aerodynamic equivalent diameter (in micrometer) based on Changet al. (1991). Deposition fractions are corrected for particle inhalability. Results are presented for a tidal volume of 1,300 mL.

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6.2.2 Stochastic Effects 6.2.2.1 Large Radiation Fields. Irradiation of large areas of the respiratory tract can arise from large external radiation fields or from inhaled radionuclides. The major stochastic effect that might arise from irradiation of large areas of the respiratory tract is cancer. Some information on cancers in the different regions of the respiratory tract associated with large-area irradiation are provided below. 6.2.2.1.1 Nasal cavity, pharynx, larynx a n d trachea. An analysis of t h e Life S p a n Study cohort of J a p a n e s e atomic-bomb s u r vivors exposed to gamma rays and neutrons indicated that a total of 44 cases of nasal cancer were observed during 1950 to 1985 (NAS/NRC, 1990). However, there was no indication of a doseresponse relationship for radiation-induced nasal cancer. Furthermore, no radiation-induced excess of nasal cancers has been evident in 14,106 patients who received a single course of x-ray treatment for ankylosing spondylitis (Darby et al., 1987); however, the average dose for these patients was only about 0.5 Gy (NASNRC, 1990). I n a report on solid tumor incidence among atomic-bomb survivors (Thompson et al., 1994), based on the Extended Life Span Study cohort, data for cancer of the pharynx and oral cavity were combined and used in evaluating RR. There was only a slight indication of a n enhanced risk for all cancers of the oral cavity and pharynx (salivary gland tumors however, showed a significant dose response). These results agree with findings based on mortality data from the Life Span Study cohort, where cancers of the tongue and pharynx were analyzed and no radiation effect was seen (Shimizu et al., 1990). However, cancers of the pharynx and larynx have been observed to arise as a late complication of fractionated therapeutic irradiation after doses in the range 30 to 60 Gy (NASLNRC, 1990). Because no significant excess in cancers of the pharynx and larynx was observed in atomic-bomb survivors or other populations exposed to doses in the range below 1 Gy, it was concluded by the National Academy of Science's Committee on the Biological Effects of Ionizing Radiation (BEIR) that the risk of radiation-induced cancers in the pharynx and larynx appears to be very low for doses in this range (NASLNRC, 1990). Data were presented in BEIR I11 (NASLNRC, 1980) related to the induction of cancer in the paranasal sinuses and mastoid air cells by deposited The carcinomas are thought to arise from alpha irradiation of the nasal epithelium from 222Rngas and radon progeny in the air above the epithelium and from emissions, primarily beta and gamma radiations, from n6Ra and its progeny in the underlying bone (NAS/NRC, 1988).

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Animal studies in which beagle dogs inhaled or received intravenous injections of beta-emitting radionuclides demonstrated that relatively high local beta andlor gamma doses and dose rates to bone can occur in the nasal cavity because of patterns of radionuclide deposition and retention and can lead to nasal cavity cancers (Benjamin et al., 1979; Boecker et al., 1986). While the dog studies indicated that the induction of nasal cavity cancers by intensive local irradiation with betdgamma emitting radionuclides could occur, they also demonstrated that the risk for such radiogenic effects is quite small in dogs. Sanders et al. (1993) evaluated data from several studies in rats of different strains (Wistar, F344, Long-Evans) related to carcinoma induction in the upper respiratory tract by 2 9 9 Palpha ~ irradiation. The rats were exposed by way of inhalation to 2 3 9 P ~ 0Activity 2. median aerodynamic diameters ranged from 1.1to 2.2 Fm. A small number of the relatively insoluble 239P~02 particles were retained for long periods in subepithelial regions of the larynx and nasal cavity. However, these 239Pu02particles contributed only a small fraction of the total dose to the airway epithelium indicating that such particle sequestration is rare. Excess tumors were observed only in the nasal cavity. There is no evidence that tracheal cancers are induced by ionizing radiation and spontaneous tracheal tumors are rare (ICRP, 1994). 6.2.2.1.2 Lung. Much of what is known quantitatively about the risk for specific types of lung cancer induced by external large-field irradiation comes from 'radiation therapy studies and from studies of survivors of t h e atomic bombs in Hiroshima a n d Nagasaki (Evans et al., 1993; Land et al., 1993; NAS/NRC 1980; 1988; 1990; UNSCEAR, 1988). In studies of the atomic-bomb survivors, radiation exposure was found to increase the risk of SCC (epidermoid) carcinoma, small cell carcinoma, and adenocarcinoma (Mabuchi, 1991). However, other epidemiological studies (Howe, 1995) have demonstrated that for highly fractionated exposure to photon radiation, the risk of radiogenic lung cancer may be less than predicted from data for single exposure a t a high rate. Much of what is known quantitatively about the risk of specific types of lung cancer arising from internally incorporated radionuclides comes from epidemiological studies of populations exposed through inhalation of radon and radon decay products (e.g., Land et al., 1993; Lubin et al., 1994; 1997; NASNRC, 1988; 1990; 1998; NCRP, 1975; 1984; Tomasek et al., 1994) or from animal inhalation exposure studies involving alpha or betdgamma emitting radionuclides (Hahn et al., 1992; NAS/NRC, 1988; 1990).

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In a comparison of the histology of lung cancers in uranium miners and survivors of the atomic bombings of Hiroshima and Nagasaki, Land et al. (1993) concluded: 1. The proportion of SCC was positively related to smoking history in both populations. 2. I n both populations, radiation induced cancers appeared more likely to be of the small-cell subtype, and less likely to be adenocarcinomas.

In a comparison of lung cancer in miners and nonminers that smoked, Saccomanno et al. (1996) found different spatial distributions of lung tumors. A higher percentage of central tumors was seen in miners and was primarily due to the distribution of a greater proportion of squamous cell and small-cell tumors. The data suggest that radon may preferentially deposit in the central region of the lungs in uranium miners. Preliminary studies of 239Pu induced lung cancer in Mayak workers by Tokarskaya et al. (1995; 1997) found that adenocarcinoma had the strongest association with alpha radiation from inhaled 239PU. They also found SCC to have the strongest association with cigarette smoking. Further, lung tumors were more frequently observed in the lower and middle lung lobes and at the lung periphery. Koshurnikovaet al. (1997)using preliminary data for Mayak workers exposed to alpha radiation Erom inhaled 2 3 9 Pderived ~ a risk coefficient 1.42 x Sv-I for the probability of fatal cancer based on a presumed linear dose-response relationship. However, results of the study of Tokarskaya et al. (1997), based on a multifactorial analysis, indicated that the dose-response relationship for 2 3 9 P ~ induced lung cancer may have a threshold. Inhalation exposure studies using dogs demonstrated that, for lung tumor induction, dose-rate patterns arising from inhaled beta1 gamma emitting radionuclides may be unimportant for doses 4 0 Gy (Grifith et al., 1992). The RR for lung cancer induction was found to be a linear function of average dose to the total lung and independent of dose-rate pattern for doses up to about 50 Gy. Other animal s t u d i e s d e m o n s t r a t e d t h a t uniformly d i s t r i b u t e d a l p h a radiation dose to the lung is more effective in inducing lung tumors than is a nonuniformly distributed dose (Bair et al., 1974; NCRP, 1975). Relative radiosensitivities of respiratory tract components. Estimates of relative radiosensitivity used in the ICRP (1994)respiratory tract dosimetry model for partitioning of radiation detriment among the regions of the respiratory tract are presented

6.2.2.1.3

6.2 RADIATION RESPONSE

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143

in Table 6.3 (Bair, 1991; James et al., 1991). For the extrathoracic and thoracic compartments, the WT that are to be apportioned are 0.025 and 0.12, respectively (ICRP, 1991a). For the ICRP respiratory tract dosimetry model, it was assumed that the relative sensitivities of the various tissues of the respiratory tract to all radiation-induced deleterious effects are the same as for cancer and that all regions of the respiratory tract are susceptible. The results provided in Table 6.3, along with the indicated WT,can be used to judge which regions of the respiratory tract are likely to be critical targets for radiation-induced stochastic effects when dose distribution over the respiratory tract is known. 6.23.2 Hot Particles. Although i t is considered unlikely that hot particles are being inhaled by workers a t nuclear power operating facilities in the United States, the potential for inhaling hot particles in the workplace poses several unique radiation protection concerns. These include assessing radiation dose distribution and evaluating risk for stochastic effects, should a hot particle be inhaled and deposited in the respiratory tract. The radionuclide content, chemical composition, size, and geometry of a n inhaled airborne hot particle will have important influences on the site of deposition and its retention, and therefore, on the associated radiation dose distribution to tissue. Movement of a hot particle within the respiratory tract (e.g., by mucociliary transport) would influence the spatial distribution of

TABLE6.3-Estimates of relative radiosensitivity for partitioning of radiation detriment among the regions of the respiratory tract (Bair, 1991; ICRP, 1994). Regions Extrathoracic Anterior nasal cavity Posterior nasal passage, larynx, pharynx and mouth Lymphatics Total for extrathoracic Thoracic Bronchial Brorichiolar Alveolar-interstitial Lymphatics Total for thoracic

Factors for Apportionment of Radiation Detriment 0.001 1

0.001 1.00 0.333 0.333 0.333 0.001 1.00

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6. RESPIRATORY TRACT

the radiation dose. While there are dosimetry models for cases in which large numbers of hot particles are inhaled (Bair, 1991; ICRP, 1994; NCRP, 1997; Phalen et al., 1991), there are no dosimetry models specifically developed for evaluating deposition, retention and associated radiation dose distribution from inhaling a single betalgamma-emitting hot particle or a small number of such hot particles (e.g.,two or three). While deterministic dosimetry models can be used when large numbers of hot particles are inhaled, stochastic dosimetry models are needed for a single hot particle and for a small number of such hot particles, except when maximum radiation dose to a given region is evaluated (Scott et al., 1993). Issues related to potential stochastic radiobiological effects in the lung associated with the release of alpha-emitting hot particles from nuclear power operating facilities have been extensively discussed in earlier publications (Bair et al., 1974; ICRP, 1969; 1972; NCRP, 1971; 1975; Tamplin and Cochran, 1974). An important conclusion related to these research efforts is that the use of average dose to the lung from alpha-emitting particles does not lead to underestimation of the risk of stochastic effects, but may lead to overestimation of the risk for such effects. The use of average radiation dose to the lung for evaluating the risk of stochastic effects is supported by animal data for lung tumors induced by x-ray microbeam irradiation (Coggle et al., 1985). Nonuniform irradiation of the lung by low-LET radiation was not demonstrated to be more effective than uniform irradiation. However, information provided in ICRP Publication 66 (ICRP, 1994) indicates that radiosensitivity for cancer induction likely varies over the lung, even though the same W T is presently assigned to different regions of the lung (see Table 6.3). Presently available information was not sufficient for developing different W T for different regions of the lung. While use of average dose to the lung may be acceptable for evaluating the risk of stochastic effects, dose should not be averaged over different regions (nose, pharynx, larynx, trachea, lung, etc.) of the respiratory tract because different regions have been reported to have very different radiosensitivities (Bair, 1991). Some modeling (Hofmann et al., 1988; Likhtariov et al., 1995; Mayneord and Clark, 1974) and experimental (Lang et al., 1991; 1995) results suggested that use of average absorbed dose for hot particles that emit low-LET radiations may lead to bias in the risk estimates when dose is averaged over a single region of the respiratory tract. The use of the risk apportionment factors presented in Table 6.3 in conjunction with the ICRP (1991a) w~ (0.025 for the extrathoracic compartment and 0.12 for t h e thoracic compartment) allows

6.2 RADIATION RESPONSE

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145

evaluation of effective dose for hot-particle exposure of the respiratory tract. However, there is currently no dosimetry model designed specifically for evaluating the absorbed-dose distribution to the respiratory tract arising from a single mobile betalgamma-emitting hot particle. Equivalent dose distribution over the respiratory tract will depend on where the particle deposits in the respiratory tract, its radionuclide content, self-absorption properties, and its behavior after deposition (e.g., dissolution, particle movement). Based on Table 6.3, the w~ appropriate for the anterior nasal cavity is 0.025 x 0.001 or 0.000025, which is 1,000-fold smaller than the W T of 0.025 for the posterior nasal passage, pharynx and mouth. This suggests that for the anterior nasal region, deterministic effects of hot-particle exposure may be the major health concern. Radioactive hot particles with aerodynamic diameters >10 km are much more likely to deposit in the upper respiratory tract (nasal and pharyngeal regions) than in the tracheal, bronchial, bronchiolar or alveolar-interstitial regions. Thus, the posterior nasal passage, pharynx and mouth may be the critical regions for limiting stochastic effects of hot-particle exposure. Information that may facilitate calculating hot-particle doses to target cells for some parts of the respiratory tract is provided in Table 6.4, based on the ICRP Publication 66

TABLE6.4-Average range of target cell nuclei depths used for dosimetry evaluations in the ICRP Publication 66 respiratory tract dosimetry model (adapted from ICRP, 1994)." Average Range of Average Thickness of Mucus Layer Cell Nuclei Depths

Site

Target Cells

Nasal vestibule Basal Oropharynx and larynx Basal Bronchi Secretory Basal Nonrespiratory Secretory bronchioles Respiratory bronchioles Secretoryd Type 11 Alveolar surface

(w)

40-50 40-50 10-40 35-50 4-12

negligiblee

-

(~m) -

15 5b

5b 2' -

aSites not indicated represent those for which the ICRP Publication 66 model does not calculate doses ( e g . , posterior nasal cavity, nasopharynx, trachea). bAverage thickness of cilia (sol) layer, 6 pm. 'Average thickness of cilia (sol) layer, 4 pm. dClara cells. T o r dosimetry purposes, surface doses will be adequate.

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respiratory tract dosimetry model (ICRP, 1994). Average ranges for target cell nuclei that are used for dosimetric evaluations in the ICRP Publication 66 model are indicated for the nasal vestibule, oropharynx and larynx, bronchi, nonrespiratory bronchioles, and respiratory bronchioles. However, calculating radiation doses to specific parts of respiratory tract that could arise from inhaling airborne hot particles is not trivial when the air concentration of such hot particles is low enough that there is no guarantee that a hot particle will be inhaled in the time period considered (Scott et al., 1992; 1993). Harley et al. (1996) also published data for target cell nuclear depths (for lung cancer induction) averaged over generations three to six, based on tissue from surgical specimens obtained at New York University Tisch Hospital. Results obtained were based on a total or 9,954 basal cell nuclei and 8,958 secretory cell nuclei and are summarized in Table 6.5.

6.2.3 Summary of Hot-Particle Irradiation in the Respiratory Tract 1. For respiratory function endpoints, no impairment in function may be induced when a small subregional mass of tissue is irradiated by a hot particle. 2. Whether a single moving (via mucociliary transport) hot particle in the upper respiratory tract or trachea could cause a significant deterministic effect is unknown.

TABLE 6.5-Average depth (in micrometer below the epithelial surface) of target cell nuclei for lung cancer induction based on tissue from surgical specimens at New York University Tisch Hospital (Harley et al., 1996)." Population

Basal Cell Nuclei (N)

Male Smokers Nonsmokers Ex-smokers

28 26 25

Female Smokers Nonsmokers Ex-smokers

27 5 1.6 (28) 27 +. 1.5 (22) 30 -+ 2.0 (17)

a 1.8 (23) ?

?

1.6 (10) 2.1 (15)

Secretory Cell Nuclei (N)

22 18 18

+ 1.4 (28) + _t

1.3 (10) 1.4 (15)

20 + 1.6 (29) 17 +. 1.0 (24) 20 -+ 1.3 (17)

"The depth of the nucleus was evaluated from the midpoint of the nucleus to the free epithelial surface. N is the number of subjects associated with the mean. Here "secretory cell" is used instead of "mucous cell."

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3. Hot-particle deposition in the alveolar region of the respiratory tract is unlikely when airborne hot particles occur in small numbers. 4. For the anterior nasal region, a deterministic effect of hotparticle exposure is judged to be the major health concern. 5. The posterior nasal passage, pharynx and mouth are judged to be the critical regions for limiting stochastic effects of hotparticle exposure when, a t most, only a few hot particles are inhaled.

7. Gastrointestinal Tract

7.1 Structure and Function The GI tract consists of the mouth, pharynx, esophagus, stomach, small intestine, large intestine, and anal canal. The tract commences a t the mouth, terminates a t the anus, and has a typical length of 8 to 10 m. The portion that is located in the head, neck and thorax consists of the mouth, pharynx and esophagus. The distance from the mouth to the beginning of the esophagus is 14 to 16 cm; the esophagus itself is 23 to 30 cm in length. The remainder of the GI tract lies in the abdomen and pelvic cavity. The distance from the top of the stomach to the anus can be as much as 9 m. The anatomical relationships among the various portions of the GI tract are shown in Figure 7.1. The different anatomical regions of the GI tract have several common structural characteristics. From inner to outer layer, each has an inner epithelial layer, a lamina propria, a submucosa, muscle layers, a muscularis mucosae, and an outer serosal layer (Figure 7.2). Each layer has additional components that serve specific functions in particular anatomical segments. The epithelial lining provides a selectively permeable barrier between the GI tract contents and body tissues. The epithelial lining, the lymphoid nodules in the lamina propria, and the submucosa, protect the body from both viral and bacterial invasion (Junqueira et al., 1975). If this barrier is severely damaged by any agent, then the potentially harmful secondary effects from viral and bacterial invasion can occur. Ingested material moves quickly from the oral cavity via the esophagus to the stomach. Ingested water passes rapidly to the small intestine where it then passes through cell junctions to the extracellular fluid and then to the blood (Davenport, 1977). Ingested food is partially digested in the stomach and then passes into the small intestine where the nutrients are absorbed. Most residual water is reabsorbed by the large intestine. The esophageal wall is estimated to be 3.5 to 5.6 mrn thick. Its epithelium is the non-keratinized stratified squamous type (Figure 7.3). However, an abrupt change in the epithelial type takes place

7.1 STRUCTURE AND FUNCTION

1

149

--Submandlbular

Junctlon of

Transverse Colon

Fig. 7.1.

Gross features of GI tract (adapted from Bergmanet al., 1989).

near the junction with the stomach, where the surface cells become columnar mucous secretory cells. Some gross and microscopic aspects of the stomach are shown in Figure 7.4. The stomach wall is estimated to be 0.6 to 1.3 cm thick and the mucosal layer 0.5 to 2.5 mm thick. The mucosal layer consists of tall, columnar mucous-secreting cells, which also line prominent invaginations (the gastric pits). Secretions of the gastric glands are discharged into these pits. The terminology used to describe features of gastric glands has never been totally standardized but the mammalian gastric mucosa is generally considered to contain three

150

1

7. GASTROINTESTINAL TRACT lnner circular muscle layerH"~~O~elium

tudinal muscle

lnner circular muscle layer Myenleric plexus Gland in submucosal layer

et

Fig. 7.2. Schematic structure of a portion of the GI tract (Junqueira al., 1975).

Fig. 7.3. Transverse section of upper esophagus (DiFiore et al., 1973).

snanur aanpoxd q a ! q ~ 's11aa yaau snoanur (E) !uo!qamas pue s!saqq - d s u a 8 o ~ s d a da!qse8 jo qjs pa3pa1~ouqa-ea m 'snaa jaqa (z) fppe a!xomaoqLq aqaxaas pue aqaxoqela y a y '(pqa~x-ed) ~ a!qulCxo (I) :sadA$ Ilaa aArJ anay pue qaemoqs a w j o Lpoq pue s n p u y aqqjo qsom ddnaao s p u a p a!?dxo ay& 'sl~aaauyaopua pue '(uraqs) sIIaa pqa!$uaxagFun 's11aa snoanur u!a?uoa pua aaguo lea8eydosa ay? xaau pqeaol axe pawau ?sxg aq& -apolLd pue a g d x o 'aypxsa :sad4 p u e p pugs!p

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and protect the stomach from some of its own secretory products; (4) undifferentiated (stem) cells; and (5) endocrine cells. The pyloric glands contain mucus-secreting cells similar to mucous neck cells of the oxyntic glands. Thus, summing over all areas of the gastric mucosa, there are five distinct cell types (Ito, 1987). More detailed reports of the morphological and dynamic features of epithelial cells of the stomach may be found in Karam and Leblond (1993). The stem cells, located at various depths in different regions of the stomach are in the gastric glands below the base of the pits, which are considered to be about 200 p,m deep (McGuigan, 1973). Stem cells have been described as an undifferentiated granule-free cells located in the isthmus of a gastric gland in the fundus and body (Kararn and Leblond, 1993). Stem cells have also been considered to be in the neck region (Awwad, 1990; Roswit et al., 1972). Cell division and DNA synthesis are limited to the isthmus and neck of the glands. Descendants of these stem cells migrate in two directionstowards the mucosal surface where they mature into the mucussecreting columnar cells and towards the bottom of the glands where they differentiate into parietal or chief cells (Awwad, 1990). Therefore,the stem cells, which are potential targets for carcinogenesis could not be reached by radiation from alpha emitters located in the stomach contents, but could be irradiated by gamma emitters and energetic beta emitters in the stomach contents (Harley and Robbins, 1994). The small and large intestine is a tube that follows a coiled course between the stomach and rectum. In humans, the small intestine is about 2 to 4 m in length and has a wall thickness of approximately 0.3 cm. It is divided into three parts-the duodenum, jejunum and ileum, which are similar to one another in structure and in their response to irradiation. The mucosa of the small intestine is covered by a simple epithelium that lines the distinctive villi and intestinal glands, also known as the crypts of Lieberkuhn. Four cell types are present: (1)simple columnar absorptive cells; (2) goblet cells producing protective mucus; (3) Paneth cells, which produce and secrete lysozyme capable of digesting bacterial cell walls; and (4) argentaffin or enteroendocrine cells, which produce a variety of hormones regulating activity of the GI system (Figure 7.5). The intestinal glands located between the bases of the villi serve as the source of new epithelial cells for the villi. Four layers of cells in the deepest portion of the glands of mice are considered to be the stem cells (Potten, 1995).The stem cell zone in humans is not known with certainty (Potten, 1995).Surrounding the intestinal glands and forming the core of each intestinal villus is the lamina propria, which

7.1 STRUCTURE AND FUNCTION

1

153

I

~arnina'propria G I & ~ S Muscularis mucosae

Fig. 7.5. Schematic diagrams illustrating the structure of the small intestine (Junqueira et al., 1975).

characteristically contains scattered lymphocytes, lymphatic aggregates, plasma cells, eosinophils, macrophages, mast cells, and smooth muscle fibers derived from the underlying muscularis mucosae. The lamina propria has a rich capillary network and a lymphatic capillary network in the core of each villus. Located in the outermost layer of t h e lamina propria is a band of smooth muscle, t h e muscularis mucosae, composed of inner circular and outer longitudinal layers (Rgure 7.5).

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7. GASTROINTESTINAL TRACT

The large intestine in humans is 1.5 to 2 m long and approximately twice the diameter of the small intestine. There are four anatomically-defined segments: cecum, appendix, colon and rectum. The colon is regionally sub-divided into ascending, transverse, descending and sigmoid areas. The large intestine begins a t the ileocecal valve, which is formed by two folds of the mucosa and submucosa and circular smooth muscle. The initial segment of the cecum is a blind pouch from which the worm-like appendix extends. The surface lining is primarily a simple columnar epithelium with some goblet cells. Lymphoid tissue in the form of solitary lymphatic nodules forms a conspicuous part of the lamina propria (Figure 7.6), particularly in the appendix. A distinctive feature of the cecum and colon, excluding the appendix, is the arrangement of the smooth muscle of the muscularis externa. The inner muscular layer is circular, while the outer longitudinal layer is aggregated into three equally spaced bands. The rectum, 12 to 18 cm in length, is very similar in structure to Serosa -,

Fig. 7.6.

Muscular~sexterna Submucosa .-, Mm

MUCOSB Larnlna oroola Eolthelium

Transverse section of the large intestine (DiFiore et al., 1973).

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RADIATION EFFECTS

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155

the colon but lacks the bands of longitudinal smooth muscle. At the rectal-anal junction, the simple columnar surface epithelium changes to a non-keratinized stratified squamous epithelium, which then changes a t the anal orifice to its keratinized form (epidermis). The structure in each region of the large intestine described is similar to the small intestine in most respects, but the epithelial lining lacks the villi that characterize the small intestine. There are crypts that are tightly packed and, except for villus structures, the same cell types are found in the large intestine as in the small intestine.

7.2 Radiation Effects 7.2.1 Deterministic Effects in the Esophagus The descriptions that follow have been separated into two categories: patient (human) studies and animal studies. Unfortunately, radiation treatment volumes are often not documented, so the influence of this variable cannot be estimated. Investigations of radiation-induced esophageal injury in patients have evolved from the estimation of a tolerance dose for injury, characterization of the early response and attempts to repair injury, and the subsequent expression of late effects, to studies intended to modify or prevent these changes and to understand the mechanisms involved. Typically, observations have been made on patients who had radiotherapy for carcinoma of the esophagus or whose esophagus was initially normal, but was of necessity included within the treatment volume. Such data have inherent limitations.

7.2.1.1 Patient (Human)Studies. The esophagus was once considered to be fairly radioresistant (Desjardins, 1931). Even though Engelstad (1934) described marked histological changes in the esophagus of irradiated dogs, subsequent investigators, including Warren and Friedman (1942), did not consider the esophagus to be especially radiosensitive. However, there were subsequent clinical reports with results similar to those of Engelstad (1934). Responses to irradiation of a portion of the esophagus have been shown to be dose-dependent and range from mild substernal discomfort during and after irradiation to permanent loss of the epithelial lining, severe inflammation (esophagitis), extensive fibrosis, and extreme difficulty in swallowing (dysphagia). Seaman and Ackerman (1957) described t h e clinical and pathological changes in t h e

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esophagus followingradiotherapy for cancer of non-esophagealstructures. The reactions included mild-to-moderate substernal burning, which typically commenced during the third week of therapy and continued for several weeks after treatment was completed. The most severe reactions included marked dysphagia, development of strictures, and the formation of channels (fistulae) between the trachea and pharynx. Esophagitis and dysphagia were noted 12 to 30 d after the initiation of radiotherapy with doses of about 2 Gy per fraction and total doses of about 20 Gy in two weeks to 45 Gy in four weeks. Regeneration of damaged epithelium, prominent changes in the submucosa, and some muscle changes were seen in esophagi examined 8 to 12 months after radiotherapy. These changes sometimes led to esophagitis, frequent narrowing of the lumen with consequential dysphagia, and occasional appearance of a stricture andlor perforation. Roswit et al. (1972) reported that almost all patients who underwent irradiation of the esophagus with fractionated doses of 20 to 30 Gy for treatment of primary esophageal cancer, bronchogenic carcinoma, or mediastinal tumors, experienced some discomfort attributable to substernal burning, narrowed lumen, and dysphagia. This conclusion is in agreement with earlier findings of Seaman and Ackerman (1957). However, lasting damage such as stricture or perforation was rarely seen in a previously normal esophagus, even after doses of conventional fractionated radiation as high as 60 Gy to the mediastinum (Roswit, 1960; Roswit et al., 1972). Rubin and Casarett (1968) summarized the pathology of the acute clinical period after a typical course of fractionated radiation therapy. Although doses below 60 Gy often led to motility changes and loss of mucosal epithelium, these changes were usually later reversed, while doses above 75 Gy were followed by severe fibrosis of the lamina propria and submucosa with subsequent stricture and perforation (Rubin and Casarett, 1972).This pattern has been noted by others (Goldstein et al., 1975; Nelson et al., 1979) Berthrong and Fajardo (1981)concluded that in most fractionated treatment schemes where the normal esophagus is in the treatment volume: (1) the esophageal epithelium is moderately radiosensitive but usually regenerates rapidly; (2) subacute and chronic ulceration may persist, even in the absence of a tumor; (3) narrowing of the lumen is rare but when it does occur, it is the result of submucosal fibrosis; (4) interstitial fibrosis and homogenization of smooth muscle may also occur; and (5)injury and fibrosis of the muscular nerve plexus may also contribute to functional abnormalities such as changes of motility.

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Lepke and Libshitz (1983) studied 40 irradiated patients who did not have carcinoma of the esophagus. Abnormalities generally occurred &er fractionated doses of 45 Gy and above. Mascarenhas et al. (1989) evaluated 38 patients who received 60Coteletherapy for carcinoma of the lung; 18 developed symptoms of acute esophagitis a short time after a fractionated dose of 30 to 40 Gy to the esophagus. Progressive dysphagia and chronic esophagitis appeared two months or more after radiotherapy. Thus, in spite of variations in patient treatment schemes, different investigators have observed many of the same patterns of radiation injury. It is also clear that few changes of significance occur when the total of conventional fractionated doses is below 20 Gy. 7.2.1.2 Animal (Non-Human) Studies. Animal studies of radiation-induced esophageal injury have yielded some useful data for predicting consequences in patients, as well as providing models for studies of procedures designed to modulate radiation-induced esophageal injury. The classic paper of Jennings and Arden (1960) describes in the rat the sequence and timing of histological changes after irradiation of only the esophagus with a single dose of approximately 30 Gy of x rays. They considered this dose to be the equivalent of 20 x 2.5 Gy fractions over four weeks. The earliest effects were noted a t day four, and consisted of a slight submucosal congestion and infiltration of leukocytes. By day six, there was mucosal necrosis and the epithelium was lost. By day seven, there was extensive sloughing of the necrotic esophageal mucosa. Although epithelial cell necrosis accompanied esophagitis during the second week post-irradiation, there was progressive healing during the third week. Submucosal fibrosis and telangiectasia were prominent even after the epithelium had recovered. Similar results have since been obtained by a number of investigators (Kurohara and Casarett, 1972; Mascarenhas et al., 1989; Sindelar et al., 1988). In rats receiving single doses of 6 or 12 Gy, changes in the esophageal mucosa were manifested as early as 1 to 2 d after irradiation. There was a considerable incidence of such changes in the mucosa after 24 Gy, but without significant effects in t h e submucosa (Kurohara and Casarett, 1972). Ambrus et al. (1984) irradiated the upper half of the esophagus of monkeys with a single dose of 20 Gy of 6 MeV x rays. Maximal esophagitis was expressed a t about three weeks after irradiation. Sindelar et al. (1988) gave single doses of 20 and 30 Gy of electrons in an intra-operative radiation therapy (IORT) mode to 6 cm of the intact esophagus of dogs. None of the seven animals receiving 20 Gy developed signs of dysphagia or weight loss during a 24 month

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observation period. In five dogs receiving a single dose of 30 Gy, IORT, all developed dysphagia and weight loss. One of these died of esophageal perforation 13 months post irradiation. The opossum is claimed as a useful animal model for studying radiation esophagitis, largely because its esophageal musculature is similar to that of humans. Northway et al. (1979) found that motility and histological changes in the opossum esophagus irradiated with single doses of 17.5,20 and 22.5 Gy were similar to those found in humans after therapy with typical clinical treatment schedules (Goldstein et al., 1975; Rubin and Casarett, 1968; Seaman and Ackerman, 1957). Phillips and Margolis (1972) carried out a systematic study in mice of histological damage to the esophagus after irradiation of only the thorax with fractionated doses of 10 to 50 Gy. Mice that died did so 10 to 20 d after irradiation with doses above 17.5 Gy. They estimated the LD50/20 dosez1to be about 25 Gy. Esophageal perforation was considered to be the cause of death. Additional details are provided in the reviews by Berthrong and Fajardo (19811, Chowhan (1990), Novak et al. (1979), and Roswit et al. (1972). 7.2.1.3

Summary of Radiation Effects in the Esophagus

1. Most studies of radiation effects in the esophagus of animals have involved single doses >6 Gy. 2. A single dose as low as 6 Gy in animals can cause denudation of the esophageal epithelium without producing significant changes in the submucosa. After several weeks, the epithelium usually regenerates. During or aRer epithelial regeneration, fibrosis of the lamina propria and submucosa may then become prominent and contribute to narrowing of the lumen and subsequent dysphagia. 3. Although there are quantitative differences, the qualitative changes in the irradiated esophagus of several mammalian species are similar. 4. Alterations in esophageal motility after irradiation are common. 5. In human patients, total conventionally fractionated doses of <20 Gy to the esophagus have caused no problems, but with higher doses, esophagitis and dysphagia can occur as early as two weeks after the last dose. 6. Strictures or perforations have been seen rarely in a previously normal human patient esophagus, even after high fractionated doses to the mediastinum. "The dose that causes 50 percent lethality in the studied population by 20 d.

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7. The most severe reactions to radiation-induced injury have occurred many years after treatment for esophageal cancer. These are often expressed as complete obstruction andfor a tracheoesophageal fistula. 8. There is no information in the literature concerning the possible effects ofhot particles on the esophagus. However, since esophageal transit is very rapid, no significant radiation dose to the esophagus would be expected from passage of a hot particle.

7.2.2

Deterministic Effects in the Stomach

There are numerous reports that describe functional or morphological injury to the irradiated stomach of humans and animals. Although the treatment volume was seldom mentioned, it appears that a substantial portion of the organ was usually included. The descriptions that follow have been divided into two categories: patient (human) studies and animal (non-human) studies. 7.2.2.1 Patient (Human) Studies. The stomach will tolerate doses up to about 40 Gy of conventionally fractionated radiation without serious risk of side effects (Roswit et al., 1972). As has often been reported, patients may have some discomfort and experience nausea, vomiting, dyspepsia, gastritis and a reduction in acid secretion. Depending on which portion of the stomach is irradiated, there may also be a delay in gastric emptying. Such a delay contributes to the "fullness" often reported by patients. These symptoms are treatable and usually transitory. However, with fractionated doses of 45 Gy and above, the probability of ulceration and perforation increases rapidly with dose. Such changes are accompanied by severe pain, which can be relieved only by surgical procedures (Roswit et al., 1972). In contrast to Roswit's conclusions, Awwad (1990) stated that although fractionated doses <20 Gy are clinically well tolerated, severe gastric responses such as those just mentioned, may occur with doses above 20 Gy. Between 1937 and 1965, irradiation of the human stomach with fractionated doses of approximately 11to 36 Gy to the upper stomach to diminish acid secretion was used as a means of treating gastric or duodenal ulcers (Palmer, 1974; Palmer and Templeton, 1939). This procedure was discontinued in the late 1960s, but has been used more recently in select situations (Awwad, 1990). In a report on the long-term follow-up of the group of patients treated over 30 y ago, cancer incidence in various parts of the GI tract was above control values (Griem et al., 1994).

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Detailed studies of selected radiation effects on the stomach after 40 Gy or more of fractionated radiation were carried out 40 to 60 y ago, but since then, very little information has become available on long-term pathological changes after large fractionated doses. The histopathological features of radiation-induced injury to the stomach have been described in detail (Casarett, 1980;Rubin and Casarett, 1968).The acute and late effects of radiation on the stomach have also been summarized by Berthrong and Fajardo (1981)and more recently by Barber and James (1995)who point out in their review the following:

1. Nausea, vomiting, anorexia and dyspepsia are common and unpleasant side-effects, even after doses as low as 1.5 Gy. 2. Radiation therapy delays gastric emptying, which amplifies patient discomfort. 3. Within one to four months after completion of radiation therapy, ulceration and perforation of the stomach are possible. 4. The late effects of irradiation on the stomach, if expressed, are likely to include persistent ulceration, especially if total doses, given as 2 Gy daily fractions, are above 40 Gy. 7.2.2.2 Animal (Non-Human)Studies. Various animal models have been used in attempts to identify the mechanisms underlying the responses of the stomach to radiation. Evaluation of histological changes observed in biopsy or autopsy specimens has constituted a major focus of most investigations. Regaud et al. (1912)irradiated dogs and observed that there was a difference in radiosensitivity between the different cell types in the stomach; certain exposures eliminated crypts and obliterated the chief cells, but spared parietal cells. Dawson (1925)also studied radiation-induced changes in the mucous-secreting cells, the neck cells, the chief cells, and the parietal cells, using a stomach pouch model. He questioned whether the epithelium itself was injured by the radiation or whether it was indirectly damaged due to a compromise in the blood supply. He reported that chief cells underwent cytolysis and although parietal cells showed little or no histological injury, they were unable to produce acid. The single dose required to produce the effect was 155 to 200 percent of a dog erythema dose. Hyperemia and cell loss from the mucosa were noted; when the mucosa regenerated, it was thinner but otherwise histologically normal. Irradiation temporarily inhibited fibroblast proliferation, perhaps because of a delay in mucosal repair. Engelstad (1938)studied the dose-response relationship for histological changes in the rabbit after single or fractionated doses of x rays, ranging from about 1.25 to 45 Gy, delivered to a volume

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encompassing the stomach. A few deaths occurred in animals receiving a single dose of 15 Gy, but 20 Gy caused high mortality. In animals receiving about 1.25 to 10 Gy, the threshold dose for damage was 5 Gy. The peptic cells were the most sensitive of those present, thus supporting the early observations of Regaud et al. (1912).In a sequential histological study carried out from 1 to 46 d after irradiation with a single dose of about 15 Gy, Engelstad (1938)described the subsequent loss of epithelium, ulcer formation, and perforation. Cell degeneration, hyperemia and leukocytic infiltration were also observed. It was concluded that the mucous membrane was the most sensitive layer and that the zymogen-producing peptic cells were the most sensitive cell type. Other tissue layers, including the lamina propria and muscularis mucosae, were much less sensitive. Weshler et al. (1988)irradiated the temporarily exteriorized stomach of rats with single doses of 3 to 30 Gy of orthovoltage x-ray irradiation. Three weeks after 5 Gy, free acid and total acid secretion rates were three to four times below normal. Morphological changes such as ulceration, inflammation and edema were minimal after 3 and 5 Gy, but more severe after higher doses. Buell and Harding (1989)described the response of the rat stomach to irradiation of the abdomen with 10 Gy of @C ' o-gamma radiation. The morphological changes included mild edema of the lamina propria 8 to 24 h after irradiation and some isolated foci of vascular congestion. Although the mucosal epithelium was intact, there were changes consistent with the classical features of inflammation within 12 h after irradiation. Ely and Ross (1947),Goodman et al. (1952),and Swift et al. (1955) reported that irradiation of rats delayed gastric emptying. Aa radiation doses were increased, so were gastric emptying times. Conard (1956)determined the emptying time of the fundic portion of the stomach in normal dogs and in dogs receiving total body gamma irradiation. While normal emptying time averaged 77 min, no delay in emptying was observed 2 to 8 d after approximately 3 Gy, or a t 3 d after approximately 6 Gy. However, a t 3 d after approximately 13 Gy, three dogs had delays as long as 7 h. Unfortunately, these observations are difficult to interpret since symptoms of anorexia, vomiting, diarrhea and dehydration were also present. Hulse (1966) irradiated various combinations of body volumes of rats with orthovoltage x rays seeking to identify an organ or part of the body responsible for initiating a delay in gastric emptying. Radiation doses roughly equivalent to 0.2 to 2 Gy were g v e n to various parts of the body and the progress of a barium meal followed 0.5 to 8 h later. Every radiation dose had some effect on gastric empyting. Hulse concluded t h a t irradiation of the small intestine and associated

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structures was the most effective protocol for producing the delay. In a related paper, Hulse and Mizon (1967)found that rats irradiated shortly after eating a barium meal refused to eat a second meal when tested four to six weeks later. The strength of this aversion seemed to be related to the severity of the delay in gastric emptying, which was related to the dose of radiation used and the particular tissue volume involved. Irradiation of the total body was more effective than irradiation of only the abdomen. Complete clearance of the stomach after a meal by rats was delayed for 10 to 12 h by single doses of 0.8 Gy of x rays or 0.4 Gy of neutrons (Myers and Hornsey, 1982). 7.2.2.3

Summary of Radiation Effects on the Stomach

1. Except for procedures designed to reduce secretion of HC1 by parietal cells as a means of controlling peptic or duodenal ulcers, or treating stomach tumors, there appear to be no other literature reports of patient studies in which it was desirable to include the stomach in the treatment volume. In most situations, the stomach has been irradiated simply as a result of it being unavoidably in the treatment volume. 2. The stomach is a complex organ with tissue layers analogous to those in the rest of the GI tract and several specialized cell types with differing degrees of radiosensitivity. There are several comprehensive studies of histological changes in the stomach after irradiation as determined from serial biopsies. The threshold dose for lowered acid secretion is estimated to be 3 Gy (5 Gy is the apparent threshold for the inhibition of peptic secretions). 3. Numerous patient studies have documented the degree of patient distress due to nausea, anorexia, vomiting, etc. 4. Fractionated total doses <20 Gy are well-tolerated by patients, but may cause mild episodes of nausea, anorexia, vomiting, reduction in acid secretion, reduction in enzyme secretion, and delays in gastric emptying. With slightly higher doses, gastric mucosal epithelium may be lost for a short time. As the total dose is increased (to doses near 40 Gy), the probability of severe ulceration rises. Such ulceration can lead to perforation and serious consequences. 5. Gastric emptying (at least in animals) can be delayed by single radiation doses as low as 0.2 Gy. Higher doses will increase emptying time almost in proportion to the dose received. 6. Animal models have provided approaches to mechanisms involved in radiation-induced stomach injury and the results have confirmed many of the human patient reports.

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7. As stated for the esophagus in Section 7.2.1.3, there are no patient studies dealing with irradiation of the stomach by hot particles. It appears reasonable to conclude that the presence of an insoluble hot particle in the stomach would be of little or no consequence during the usual residence time for food material of 1 to 2 h.

7.2.3 Deterministic Effects in Small Intestine The possibility of GI tract injury following radiation exposure was recognized early by Walsh (1897) and Regaud et al. (1912). The entire tract is considered radiosensitive with the order of decreasing sensitivity considered to be duodenum, jejunum, ileum, esophagus, stomach, colon and rectum (Casarett, 1980). In studies that focus on "early effects," i.e., changes within hours to days, damage to the intestinal epithelium and its possibilities for regeneration constitute the primary interests. Investigations of "late effects" typically relate to documentation of changes that occur over days to years after irradiation and include ulceration, obstruction, stricture and perforation of the intestine with an accompanying decrement in function (Osborne, 1995). Theoretically, a hot particle could cause either an early effector a late effect. Ifan early significant change was induced, it would likely be the result of a very high radiation dose to a small volume causing epithelial denudation with little or no subsequent regeneration. The possible secondary changes could include infection, ulceration and perforation. If prominent changes occurred considerably later, they could be expressed as fibrosis, ulceration, or as neoplastic growth (including cancer) following somatic mutation in the crypt stem cells.

7.2.3.1 Patient (Human) Studies. Barber and James (1995) noted that most of the clinical data on radiation-induced bowel changes derive from studies in which the organ was unavoidably in the treatment volume during brachytherapy of a nearby structure such as the cervix. In such cases, the dose to a segment of either the large or small intestine could vary from a fraction of a gray to more than 10 Gy. Studies of radiation effects on the small intestine also include those in patients where the firmly attached duodenum or more mobile jejunum and ileum are included in the treatment volume during radiotherapy with an external beam. In such cases, single or several small volumes of small intestine are irradiated and the doses received vary considerably.

7.2.3.2 Animal (Non-Human) Studies. Much of what is known about radiation-induced deterministic effects in the small bowel has been obtained from animal studies. Several different species and model systems have been used with most results in good agreement (Osborne, 1995). Many combinations of volumes irradiated, dose rate, radiation quality and quantity, single, fractionated and continuous exposure, and endpoints have been used (Osborne, 1995).Single doses of about 10 Gy and above delivered to the total body elicit the GI syndrome with its characteristic features (Quastler, 1956). In this situation, the small intestinal epithelium is denuded and is never replaced before the animal dies 3 to 5 d after exposure. Lower single doses cause varying degrees of change in the mucosa and other layers of the bowel. Several reports that describe the chronology of cellular changes in various structures of the irradiated small bowel have been summarized (Osborne, 1995). Several classic reports are illustrative (Bloom and Bloom, 1954; Friedman, 1945; Jervis et al., 1968; Lesher, 1957; Montagna and Wilson, 1955; Tillotson and Warren, 1953; Williams et al., 1958). Stem cells, located a t the base of the intestinal crypt, have been studied with great interest. Because these undifferentiated cells are rnitotically active, they are very radiosensitive. A survival assay has been developed (Withers and Elkind, 1970).Do values of about 1.5 Gy are common. The term Do refers to the dose on the straight line portion of the survival curve that will reduce a cell population to 37 percent of its original size. At least two cell types hypersensitive to radiation have been identified. One type, located deep in the crypts, has a Do for x or gamma irradiation of about 0.1 Gy (Ijiri and Potten, 1984). Another type, the layer of fibroblasts in the pericryptal fibroblast sheath located subjacent to the crypt epithelial cells, is also hypersensitive. The Do found for death aRer irradiation through apoptosis was 0.106 Gy (Neal and Potten, 1981). Villi are 0.5 to 1.5 mm in length (Junqueira et al., 1975) and the distance from the crypt openings a t their bases to the stem cells located a t the bottom of the crypt is 0.3 to 0.5 mm (Leeson and Leeson, 1966). Villi and crypts are covered with mucous. Whether a hot particle has a lower or higher probability of remaining near a crypt opening because of the mucus is open to speculation. However a beta- or gamma-emitting hot particle located a t the entrance to a crypt, depending on its activity and time of residence there, could deliver a significant dose to the stem cells located in the first few columns of cells a t the base of the crypts. The late effects in the small intestine of animals subjected to various irradiation protocols are summarized by Osborne (1995).

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The most dramatic outcomes are collagen deposition in connective tissue, fibrosis in various intestinal layers, bowel obstruction, and bowel perforation. There is not full agreement on the sequence of events responsible for such significant effects (Osborne, 1995). The relationship of early changes in the mucosa to the expression of late effects is still a matter for debate, but there is evidence that they are related (Casarett, 1980). The lowest dose used, as noted in the summary of late effect studies done during the last 25 y, was 3.5 Gy. This dose and others used in the multitude of studies completed is well above those the small bowel could reasonably receive from a moving or even a temporarily sequestered hot particle. 7.2.3.3

Summary o f Radiation Effects on the Small Intestine.

1. The small intestine is the most radiosensitive portion of the GI tract. 2. The epithelial cells in the crypts are radiosensitive and their response has been quantified in several ways, including the Do value, which is generally about 1.5 Gy. A few cells near the base of each crypt are considered to be hypersensitive with a Do of 0.10 Gy. A population of fibroblasts, located subjacent to the crypts, has been found to have a Do for death through apoptosis of 0.106 Gy. 3. In the dose range of 0.5 to 10 Gy, a variety of responses is possible. This could vary from early mild nausea and vomiting and some repairable mucosal damage to dramatic changes in morphology and intestinal function such as collagen deposition, fibrosis, reduction of peristaltic activity, and stricture. 4. Since there are no data relating to the effects of hot particles on the small intestine, one would have to construct a very artificial scenario to account for significant damage to the small bowel from hot particles. One would need to postulate sequestration of a hot particle in a crypt or intestinal fold (both unlikely), unrepaired mucosal damage, possibly followed by infection (and its consequences) andlor fibrosis. The likelihood of a hot particle reaching a critical spot and causing such changes is extremely low, especially since the associated radiation doses are likely to be far too low for damage t o be possible.

7.2.4 Deterministic Effects in Large Intestine

As with the small intestine, damage to the large intestine after radiotherapy was noted early in the century (Mulligan, 1942). Information on the biological effects of radiation on the large intestine

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has since been obtained from two main sources: (1)human patient studies wherein a relatively immobile normal large bowel was irradiated in the course of external radiation therapy or brachytherapy for treatment of cancer i n the cervix, bladder or prostate; and (2) studies with mice and rats directed a t characterizing a number of responses of the large bowel to various treatment schemes, especially those protocols relevant to dose schedules often used in patients. Except for the absence of villi, the large intestine has many morphological features in common with the small bowel and many of their reactions to radiation insult are similar. Even so, the large intestine is considered to be less radiosensitive for deterministic effects than the small intestine (Roswit et al., 1972). The large intestine can express a n acute early reaction to irradiation within two weeks as well as a more chronic late reaction whose time of appearance is highly variable and may be months to years later. The early response consists of partial or total epithelial cell denudation and, if the dose is sufficient, adhtional symptoms such as anorexia, nausea, vomiting and diarrhea (Summers and Hayek, 1993). The progression of some of these changes can be followed in patients and animals by sequential endoscopy (Breiter et al., 1986). Some reactions such as nausea, however, can be documented only by the reports from patients during the course of their treatments. The late changes in the large bowel of animals after irradiation include mucosal ulceration, fibrosis and stenosis, among others (Osborne, 1995). Scoring schemes have been devised to obtain an injury score that serves as an indicator of the overall response of the irradiated large bowel a t one or more time intervals (Black et al., 1980). 7.2.4.1 Patient (Human) Studies. Within 4 to 7 d after the first treatment of the pelvis with radiotherapy, most patients experience inflammation of the colon with prominent features like frequent and watery stools (Barber and James, 1995). Biopsies of rectum after doses up to 20 Gy have shown edema, an inflammatory cell infiltrate, and the absence of lymphatic tissue (Gelfand et al., 1968). The pathological features of late effects are well known and include fibrotic processes and congested portions of bowel, an atrophic and sometimes edematous mucosa, a mucosa that is regenerated and in which crypts are hstorted, and an abnormal lamina propria that has undergone hyaline fibrosis. As a result of these changes, many patients have strictures (Haboubi et al., 1988). Some patients without strictures are ill because of chronic mucosal damage. These difficulties often lead to resection of large bowel segments (Haboubiet al., 1988). The tolerance dose for a five percent severe complication rate

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within 5 y after treatment is about 4.5 Gy. The dose that results in a 50 percent severe complication rate a t 5 y is 65 Gy (Rubin and Casaratt, 1972). 7.2.4.2 Animal (Non-Human) Studies. There are many reports in the literature that deal with the late effects of irradiation on the large bowel (Osborne, 1995). Rats and mice have been the animals of choice in most situations studied. A common type investigation with mice involved irradiation in situ with one or more fractions of x or gamma radiation, total doses ranging from 5 to 35 Gy for single doses and u p to 66 Gy for 10 fractions with observations made a t intervals up to 84 weeks or at death (Dewit et al., 1987;Followill et al., 1993;Ito et al., 1986; Martin e t al., 1992;Terry and Denekamp, 1984;van der Kogel et al., 1988). Endpoints of fecal deformity, body weight, lethality, and a scoring method based on histologic parameters have been used (van der Kogel et al., 1988).A series of assays and characterization of fibrosis that was prominent a t 6 months have been employed (Terry and Denekamp, 1984).In one scheme with up to 30 fractions of conventional doses, the effective dose to cause lethal rectal stenosis in 50 percent of the animals was about 20 Gy (Dewit et al., 1987). Doses >20 Gy caused persistent epithelial denudation and obstruction within four weeks, while doses <20 Gy led to crypt cell depletion and repopulation followed by obstruction after 40 weeks (Followill e t al., 1993). Studies similar to those just described for mice have been done in rats. Segments of rectosigmoid colon 2.2 to 2.5 cm in length have been irradiated in situ and observed for varying periods of time. Doses have generally been above 15 Gy and the number of fractions as high a s 30.To give an example, in rats given 15 to 30 fractions and observed for up to 700 d, fibrosis, rectal stricture, obstruction, and death were observed a s they occurred (Hubmann, 1981).The dose for 10 percent obstruction (ED,o)30 to 250 d after irradiation was 17.5 Gy; for an EDSO, 21.5Gy; and for an EDg0,28.5Gy. Similar results have been documented (Hubmann, 1982; Kal et al., 1986; Trott, 1984).

Summary of Radiation Effects in the l a r g e Intestine. Irradiation of the large intestine as a consequence of radiotherapy of the pelvic region occurs commonly. Related animal studies have generally focused on ways to prevent or ameliorate late damage. The effects of irradiation of the large intestine are summarized below. 73.4.3

1. There are early responses to radiation injury, which can include anorexia, nausea, vomiting and diarrhea.

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2. Damage to the epithelium and subsequent repair occurs in most clinical situations where the large bowel is unavoidably in the treatment volume. 3. Clinically, the most important issue is the progressive ulceration, collagen deposition, fibrosis, and obstruction, which can occur in the rectosigmoid colon weeks t o months after irradiation leading to obstruction and death, if there is not surgical intervention. 4. A number of factors interact to modulate the frequency and severity of stenosis, the forerunner of obstruction. The effective fractionated dose for obstruction in 1 to 2 y in 50 percent of treated individuals is well above 20 Gy. 5. There are no data available for the effects of hot particles on the large intestine. The mucus covering of the mucosa and the usual movement of intestinal contents make it very unlikely that a hot particle would sequestrate in a crypt. Straight tubular crypts up to 0.7 mm in length are normally present in the colon and extend from the muscularis mucosae to the flat absorptive surface (Sleisenger, 1973).Therefore, energetic beta particles or gamma photons could conceivably reach the stem cells located in the lower portion of a crypt and influence cell kinetics or cause a mutation.

7.2.5

Stochastic Effects to the Gastrointestinal Tract

Stochastic effects from irradiation of the, stomach, colon, esophagus and small intestine are discussed in this Section. A recent review of the epidemiologicliterature on radiation carcinogenesis, including that for the GI system, can be found in UNSCEAR (1994). More detailed discussions of the transportation of risk from one population to another may be found in ICRP (1991ai and of the development of organ-specific lifetime risk estimates (including stomach and colon) in Gilbert (1991). 7.2.5.1 Stomach Cancer Induction by Radiation. Among Japanese atomic-bomb survivors the risk of stomach cancer was significantly elevated (Table 7.1). This ERR was greater among females than males and the magnitude of effect diminished with age at exposure (Thompson et al., 1994). For those irradiated a t ages 10 to 19,20 to 39, or 240 the ERR estimates were 69,43 and 12 percent per sievert, respectively. There was a highly significant linear dose-response trend O, < 0.001), but no indication of quadratic curvature O, > 0.5). Across all ages t h e average ERR per sievert was 32 percent

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(CI = 16 to 50 percent) for stomach cancer incidence, while the excess absolute risk (EAR) was 4.8 (CI = 2.5 to 7.4) per lo4 PY Sv. For stomach cancer mortality the ERR was 23 percent per sievert (CI = 13 to 34 percent) and the EAR was 2.1 (CI -. 1.2 to 3.1) (Shimizu et al., 1990). A few radiation studies besides the Japanese atomic-bomb survivor study have shown statistically significant or suggestive excesses of stomach cancer (Table 7.1). The international study of cervical cancer patients (Boice et al., 1988), with a mean stomach dose of about 2 Gy among the approximately 150,000 patients, showed a substantial excess of stomach cancer [observedlexpected (Om) = 3481167 = 2.081, which translates into an ERR of 69 percent per sievert. Peptic ulcer patients who were treated with high doses to the stomach (mean of approximately 14.8 Gy) also showed excess stomach cancer (Om = 40114.4 = 2.77) and an ERR of 12 percent per sievert. One study of patients given 1311 treatments for hyperthyroilsm (Holm et al., 1991) had mean stomach dose of 0.25 Gy. It showed a small excess of stomach cancer. Several other studies with stomach doses 20.3 Gy did not show an excess (Table 7.1). These included the study of 14,000 ankylosing spondylitis patients treated with x rays (Weiss et al., 1994) who had an estimated mean stomach dose of 3.21 Gy, and tuberculosis patients with multiple fluoroscopic examinations (Davis et al., 1987) for whom the mean stomach dose was roughly 0.3 Gy. Among occupational studies, only the United States radium dial painters have shown a positive result (Stebbings et al., 1984), with an estimated mean stomach dose of 0.29 Gy, showed a significant excess of stomach cancer (Om = 1517.8 = 1.92). Several other highdose occupational studies showed no elevation in risk; the studies of early United Kingdom radiologists (Smith and Doll, 1981),Chinese medical x-ray workers (Wang et al., 1990), and Japanese m e l c a l radiation workers (Aoyama, 1989). Stomach cancer was not elevated in a number of studies with lower doses (<0.3 Gy): patients with uterine bleeding (Inskip et al., 1990), residents near the Techa River (Kossenko and Degteva, 19941, or United States nuclear shipyard workers (Matanoski, 1991). The recent pooled analysis of large worker cohorts, with 275 stomach cancers among 95,000 radiation workers with a mean dose of 0.04 Gy, yielded a dose-response trend that was slightly in the negative direction (Cardis et al., 1995). A crude meta-analysis of the stomach cancer data was conducted as part of the preparation of this Report. When all the studies

CL

TABLE 7.1-Stomach cancer radiation risk estimates.

Study Group (Reference)

Atomic-bomb survivor mortality (Shimizu et al., 1990) Atomic-bomb survivor incidence (Thompson et al., 1994) Ankylosing spondylitis (Weiss et al., 1994) Cervical cancer therapy (Boice et al., 1988) 226Raor x-ray therapy for uterine bleeding (Inskip et al., 1990) X-ray therapy for uterine bleeding (Darby et al., 1994) Radiotherapy for peptic ulcer (Griem et al., 1994) 1311for hyperthyroidism (Holm et al., 1991) Techa River release (Kossenko and Degteva, 1994) Early U.K. radiologists (Smith and Doll, 1981) U.S. radium-dial painters (Stebbings et al., 1984)

Mean Dose (mSv)

Observed/ Expected (RR)

o -a

Percent ERR Sv-I (95%CI)

228

1,11011,063.5 = 1.04

236

1,30711,215 = 1.08

Excess Cancers per 104pysv

\

9

23 (13, 34Pb 32 (16, 50)"

3,210

1271128.7

=

0.99

-0.4 (-5, 5)"

2,000

3481167.3

=

2.OBb3'

69 (1, 325)b 15 (10,22)"

0."

210

2324.4

=

0.94d

230

3326.8

=

1.23

100 (-60, 308)

4.7

14,800

40114.4

=

2.77

12 (4.1,26)

0.6

250

58/43.6

=

1.33'

132 (7, 282)

9.6

33 ( - 25,91Y

1.8

2 C)

133

1481141.8 = 1.048

-3,000'

13114.65 = 0.89

- 3.8 ( - 17, 16)

- 0.1

-290'

1517.81 = 1.92

317 (40, 720)

2.4

Chinese medical x-ray workers (Wang et al., 1990) Japanese medical radiation workers (Aoyama, 1989) U.S. nuclear shipyard workers (Matanoski, 1991) U.S. DOE, U.K., and Canada pooled analysis (Cardis et al., 1995)

-

1,000

36145.4

=

0.79

-227 (-310, -80)

-550

60158.92

=

1.02

3.3 ( - 39, 55)

-50.5

23124.52

=

0.94

40.2

1171119.9 = 0.98h

-

123 ( - 770, 760)

- 60 ( - 480, 422)h

-

1.5 0.2

-

1.2

- O.gh

= Rough estimate given by the authors.

-

Estimate made for the present tabulation from the available information. "isk estimate based on the dose-response relation. b90percent confidence interval given rather than the 95 percent confidence interval. 'Dose-response trend ( p = 0.12). dExcludes0 to 9 y after irradiation. 'Observed and expected values for >10 y after irradiation. '3,000 mGy assunled; authors indicated 1,000 to 5,000 mGy for the 1920 to 1945 cohort and even higher doses prior to 1920. gAverage dose of -90 mSv alpha and -200 mGy external gamma. hobserved and expected values for workers with cumulative dose 2 1 0 mSv (as compared to workers with <10 mSv). Dose response slope was in the negative direction.

g Ft,

55 z z 2

2m

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GASTROINTESTINALTRACT

with a mean dose of 2 0 . 3 Gy were included, there were about 378,000 P Gy, and the weighted (by expected numbers times mean doses) EAR was 1.5 per 10,000 PY Gy. This number is somewhat lower than the Japanese atomic-bomb incidence data for which the EAR is 4.8. Next, just the low-dose studies of low-LET radation (i.e., average dose <0.3 Gy) were examined. They had a total of about 14,800 P Gy, and yielded an EAR estimate of 1.4 per 10,000 PY Gy. These estimates suggest that the AR of stomach cancer is probably not higher than that estimated from the Japanese atomic-bomb data and may be somewhat lower (Gilbert, 1991; ICRP, 1991a). There was no evident distinction among the risk estimates in the high-dose studies in terms of whether the exposure was acute, fractionated or protracted, nor was there a distinction according to whether the dose to the stomach was uniform. There are no data that address the issue of whether the risk from a hot particle would be expected to be different than that from an equivalent average stomach dose with uniform irradiation. It is assumed that the average organ dose provides a reasonable first approximation for estimating the stochastic risk from hot particles. 7.2.5.2 Colon Cancer Induction by Ionizing Radiation. Colon cancer has assumed a major role in the assessment of radiation risk by the ICRP (1991a) and the BEIRV committee (NAS/NRC, 1990). This is because of the relatively large ERR coefficient seen in the analysis of the Japanese atomic-bomb survivor data (Table 7.2). It might be more appropriate, however, to use the EAR value for transporting the risk estimate to United States populations, since the baseline risk of colon cancer in Japan is much lower than in United States populations and ERR estimates are affected inversely by the baseline rates. Specifically, the analysis of the colon cancer incidence data among Japanese atomic-bomb survivors (Thompson et al., 1994) showed a strong linear dose-response relationship (p < 0.001) and no clear evidence for upward quadratic curvilinearity (p = 0.15). There was no statistically significant radiogenic risk for rectal cancer, so the rectum will not be considered further. Statistical tests of differences in colon cancer risk by sex or by age a t irradiation were not significant, although it appeared that those <10 y old at exposure had about two times as much risk as older groups. The risks were significantly modified by temporal factors; excess risk decreased with increasing time since exposure and with increasing attained age. The colon cancer ERRS were rather similar for the mortality study (85 percent per sievert; 95 percent CI = 39 to 145 percent) and the incidence study (72 percent per sievert; CI = 29 to 128 percent).

7.2 RADIATION EFFECTS

1

173

The colon-cancer risk estimate from the ankylosing spondylitis study (Weiss et al., 1994) was appreciably lower than that among atomic-bomb survivors. The ERR was only eight percent per sievert. For two cervical cancer radiotherapy studies the risk was essentially zero (Boice et al., 1988; Storm, 1988), but this may have been because the doses to the p a d s of the colon that were proximal to the cervix were exceedingly high, in the cell-killing range, while doses to the more distant parts were low. Among medical irradiation series, three other studies are potentially very informative because of their long-term follow-up and exposure level. I n t h e s t u d y of (mostly) 226Rat r e a t m e n t for uterine bleeding disorder (Inskip et al., 1990), the average colon dose was approximately 1.3 Gy and 75 colon cancers were observed (RR = 1.29; ERR = 22 percent per sievert). A second uterine bleeding study (Darby et al., 1994) of substantial size had an average colon dose of 3.2 Gy from x-ray treatments. Based on 47 colon cancers, the RR = 1.42 and the ERR was 13 percent per sievert. A study of x-ray therapy for peptic ulcer (Griem et al., 1994) had an average colon dose of approximately 0.33 Gy and 31 colon cancers were observed (RR = 1.29, ERR = 89 percent per sievert); however, the dose varied across different regions of the colon from 0.1 to 12.3 Gy. In summary, in the two large uterine bleedlng studies, the ankylosing spondylitis study, and the two cervical cancer studies, the ERR estimates for colon cancer were lower than in the Japanese atomicbomb study, and for several of these the confidence intervals did not even include the central estimate of risk in the atomic-bomb study (see Table 7.2). The only studies with relatively high-risk estimates were the Japanese atomic-bomb study and the relatively small peptic ulcer study. Four occupational radiation studies had relatively high doses (i.e., estimated average doses of over 0.3 Sv): the radium dial painters (Stebbings et al., 1984), early United Kingdom radiologists (Smith and Doll, 1981), Chinese (Wanget al., 1990), and Japanese (Aoyama, 1989) medical radiation workers (see Table 7.2). The studies of the radium dial painters and the Japanese medical radiation workers showed a n excess of colon cancer, but in the case of the radium dial painters, part of their exposure was from alpha-emitting radionuclides rather than low-LET radiation. The ERR risk estimate for the radium dial painters was about 150 percent per sievert, whereas that for the Japanese medical radiation workers was 222 percent per sieved, but in both cases the ERR confidence intervals were compatible with much lower risks. The risk estimates for the United Kingdom radiologists and the Chinese medical radiation workers, with estimated doses higher t h a n those of t h e dial painters or

t-

TABLE7.2-Colon cancer radiation risk estimates.

Study Group (Reference) Atomic-bomb survivor mortality (Shimizu et al., 1990) Atomic-bomb survivor incidence (Thompson et al., 1994) Ankylosing spondylitis (Weiss et al., 1994) Cervical cancer therapy (Storm,

Mean Dose (mSv) 246"

Observedl Expected Colon Cancers = RR 1291113.4

=

1.14

6 4

Percent ERRISv (95% CI) 85 (39, 145)a,b

\

AR per lo4 PY Sv 0.6.

227

2231191.7 = 1.16

72 (29, 128)"

4,100

113185.2 = 1.30

8 (2, 14)"

-20,000'

77181.7 = 0.94

- 0.29 ( - 1.3, 0.9)

0.2 -0.03

24,200

4091409

=

1.00

0.0 ( - 0.3, 0.4)

0.0

2

g

8

2 C]

1988)

226Rao r x-ray therapy for uterine bleeding (Inskip et al., 1990) X-ray therapy for uterine bleeding (Darby et al., 1994) Radiotherapy for peptic ulcer (Griem et al., 1994) "'I for hyperthyroidism (Holm et al., 1991) U.S.radium-dial painters (Stebbings et al., 1984)

g? 3

UI

1988)

Cervical cancer therapy (Boice and Fry, 1995; Boice et al.,

+

4

1,300

75158.2 = 1.2gd

22 (1.6, 47)

1.5

3,200

47133.0 = 1.42

13 (1.8, 27)

0.9

31124.0 = 1.29

89 ( - 92,400)

7.5

50

2091190.0 = 1.10

200 ( - 88, 520)

39

-360'

32120.75 = 1.54

151 (20, 320)

3.4

325*

Early U.K. radiologists (Smith and Doll, 1981) Chinese medical x-ray workers (Wang et a1.,1990) Japanese medical radiation workers (Aoyama, 1989) U.S.nuclear shipyard workers (Matanoski, 1991) U.S. DOE, U.K., and Canada pooled analysis (Cardis et al., 1995)

-3,0009 -1,000 -550' -50.5 40.2

- 3.8 ( - 16, 14)

15116.92 = 0.89

-

0.1

0.67

- 33 ( - 74, 74)

- 0.1

20/9.00 = 2.22

222 (72,430)

1.6

430 ( - 850, 100)

- 9.2

619.00

41152.42

=

=

0.78

1231148.6 = 0.83h

-

- 428 ( - 776,

-

31)b

- 7.5b

= Rough estimate given by the authors. Is estimate made for the present tabulation from the available information. "Risk estimate based on the dose-response relation. b90 percent CI given. 'Dose range 1,000 to 70,000 mSv by anatomical location. Obsemed and expected values for 10 + y post-irradiation. *3,000 mGy assumed; authors indicated 1,000 to 5,000 mGy for the 1920 to 1945 cohort and even higher doses prior to 1920. ODose range of 100 to 12,300 mGy, depending on anatomic location in the colon. 'Average dose -160 mSv alpha and -200 mGy external gamma. PExcludes years 0 to 9 after irradiation. hComparison of workers with 210 mSv to those with 0 to 9 mSv. Dose-response slope was in the negative direction.

-

?

N

E 5 P

", 4 m

0

2

176

/

7. GASTROINTESTINALTRACT

Japanese workers, were both in the negative direction. Finally, the recent analysis of pooled worker cohorts in the United States, Canada, and Great Britain, with over 95,000 rahation workers and 343 colon cancer deaths, yielded a nonsignificant dose-response trend in the negative direction (Cardis et al., 1995). This study should not be overinterpreted, however, because the statistical power for the colon cancer endpoint was low because of the low doses sustained by the workers. Several points from the available studies are worth noting in estimating colon cancer risk. 1. In Japan, colon cancer is much less common than in the United States or other western countries. The EAR coefficient for radiogenic colon cancer is not especially large in the Japanese data (0.6 per lo4PY Sv for mortality and 1.8 for incidence) (Shimizu et al., 1990; Thompson et al., 1994).However, the extrapolation method used by the BEIR V committee (NAS/NRC, 1990) was based on the ERR, which in the principal reports of the Japanese data was 85 percent per sievert for colon cancer mortality and 72 percent per sievert for incidence (Thompson et al., 1994). When the BEIR V (NASNRC, 1990) percentage is applied to the larger baseline rates in the United States, it yields larger estimates of the EAR, namely, about 1.5 per lo4PY Sv for colon cancer mortality and 2.5 for incidence. 2. A crude meta-analysis of the colon cancer data was conducted as a part ofthe preparation of this Report, weighting the studies according to the approximate inverse variance of the EAR. When the eight studies with a mean dose between 0.3 and 10 Sv were included (a high enough dose to have a prospect of seeing an effect, but not so high as to have major cell killing), the weighted EAR was 0.4 per 10,000 PY Sv. This number is somewhat less than the EAR coefficient for colon cancer mortality in the Japanese atomic-bomb data of 0.6 per 10,000 PY Sv. 3. The worker data do not provide any indication of an excess of colon cancer among workers in the nuclear industry a t the dose levels sustained there, although this is not a definitive result because the statistical power of these analyses is low. A hot particle is expected to irradiate only a small fraction of the tissue in its passage through the colon, so the question is how to estimate colon cancer risk in this situation. There do not appear to be any findings pertinent to the issue of whether hot-particle irradiation would yield a risk equivalent to uniform irradiation of the colon. Three studies had high doses to part of the colon but much lower doses to the remainder (Boice et al., 1988; Griem et al., 1994;

7.3 DOSIMETRIC MODELING O F THE GI TRACT

1

177

Storm, 1988); two showed essentially no risk while the third gave a risk coefficient approximately comparable to the one from the Japanese atomic-bomb study. Thus, although there are no directly applicable data, the average organ dose appears to be a reasonable first approximation for estimating stochastic risk, similar to that for the lung and other areas of the GI tract. 7.2.5.3 Esophagus Cancer Induction by Ionizing Radiation. The induction of cancer in the esophagus by radiation is equivocal. In the Japanese atomic-bomb study, the dose-response for the incidence data (ERR = 0.3 Sv-I, 90 percent CI =
Small Intestine Cancer Induction by Ionizing Radiation. Cancer of the small intestine is quite rare and radiation-induced cancers are also evidently quite rare a t this site since they have not been tabulated in most of the major studies that had substantial doses to the abdomen. Two studies have reported small excesses of cancer of the small intestine in irradiated cohorts (Boice et al., 1984; Smith and Doll, 1976), but there is insufficient evidence to establish a reliable risk estimate. 7.2.5.4

7.3 Dosimetric Modeling of the Gastrointestinal Tract

The GI dosimetry model adopted by ICRP Publication 30 (ICRP, 1979-1989) includes four compartments based on earlier reports (Dolphin and Eve, 1966; Eve, 1966).After radionuclides are ingested or cleared from the lungs and reach the stomach, they are considered to move through the various compartments with exponential flow governed by first-order kinetics, irradiating only the adjacent portions of the compartment walls as they pass. The four compartments are stomach, small intestine, upper large intestine, and lower large intestine; the associated mean residence times are 1 , 4 , 1 3 and 24 h,

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7. GASTROINTESTINALTRACT

respectively. The ICRP (1979-1989) recommends that the wall of each compartment be considered a separate organ for the purposes of dosimetry calculations. If a certain fraction of ingested material is absorbed by the small intestine, then more uncertainty is introduced into the validity of dosimetric calculations. A revised transit model, termed the RIDIC Model, has been developed (Stubbs, 1992). This mathematical description of GI kinetics utilizes motility data generated by scintigraphic techmques and a combination of zero and first-order kinetics. This model also takes into account sex and age differences. Harrison (1995), states that differences in the ICRP 30 model and the Stubbs model have not yet been fully assessed. Calculation of the radiation dose to the walls of various portions of the GI tract is a subject of continuing interest. Approaches to absorbed energy calculations have included the concepts in ICRP Publication 2 (ICRP, 1959), MIRD Pamphlet No. 1 (Loevinger and Berman, 1968), and MIRD Pamphlet No. 5 (Snyder et aZ., 1969; 1978). Some aspects of the calculation of radiation energy distribution currently used by the medical community, and the different methodology used by the nuclear industry, have been discussed in detail (Poston et al.,1996a; 1996b). In addition to describing various assumptions and modifications to older dose calculation methods, Poston et aZ.(199613)have described a method for using EGS4 computational package to perform coupled photon-electron transport calculations of specific absorbed fractions. To do this, they coded the GI tract model of the MIRD 5 phantom, as modified by Cristy and Eckerman (1987). Specific absorbed fraction values calculated by Postonet al.(1996a) agreed with earlier data of Cristy and Eckerman (1987) even though the latter group dld not consider electron transport. The use of electron transport for calculation of electron absorbed fraction values for the Cristy and Eckerman model inchcated that prior estimates of energy deposition in the GI tract were overly conservative. The decrease in energy deposition would thus permit an increase in the annual limit on intake of radionuclides. In a succeeding paper, Poston et al. (1996b) developed a more complete GI tract model for use in internal dose assessment. A simple model of the small intestine was used and took into account that cells a t one depth may be more sensitive to radiation than cells a t another depth. They calculated photon absorbed fraction values for different depths without naming specific cell types. Biological factors that would influence the fate of a hot particle or any particulate matter ingested include the nature and quantity of GI tract contents at time of ingestion, delays in gastric emptying, and motility and peristaltic action. In the Stubbs model (Stubbs,

7.4 EVALUATION O F RISK POSED BY HOT PARTICLES

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179

1992),transit through the small intestine is taken to be independent of gastric emptying rates. ICRP Publication 30 (ICRP, 1979-1989) and subsequent similar r e p ~ r t s(e.g., NCRP, 1985b), are minimally relevant to the hotparticle issue. For calculations of dose equivalents to each GI segment, uniform distribution of the radionuclides in the contents and standard occupancy times in each segment are assumed.

7.4 Overall Evaluation of Risk Posed by Hot Particles in

the Gastrointestinal Tract If an individual swallows a hot particle containing only pure betaemitting radionuclides, or if the hot particle is first inhaled, but then reaches the stomach via the pharynx and esophagus, detection with an external radiation detector may not be possible. If, however, the decay scheme involves gamma-ray emission, detection in the stomach and beyond may be possible, depending on the activity of the particle. Whereas no published accounts of uptake and elimination of hot particles through the GI system were published in the open literature, there are company reports of a hot particle that was followed through the GI tract until excretion occurred. If one assumes normal occupancy times for the GI contents, hot particles will, on average, be excreted within approximately 42 h (Eve, 1966). In such cases, the absorbed radiation dose to the various portions of the GI tract due to a hot particle moving with normal tract contents would be calculated in a manner similar to methods in place for calculation of a dose due to a uniform bolus of radioactivity moving a t a normal rate through the GI tract. However, certain assumptions about where the particle passes relative to the tract walls would need to be made. For the sake of discussion, consider the possibility that a hot particle is trapped somewhere between entry and exit. The two most likely places for trapping to occur (and this is considered remote) would be in the folds of the esophagus, stomach or intestine; or, alternately, in the crypts of the stomach and intestine. Since there is no pertinent literature dealing with hot particles in the GI tract of humans, gastroenterologists with many years of experience were asked about these possibilities. Their first response, based on their own experience and knowledge of the literature, was that objects with the dimensions of hot particles would not be trapped in the GI tract. They commented also that the shapes of the folds vary considerably and these are continually changing, thereby facilitating passage of

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GASTROINTESTINAL TRACT

material. They also felt that the peristaltic activity of the GI tract and the thick mucus that continually covers the top of the crypts, would preclude hot particles from being sequestered in the folds or the crypts. If an individual had a case of intestinal stasis, due to connective tissue disease, bacteria would accumulate in a n area. Although it follows that a hot particle might also not be advanced in the case of intestinal stasis, it is unlikely that a worker with a hot particle in the GI tract would also have stasis due to intestinal disease. There is yet another factor that favors the non-sequestration of a hot particle. In humans, there is a "housekeeping" wave of peristaltic activity every 45 to 60 min, especially important in the fasting state, which leads to emptying of the stomach and the subsequent passage of contents through the remainder of the GI tract. Thus, several considerations argue against sequestration of a hot particle. There is another possible fate of a particle, which relates to the process termed persorption. The process is a secondary feature of the GI process and involves the passage of large, solid, undissolved food particles in the 75 pm range from the intestinal lumen into the vascular system. Particles reach the subepithelial region v i a the spaces between the epithelial cells and are removed by the blood a n d lymph vessels (Volkheimer and Schulz, 1968). Studies in humans have shown that a t least a small fraction of ingested asbestos fibers is absorbed. Fibers originating in drinking water and absorbed in the GI tract are excreted in the urine (Cook and Olson, 1979). Penetration of asbestos fibers 0.2 to 20 pm long (introduced intragastrically) through the GI tract and subsequent accumulation in blood and other tissues has been shown in the rat. The mode of fiber entry is thought to be through the cell desquamation zone a t the tip of the villus, perhaps by pinocytosis (Pontefract and Cunningham, 1973). Since hot particles are considered to have diameters >10 pm and < 3 mm, it is conceivable that a hot particle could be absorbed. Hot particles do not appear to represent any unusual risk to the GI tract. They are not expected to be absorbed due to their limited solubility. Considering the efficiency with which the GI tract normally moves its contents, hot particles are not expected to be sequestered in a single location. Individuals suspected of having a hot particle in their GI tract should be monitored frequently to achieve assurance that the hot particles have been eliminated. Radiation dose estimates should be made based on GI tract models for the handling of insoluble materials and estimated residence times.

8. Approaches to Limits As stated in NCRP Report No. 116 (NCRP, 1993), "the goal of radiation protection is to prevent the occurrence of serious radiationinduced conditions (acute and chronic deterministic effects) in exposed persons and to reduce stochastic effects in exposed persons to a degree that is acceptable in relation to the benefits to the individual and to society from the activities that generate such exposures." This Section discusses various approaches to limiting deterministic and stochastic effects of localized irradiation of tissue by hot particles. For hot-particle induced deterministic effects in the respiratory and the GI tracts, dose distribution is generally time-dependent because a deposited hot particle is usually not stationary. For a moving hot particle, a larger volume of tissue is likely to be irradiated than for a stationary particle. Also, doses would be more uniformly distributed than from a stationary hot particle. For a moving hot particle in the respiratory or GI tract, stochastic effects are the most important to control. An exception to the assumption of a moving hot particle can occur in the nose where a hot particle in the anterior nasal cavity can be stationary. However, the nose is radioresistant to the induction of stochastic effects, so that deterministic effects are the most important to control in this case. For the skin, eye and ear (including the eardrum), deterministic effects are considered the most important to control for hot-particle exposure because limits for these tissues, as shown by arguments in Sections 4 and 5, are more restrictive for deterministic effects than stochastic effects. Thus, for stationary hot particles on the skin, in the nose, in the eye, or in the ear, only limits for deterministic effects are needed.

8.1 Review of Approaches to Limits in Previous Recommendations 8.1.1 Approaches to Limiting the Risk of Hot-Particle Stochastic Effects 8.1.1.1 Approach in NCRP Report No. 46. It was concluded in NCRP Report No. 46 (NCRP, 1975), based on extensive analyses of

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8. APPROACHES TO LIMITS

then-available data, that the practice of averaging the absorbed dose from particulate alpha-emitting aerosols over the total lung is an acceptable procedure for estimating stochastic risks, in that doing so did not underestimate the risk to the lung for such exposures. The conclusion was based on the implied assumption that, for humans, radiosensitivity for stochastic effects did not vary for different regions of the lung. More recent information, presented in ICRP Publication 66 (ICRP, 1994), indicates that, for humans, radiosensitivity for stochastic effects likely varies for different regions of the lung. However, the ICRP respiratory tract dosimetry model (ICRP, 1994) assigned equal weighting factors of 0.333 to the bronchial, bronchiolar and alveolar-interstitial components of the thoracic region. Thus, continued use of average dose to the total lung when evaluating stochastic effects of irradiation would seem appropriate. 8.1.1.2 Other Approaches. To facilitate limiting the risks of stochastic effects of hot-particle irradiation of tissue in a given organ, the fractional mass irradiated, MkIMd, can be used to convert the local absorbed dose, Dim,to the corresponding average absorbed dose to a larger reference tissue mass. Here, M, is the mass of the irradiated tissue and Mmfis the reference mass over which the hot-particle absorbed dose is to be averaged. For skin, the fractional mass irradiated will correspond to the fractional area, AirrIArd,of the skin irradiated, where Ai, is the irradiated area and Ad is the larger reference area over which dose is being averaged (e.g., the total-body surface area of approximately 18,000 cm2).For most other organs, the fractional mass irradiated by a single hot particle can correspond to the fraction of the organ irradiated.22 The average equivalent dose to the reference mass for a single betaor betdgamma emitting hot particle is therefore given in sievert by the equation:

HT

Mi" Mmr

= W R .Dirr.-

where: the radiation weighting factor for beta or betdgamma radiation (ICRP, 1991a; NCRP, 1993) = the absorbed betdgamma dose (gray) to the irradiated mass of tissue = the mass (gram) of the fraction of the organ irradiated = the reference mass (gram) over which the dose is to be averaged

W R ( = 1) =

Dirr Mirr Mref

"Exceptions occur when the organ or tissue is known not to be homogeneous with regard to radiosensitivity.

8.1 REVIEW OF APPROACHES TO LIMITS

1

183

For stochastic effects, the contribution to effective dose (El, from irradiation by a single hot particle, is calculated as wTHT, where W T is the tissue weighting factor (Table 8.1) appropriate for the organ or tissue irradiated and HTis evaluated for that organ or tissue. Tissue weighting factors have not been developed for the eye and ear. However, for the eye, ear and nose, deterministic effects are judged to be the most important to control and contributions to the effective dose arising from hot-particle exposure to these organs are considered negligible. Although a wT for skin is provided in Table 8.1, i t was intended for large-field irradiation. For hotparticle irradiation of skin, MkIMreIis <
WT

Gonads Bone marrow Colon Lung Stomach Bladder Breast Liver Esophagus Thyroid Skin Bone surface Remainderb "Values were developed from a reference population with equal numbers of both sexes and a wide range of ages. See Table 6.3 for information on partitioning of radiation detriment among the regions of the respiratory tract. bFor the purpose of calculations, the remainder is composed oE adrenals, brain, upper large intestine, small intestine, kidney, muscle, pancreas, spleen, thymus, and uterus. 'In the exceptional cases in which one of the remainder organs or tissues receives an equivalent dose in excess of the highest dose in any of the 12 organs for which a weighting factor is specified, a weighting factor of 0.025 should be applied to that tissue or organ and a weighting factor of 0.025 to the average dose in the other remainder tissues or organs.

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1

8. APPROACHES TO LIMITS

1989), even though UVR-exposed areas are about 17 times more sensitive to stochastic effects of localized exposure to ionizing radiation than are UVR-protected areas (ICRP, 1991b).

8.1.2 Approaches to Limiting Hot-Particle Deterministic Effects 8.1.2.1 Appmach in NCRP Report No. 106. In NCRP Report No. 106 (NCRP, 1989), it was concluded that, for beta-emitting radionuclides in hot particles on the skin, the effect to be controlled is acute deep ulceration, although "deep" was undefined. The recommended limit for exposure to hot particles in contact with the skin was 101° beta particles. This limit was developed from data for high-energy beta particles. The limit was likely conservative for low-energy beta particles and did not apply to hot particles off the skin (e.g.,on clothing). 8.1.2.2 Approach in ICRP Publication 59. In ICRP Publication 59 (ICRP, 1991b), different limits from those published in NCRP Report No. 106 (NCRP, 1989)were recommended for the deterministic effects of hot-particle exposure of the skin. It was recommended that the average equivalent dose delivered within a few hours over a n area of 1 cm2,measured between depths of 100 to 150 pm, should be limited to 1Sv to prevent acute transient ulceration in the skin and to about 5 Sv or 101°beta particles to prevent what was termed acute deep ulceration. 8.1.2.3 Approach in ICRP Publication 60 and NCRP Report No. 11 6. For limiting deterministic effects of localized irradiation of the skin, the ICRP (1991a) and NCRP (1993) recommended an annual equivalent dose limit of 500 mSv, averaged over a 1cm2area, a t a nominal depth of 70 pm, regardless of the surface area irradiated. For betaand gamma-emitting radionuclides in hot particles on the skin, this limit would also include the gamma dose component. However, an equivalent dose limit per exposure would seem more appropriate t h a n an annual equivalent dose limit, for hot-particle exposure, because repeated exposures to the same small area are extremely unlikely. Although the recommendations in ICRP Publication 59 (ICRP, 1991b) were considered by the ICRP, they chose not to adopt those recommendations within ICRP Publication 60 (ICRP, 1991a). Instead they simply adopted the limit already established for irradiation of the entire skin. In NCRP Report No. 116 (NCRP, 1993), the NCRP did not reiterate its recommendations for hot-particle exposure limitation made in NCRP Report No. 106 (NCRP, 1989) or

8.2 APPROACHES TO LIMITS M THIS REPORT

1

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recommend any changes to those recommendations, thus leaving the recommendations of NCRP Report No. 106 in effect a t that time.

8.1.3 Approaches for Large Fields 8.1.3.1 Approaches to Limiting the Risk of Stochastic Effects. For limiting the stochastic effects of occupational exposure of large fields, the ICRP (1991a) has recommended an annual E limit of 20 mSv, averaged over 5 y (100 mSv in 5 y), with the maximum in any of the 5 y being 50 mSv. For skin, the limit applies to doses averaged over the entire surface of the skin. The eye and ear are excluded in calculating E. Tissue weighting factors are presented in Table 8.1 for key organs and tissue. The category "remainder" in the table can be used to account for organs or tissue not included in the table, subject to constraints outlined in ICRP (1991a) and NCRP (1993). If a single organ or tissue in the remainder category receives an equivalent dose in excess of the highest dose in any of the twelve organs for which wT values are specified, a WT value of 0.025 should be applied to that organ or tissue and to the average dose for organs and tissue making up the rest of the remainder category. In NCRP Report No. 116 (NCRP, 1993), the recommended cumulative effective dose limit is 10 mSv times a n individual's age in years with an annual limit of 50 mSv. 8.1.3.2 Approaches to Limiting Deterministic Effects. For largefield irradiation, the ICRP (1991a) has recommended a n annual equivalent dose limit of 500 mSv for t h e skin, hands and feet. For t h e lens of t h e eye, a 150 mSv equivalent dose limit was recommended. These limits for large-field irradiation were also recommended in NCRP Report No. 116 (NCRP, 1993).

8.2 Approaches to Limits in this Report 8.2.1 Approach to Dose Limitation for Hot-Particle Exposure of the Skin As discussed in Section 4, the risk for stochastic effects from hotparticle exposure to skin is negligible in comparison to deterministic effects. In considering a dose limit to protect against the occurrence of adverse deterministic effects to the skin from hot-particle exposure, it is essential to consider the nature of the lesions that might

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be produced that would result in a breakdown of the barrier function of the skin. Experimental studies have demonstrated that the type of skin lesion that may be produced is dependent on the energy of the beta emissions from the hot particle. The severity of the lesion may also be dependent on whether the particle is on or off the skin. Following exposure to low-energy beta rays (<0.5 MeV from hot particles on the skin) the lesion of concern is acute epidermal necrosis. This effect results from the early death of post-mitotic epithelial cells above the basal layer of the epidermis a t a n approximate depth of 50 pm. For intermediate (20.5to 1.5 MeV) and higher energy betaemissions (>1.5 MeV) the target cells involved in the development of lesions are in the dermis a t a depth of 100 to 150 pm. The early death of both endothelial cells and fibroblasts, at interphase, results in the development of acute ulceration, so termed because of the involvement of dermal tissue. Such lesions, when established, tend to have a longer duration than is associated with acute epidermal necrosis, after doses that produce a comparable incidence of each specific lesion. There is also a trend for lesions produced by lowerenergy beta emissions combined with gamma emissions to be slightly more severe, in terms of their persistence, compared with a pure beta-particle source of comparable energy. These differences in biological response would provide more than adequate justification for a separate dose limit to be set for low energy, as compared with intermediate or high-energy beta-emitting radionuclides in hot particles. The doses to limit the occurrence of the different skin lesions would need to be prescribed a t different depths in the skin. However, in the working environment, exposure may result from hot particles derived from activation products or fuel elements, which typically contain relatively low- and highenergy beta-particle emitting radionuclides, respectively. This would argue for a single dose limit that would be appropriate for a range of different energy beta sources. It must be emphasized that the single depth a t which the dose would then have to be expressed would have to be arbitrary. It would have no biological, pathological or mechanistic significance with respect to the depth of the target cells for the lesion associated with the different energy beta emissions from hot particles. The area of the skin surface over which the dose should be averaged must also be somewhat arbitrary. The smallest lesions of the skin, easily detectable by eye, are approximately 1 mm in diameter and hence the dose to such a small area has the most obvious biological relevance in terms of energy that has to be deposited in tissue to produce that lesion. However, dosimetry measurements over such small areas have certain practical difficulties for routine evaluations.

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The concept of averaging dose over a n area of 1cm2 of the skin for highly nonuniform exposure was first proposed by ICRP (1964) and possible problems associated with such averaging were considered later (ICRP, 1966). For hot-particle exposure from a single source in a fixed position in contact with the skin, it should be recognized again that such averaging has no biological or mechanistic significance. Indeed, as the source energy decreases, a proportionately smaller part of the 1cm2area will be exposed to radiation. However, such an approach was adopted by ICRP (1991b) for hot-particle exposure and a limit of 1Sv was proposed to prevent transient acute ulceration. The dose was prescribed a t 100 to 150 pm depth because only lesions associated with intermediate t o high-energy exposure were considered. At that time, only minimal information was available on the effect produced by low-energy beta particles. However, the limit derived for the higher energies was considered to be safe for those lower-energy emissions from hot particles, particularly as the lesion produced was, in the absence of infection, considered to be less severe. The available data from studies carried out on the skin of pigs for hot particles of differing energy in a fixed position in contact with the skin are summarized in Figure 8.1. Doses associated with the ED10 and ED50for the acute lesion responsible for the breakdown in the functional barrier of the skin are plotted as averaged over 1cm2 a t a depth of 70 pm. It should again be emphasized that this method of expressing dose has no biological or mechanistic significance, but can be used to compare the effects of different energy beta particles. Using this approach, the EDSovaluesobtained for either acute epidermal necrosis or acute ulceration vary by only a factor of approximately two, i.e., from approximately 5 Gy for 17"Tmirradiation to approximately 10 Gy after irradiation from 236UCz microspheres. The EDlo values show much larger variation, i.e., by a factor of seven, the lowest value being 1 Gy after lT6Ybirradiation. This variation may, to some extent, reflect uncertainties in assessing the presence of lesions after doses where the occurrence is low and the area of involvement is usually, but not always, small. Moreover, healing is frequently rapid and leaves no permanent detriment, except perhaps where an opportunistic infection may take advantage of the break in the barrier function of the skin. Healing of the lesion could then be significantly delayed if it were to remain untreated. In a working environment where exposure to hot particles is a distinct possibility, it is clearly desirable to set a dose limit such that the occurrence of lesions that would result in a breakdown of the banier function of the skin is unlikely. Similarly, for practical purposes, this limit should not be so restrictive that it will introduce

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"co

. . . . . .

. "%b

t---. 50% Incidence

m- -m I

I

I

10% Incidence I

Maximum Energy Beta (MeV)

Fig. 8.1. Variation in dose associated with either a 50 percent incidence (0-0) or a 10 percent incidence EDlo(m-M) of acute lesions following (EDSO) exposure of pig skin to hot particles from specific nuclides. The doses quoted are those averaged over 1 cm2 a t a depth in tissue of 70 km. This dose description has no biological basis but is an arbitrary criterion adopted to enable comparisons to be made. (For the 236UC2 source, the point is positioned a t the average of the maximum principal energies. The 90SrPYsource is effectively just a 9CY source because the covering over the source absorbs essentially all of the beta particles from 93r.)

other problems such as significantly increased whole-body stochastic risk and unjustified costs associated with modified work and monitoring practice^.^^ Lesions that occur a t a very low probability, e.g., EDol, would be likely to be small and more superficial and therefore, to heal more rapidly with no long-term detriment. However, for the reassurance of workers that potential hazards are not being ignored, the possible effects of exposure to individuals with doses that could result in a low probability of a breakdown of the skin barrier function should be monitored and action taken if a lesion were to develop. Based on the available evidence from experimental studies in the pig, whose skin is similar to that of human skin, a dose limit of 5 Gy W o r k zones in which hot particles are found frequently have elevated external radiation fields. Personnel monitoring for hot particles in these zones may incur increased external dose. To the extent that monitoringfor hot particles is unnecessary, this external dose and its attendant stochastic risk is not justified.

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could be set for an individual particle of any energy on the skin, with the dose being assessed as the average over 1 cm2 a t 70 pm depth. This dose is above the ED50for acute lesions a t all betaparticle energies studied. Such a dose limit is comparable to the 10'' beta particles or 75 kCi h recommended by NCRP (1989) to prevent what was termed "deep ulceration." However, if a biological effect were to result from a hot-particle exposure near or exceeding the recommended limit, the result is an easily treated medical condition still involving extremely small risk. Such occurrences would be indicative of the need for improvement in radiation protection practices, but should not be compared in seriousness to exceeding whole-body exposure limits. The dose level at which investigations and observations should be initiated for a period of four to six weeks after a suspected exposure is more difficult to establish given the wider variation in EDloand the possible threshold doses for the lesion of interest. A dose of 1Gy averaged over 1cm2a t a depth of 70 pm in skin is suggested as the dose at which the observation of individuals should be initiated as to the possible, but unlikely, appearance of effects. This would encompass all ED,, values found, even that for 175Yb.This could be considered overly restrictive for all other radionuclides investigated since their EDlovalues were >2 Gy. However, as was stated earlier, there is considerable uncertainty about the threshold dose for these effects. By way of a n example, the EDol value for acute ulceration from hot particles of 170Tm was estimated as approximately half that of the EDlovalue (see Section 4). In the situation where a hot particle is on clothing, off the skin, the available data indicate that a similar limit would be applicable if the particle were in a fixed position and only a relatively short distance off the skin. However, in the working environment a hot particle on clothing may move relative to a specific skin site, and may be a t a variable distance from the skin surface. Both of these factors will result in a more homogenous dose to a larger area of skin. The anticipated movement of a particle on clothing, relative to the skin, would also make it difficult to identify the most highly exposed 1 cm2 of skin. The high heterogenous dose and hence the specific biological features associated with hot-particle exposure would eventually be lost and the general annual skin dose limit of 0.5 Gy should then apply (ICRP, 1991a; NCRP, 1993). However, for hot particles off the skin, e.g., on clothing, the degree of movement and separation is difficult to quantify and hence a limit has to be derived that would take account of a range of potential geometries specific to hotrparticle exposure that d l prevent deterministic effects.

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A dose limit of 0.5 Gy from an individual hot particle, with the dose being averaged over 10 cm2 a t 70 pm, would provide a simple way to fulfill this requirement for all exposure situations involving a particle on clothing off the skin as well as for a particle on the skin. Exposure of the same 10 cm2of skin with more than one particle, within a 12-month period, with a cumulative dose of >0.5 Gy would result in the annual general skin dose limit being exceeded. Alternatively, a limit for hot particles on skin of 5 Gy averaged over 1cm2 of skin at a depth of 70 pm and a separate limit for hot particles off the skin of 0.5 Gy averaged over 10 cm2a t a depth 70 ym would offer equivalent protection, but this approach would result in a somewhat more complex recommendation. A dose of 0.1 Gy averaged over 10 cm2 a t 70 pm depth, the dose level a t which observations should be initiated, should apply even for exposure from a hot particle on clothing, offthe skin. The appearance of a discrete lesion, erythema, ulceration or a scab would be indicative of very localized exposure in such a situation. If the alternative method were to be used to establish limits, observations should be initiated for hot particles on skin a t 1 Gy averaged over 1cm2of skin a t a depth of 70 pm and for hot particles off the skin, a t 0.1 Gy averaged over 10 cm2a t 70 pm depth. (Recommendations on dose limits are set out in Section 9).

8.2.2

Approach to Dose Limitation for Hot-Particle Exposure of the Eye

For hot-particle exposure of the eye, deterministic effects are considered the most important to control. Because of the paucity of reports on ocular neoplasia following broad field exposure to radiation, and for the same rationale that applies to skin exposures from hot particles, it is concluded that the probability of radiation carcinogenesis in the ocular tissues is extremely low. For hot particles in the eye, only limits for other possible effects are needed. Available data, experimental or otherwise, are insufficient to allow one to predict confidently the outcome of a high dose delivered to a portion of the eye from an intense small source such as is represented by a hot particle. However, it is reasonable to assume that small field effects would not exceed the expectation of damage from the same dose delivered to a larger area of tissue. Based on the experimental experience with skin, the tissues potentially most likely to exhibit a n adverse reaction are the cornea and the region a t the corneallscleral border. Because the cornea is only about 500 pm thick, a high-energy beta source resulting in a dose of 6 Gy could

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cause corneal ulceration and liquefaction of the stroma, ultimately resulting in breaching of the eye. Although 5 Gy averaged over 1cm2 a t 70 p,m depth represents an EDbofor skin lesions, only a very small fraction of such lesions would extend to depth equivalent to the full corneal thickness (see Section 4). Non-transcorneal wounds would not be expected to produce other than very small imperfections in corneal topography, which would have little likelihood of influencing visual function or acuity. Doses to the cornea insufficient to cause transcorneal ulceration would not be likely to compromise eye function. For example, a t such doses the development of detectable cataracts are likely to be an event of vanishingly low probability in the case of the nearest susceptible intraocular tissue, the lens. Based on doses delivered by a hot particle to tissues in the various strata, it is clear that potential corneal damage is limiting (see Table 5.5). Therefore, it is appropriate to use the convention applied to skin in the context of the eye. Almost no data exist on ocular exposures from hot particles to assess possible outcomes. So to be conservative, the possibility must be considered that a transcorneal lesion caused by hot-particle radiation may not repair, as might a mechanical injury, and that a permanent breaching of the globe could result. A limit of 5 Gy averaged over 1cm2a t 70 Fm depth is expected to be protective. However, because of the absence of directly relevant information, medical observation of the eye for a period of four to six weeks would be appropriate following a dose exceeding 1Gy averaged over 1 cm2 at 70 p,m depth.

8.2.3 Approach to Dose Limitation for Hot-Particle Exposure of the Respiratory System Hot-particle sequestration in the respiratory tract is a mode whereby relatively large local radiation doses could be delivered. Because only beta- or betalgamma-emitting particles with diameters of 10 p,m or larger (up to 3 mm) are considered hot particles (see Section I), respirable hot particles are greater than nine times more likely to deposit in the nasopharyngeal region ofthe respiratory tract than in other regions (see Section 6). However, because radiosensitivity for the induction of stochastic effects is much greater for the lung than for the nasopharynx (ICRP, 1994), the lower-probability deposition of hot particles in the lung should be considered. The joint probability of a hot particle being airborne, inhaled and deposited in the lung will be very small for United States nuclear industry

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workers unless highly unusual conditions exist that cause a significant concentration of airborne hot particles. Based on comparing ICRP (1994) deposition fractions for sequestration versus no-sequestration compartments in the ICRP respiratory tract dosimetry model, only 5 out of 10,000 particles deposited in the nasopharynx or larynx would be expected to be sequestered, while only 7 out of each 1,000 particles deposited in the bronchi or bronchioles would be expected to be sequestered. Thus, for very low air concentrations of hot particles, inhalation, followed by deposition, followed by sequestration of a hot particle in the respiratory tract is extremely unlikely. For such circumstances, it is suggested that hot-particle sequestration in the respiratory tract be presumed not to occur unless worker monitoring data (e.g.,from in vivo bioassay, whole-body counting, etc.) indicate the contrary. It is unlikely that a hot particle in the respiratory tract would result in a serious deterministic effect, even if sequestered. Clinical data indicate that serious clinical symptoms may not arise if <20 percent of the lung is irradiated. For some functional endpoints, impairment in function will not be induced when a small subregional mass oftissue is irradiated by a hot particle. Whether a single moving hot particle in the upper respiratory tract or trachea could produce a dose in excess of the threshold for deterministic radiobiological effects is currently unknown. Little information is available that directly relates to deterministic effects of localized irradiation of the anterior nasal compartment (nasal vestibule) by hot particles. However, the wall of the nasal vestibule is lined with skin (ICRP, 1994). Thus, limits similar to those developed for controlling deterministic effects in skin could also be applied to hot particles that deposit in the anterior nasal compartment. Issues related to potential radiobiological effects in the lung associated with the release of hot alpha-emitting particles from nuclear facilities have been extensively discussed in earlier publications (see Section 6). An important conclusion related to these research efforts is that the use of average dose to the lung from alpha-emitting particles does not lead to underestimation of the risk of stochastic effects, but may lead to overestimation. Presently available information is not sufficient for developing different w~ for different regions of the lung. While use of average dose to the lung may be acceptable for evaluating the risk of stochastic effects, dose should not be averaged over different regions (nose, pharynx, larynx, trachea, lung, etc.) of the respiratory tract because different regions have very different radiosensitivities (see Section 6).

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The use of the risk apportionment fadors presented in Table 6.3 in conjunction with the values of W T (ICRP, 1991a; NCRP, 1993) allows evaluation of effective dose for hot-particle exposure of the respiratory tract if absorbed doses can be ascertained. However, there is currently no dosimetry model designed specifically for evaluating the absorbed-dose distribution to the respiratory tract arising from a single mobile hot particle. The equivalent dose distribution over the respiratory tract will depend on where the particle deposits in the respiratory tract, its radionuclide content, self-absorption properties, and its behavior after deposition (e.g., dissolution, particle movement). Furthermore, calculating the radiation doses to specific parts of the respiratory tract that could arise from inhaling airborne hot particles is not trivial when the air concentration of such particles is low enough that there is low probability that a hot particle will be inhaled in the time period considered. Lacking a specific model for single hot-particle dosimetry, perhaps the best that can be done presently is to estimate E using general respiratory system models, i.e., ICRP (1994) and residence times for insoluble material. Adjustments could be made to the general respiratory system models for the purpose of calculating E if in vivo bioassay data indicate that particle locations and residence times deviate significantly from the default model values.

8.2.4

Approach to Dose Limitation for Hot-Particle Exposure of the Gastrointestinal System

Hot-particle sequestration in the GI tract is another mode whereby relatively large local radiation doses could potentially be delivered by a single hot particle, but, as discussed in Section 7, this is extremely improbable. With the dosimetric model of Eve (1966; Dolphin and Eve, 1966; ICRP, 1979)for the GI tract, there is no particle sequestration compartment. No reports of hot-particle sequestration in the GI system have been found in the literature. Thus, it is suggested that hot particles be presumed not to become sequestered in the GI tract unless worker monitoring data (e.g., whole-body counts) indicate the contrary. As for the respiratory tract, the currently available models do not address the issue of a single hot particle traveling through the GI system. Lacking a specific hot-particle model, limitation could be based on currently applicable effective dose limits, with the effective dose determined using general GI system models, i.e., ICRP (1979) and residence times for insoluble material. Adjustments could be made to the general GI system models for the purpose of calculating

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effective dose if in vivo bioassay data indicate that particle locations and residence times deviate significantly from the default model values.

8.3 Some Practical Considerations

The limits discussed in this Section (and summarized Section 91, may present practical challenges when implemented. Hot particles, especially on skin, have been an issue in nuclear facilities for more than a decade, and health physicists have developed methods for their control and the assessment of dose when exposure occurs (e.g., Doolittle et al., 1992; Durham and Bell, 1992; Russell et al., 1988; Taylor et al., 1997). Although detailed guidance for operational programs to control radiation exposure from hot particles is outside the scope of this Report, a few general comments can be made. Radiation dose received routinely by workers from sources other than hot particles can normally be anticipated. Compliance with limits for external dose is a matter of careful measurements of dose rates and of work control, supplemented as necessary with active dosimeters (e.g.,electronic personal dosimeters). Compliance is usually confirmed with passive personal dosimeters (e.g., thermoluminescent dosimeters). Internal dose from distributed airborne contamination can be anticipated from measurements, limited with work control, decontamination, and respiratory protection, and confirmed with bioassay. Dose received from hot-particle exposures, on the other hand, cannot be anticipated with the same degree of reliability as that from external ''whole-body" dose and internal dose from distributed airborne contamination. Based on plant experience, operating staff should conduct radiological control activities, such as personal monitoring, at frequencies and levels of thoroughness sufficient to reduce the likelihood of an overexposure. To date, most reported exposures have been from hot particles on clothing or skin. The incidence of exposures can be reduced by increased control over the sources of hot particles or increased decontamination efforts. Assuming that some particle exposures will still occur, the dose per particle can be reduced by increased frequency and thoroughness of monitoring. Once found, hot particles can be removed, ending the accumulation of dose. Should hot-particle exposures of organs and tissues other than skin become a problem, similar contamination control measures, increased use of personal protective clothing and other devices such as full-face respirators, and increased

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monitoring are expected to be effective. The methods used to calculate dose to skin from hot particles, e.g., VARSKIN (Durham and Bell, 1992), may have to be adapted to the special cases of the eye and the surfaces of the nasal passages. The level of effort expended in the control of hot particles will have to be balanced against other factors such as additional wholebody dose that might be received due to increased monitoring and decontamination activities and cost.

9. Recommendations on

Radiation Exposure Limits for Hot Particles The bases for the following recommendations are discussed in Section 8.

9.1 Skin and Ear

I t is recommended that: For hot particles on skin (including ear), hair or clothing, limitation of irradiation be based on ensuring that irradiation from a hot particle would not be expected to result i n breakdown of the skin barrier finction with the consequent possibility of infection. The dose to skin at a depth of 70 pm from hot particles on skin (including ear), hair or clothing be limited to no more than 0.5 Gy averaged over the most highly exposed 10 cm2 of skin. This can be viewed as a per-particle limit so long as the areas o f skin exposed by the hot particles do not overlap. In the event that the areas of skin exposed b y two or more hot-particle exposure events overlap, then the limit applies to the calendar year, rather than to the individual events. Observation of the exposed area of skin for four to six weeks be initiated whenever the dose evaluated at a depth of 70 pm exceeds 0.1 Gy averaged over the most highly exposed 10 cm2 of skin.

9.2

Eye

I t is recommended that: For hot-particle exposure of the eye, limitation of irradiation be based on ensuring that irradiation from a hot particle would

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not be expected to result i n any loss of visual function, breaching of the eye (e.g., resulting from severe damage of the cornea), or breakdown of the barrier function of eye-related skin (e.g., lid) with the consequent possibility o f infection. The dose at a depth of 70 pm to any ocular tissue from hot particles be limited to 5 Gy averaged over the most highly exposed 1 cm2 of ocular tissue. Because of the small size of the eye, this should be viewed as an annual limit for each eye, even if hot particles are believed to have been present a t different locations and/or times. Observation of the eye for four to six weeks be initiated whenever the dose, evaluated a t a depth of 70 pm, exceeds 1 Gy averaged over the most highly exposed 1 cm2 of ocular tissue. 9.3 Respiratory System It is recommended that:

Limitation be based on currently applicable effective dose limits, with the effective dose determined using general respiratory system models and residence times for insoluble material. Adjustments be made to the general respiratory system models for the purpose of calculating effective dose if i n vivo bioassay data indicate that particle locations and residence times deviate significantly from the default model values. For the special case of hot-particle sequestration i n the anterior nasal compartment, the dose at a depth of 70 p m to nasal tissue from hot particles be limited to 5 Gy averaged over the most highly exposed 1 cm2. Because of the small size of the anterior nasal compartment, this should be viewed as a n annual limit, even if particles are believed to have been present a t different locations and/or times. Medical referral be made if i n vivo bioassay d a t a indicate sequestration o f a hot particle and respiratory symptoms appear. 9.4 Gastrointestinal System It is recommended that:

Limitation be based on currently applicable effectivedose limits, with the effective dose determined usinggeneral GZsystem models and residence times for insoluble material.

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Adjustments be made to the general GI system models for the purpose of calculating effective dose if in vivo bioassay data indicate that particle locations and restdence times deviate significantly from the default model values. Medical referral be made if i n vivo bioassay d a t a indicate sequestration of a hot particle and GI symptoms appear.

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VOLKHEIMER, G. and SCHULZ, F.H. (1968)."The phenomenon of persorption," Digestion 1, 213-218. VON ESSEN, C.F. (1969). "Radiation tolerance of the skin," Acta Radiol. Ther. Phys. Biol. 8, 311-330. VYNCKIER, S. and WAMBERSIE, A. (1982). "Dosimetry of beta sources in radiotherapy. I. The beta point source dose function," Phys. Med. Biol. 27, 1339-1347. VYNCKIER, S. and WAMBERSIE, A. (1986). "Dosimetry of beta sources in radiotherapy: Absorbed dose distributions around plane sources," Radiat. Prot. Dosim. 14, 169-173. WALSH, D. (1897). "Deep tissue traumatism from roentgen ray exposure," Brit. Med. J. 2, 272-273. WANG, J.X., INSKIP, P.D., BOICE, J.D., JR., LI, B.X, ZHANG, J.Y. and FRAUMENI, J.R., JR. (1990)."Cancer incidence among medical diagnostic x-ray workers in China, 1950 to 1985," Int. J. Cancer 45, 889-895. WARNOCK, R.V., BRAY, L.G., COOPER, T.L., GOLDIN, E.M., KNAPP, P.J., LEWIS, M.M. and RIGBY, W.F. (1987). "A health physics program for operation with failed nuclear fuel," Radiat. Prot. Manag. 4, 21-30. WARREN, S. and FRIEDMAN, N.B. (1942). "Effects of radiation on normal tissues," Arch. Path. 31, 749-787. WEEDON, D. and WALL, D. (1975). "Metastatic basal cell carcinoma," Med. J. Aust. 2, 177-179. WEINSTEIN, G.D. (1965). "Autoradiographic studies of turnover time and protein synthesis in pig epidermis," J. Invest. Dermatol. 44, 413-419. WEINSTEIN, G.D. and FROST, P. (1969). "Cell proliferation kinetics in benign and malignant skin diseases in humans," Natl. Cancer Inst. Monogr. 30,225-246. WEISS, H.A., DARBY, S.C. and DOLL, R. (1994). "Cancer mortality following x-ray t r e a t m e n t for ankylosing spondylitis," Int. J. Cancer 59, 327-338.

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The NCRP

The National Council on Radiation Protection and Measurements is a nonprofit corporation chartered by Congress in 1964 to: 1. Collect, analyze, develop and disseminate in the public interest inforrna-

tion and recommendations about (a) protection against radiation and (b) radiation measurements, quantities and units, particularly those concerned with radiation protection. 2. Provide a means by which organizations concerned with the scientific and related aspects of radiation protection and of radiation quantities, units and measurements may cooperate for effective utilization of their combined resources, and to stimulate the work of such organizations. 3. Develop basic concepts about radiation quantities, units and measurements, about t h e application of these concepts, and about radiation protection. 4. Cooperate with the International Commission on RadiologicalProtection, the International Commission on Radiation Units and Measurements, and other national and international organizations, governmental and private, concerned with radiation quantities, units and measurements and with radiation protection.

The Council is the successor to the unincorporated association of scientists known as the National Committee on Radiation Protection and Measurements and was formed to carry on the work begun by the Committee in 1929. The participants in the Council's work are the Council members and members of scientific and administrative committees. Council members are selected solelv on the basis of their scientific ex~ertiseand serve as individuals, not a s representatives of any particular organization. The scientific committees, composed of experts having detailed knowledge and competence in the particular area of the committee's interest, draft proposed recommendations. These are then submitted to the full membership of the Council for careful review and approval before being published. The following comprise the current officers and membership of the Council:

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LAURISTON S. TAYLOR, Honorary President WARREN K S ~ N C W President R, Emeritus W. ROGERNEY, Executiue Director Emeritus PATRICLA W.DURBIN THOMAS S. ELY RICHARD F.FOSTER HYMERL. FRIEDELL R.J. MICHAEL FRY ROBERT0.GORSON ARTHURW. GUY JOHNW. HEALY BERNDKAHN WILFRID B. A ANN DADEW.b f 0 ~ ~ l . E ~ A ALAN MOGHISSI J. NELSEN ROBERT

Lauris ton S. Taylor Lecturers The Squares of the Natural Numbers in Radiation Protection Why be Quantitative about Radiation Risk Estimates? Radiation Protection - Concepts and Trade Offs From "Quantity of Radiation" and "Dose" to ''Exposure'' and "Absorbed Dosem-An Historical Review How Well Can We Assess Genetic Risk? Not Very Ethics, Trade-offs and Medical Radiation The Human Environment - Past, Present and Future Limitation and Assessment in Radiution Protection Truth (and Beauty) i n Radiation Measurement Biological Effects of Non-ionizing Radiations: Cellular Properties and Interactions How to be Quantitative about Radiation Risk Estimates How Safe is Safe Enough? Radiobiology and Radiation Protection: The Past Century and Prospects for the Future Radiation Protection and the Internal Emitter . Saga When is a Dose Not a Dose? Dose and Risk i n Diagnostic Radiology: Hour Big? How Little? WARREN K SINCWR Science, Radiation Protection and the NCRP RJ. MICHAELFRY Mice, Myths and Men ALBRECHTKELLERER Certainty and Uncertainty in Radiation Protection SEYMOUR ABRAHAMSON 70 Years of Radiation Genetics: Fruit Flies, Mice and Humans Radionuclides in the Body: Meeting the Challenge! From Chimney Sweeps to Astronauts: Cancer Risks in the Workplace Back to Background

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Currently, the following committees are actively engaged in formulating recommendations: Basic Criteria, Epidemiology, Radiobiology and Risk SC 1-4 Extrapolation of Risks from Non-Human Experimental Systems to Man SC 1-6 Linearity of Dose Response SC 1-7 Information Needed to Make Radiation Protection Recommendations for Travel Beyond Low-Earth Orbit SC 1-8 Risk to Thyroid from Ionizing Radiation Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 10 MeV Operational Radiation Safety SC 46-8 Radiation Protection Design Guidelines for Particle Accelerator Facilities SC 46-10 Assessment of Occupational Doses from Internal Emitters SC 46-11 Radiation Protection During Special Medical Procedures SC 46-13 Design of Facilities for Medical Radiation Therapy SC 46-14 Radiation Protection Issues Related to Terrorist Activities that Result in the Dispersal of Radioactive Material SC 46-15 Operational Radiation Safety Program for Astronauts SC 57-10Liver Cancer Risk SC 57-15 Uranium Risk SC 57-17 Radionuclide Dosimetry Models for Wounds Environmental Issues SC 64-17 Uncertainty in Environmental Transport in the Absence of Site-Specific Data SC 64-18 Ecologic and Human Risks from Space Applications of Plutonium SC 64-19 Historical Dose SC 64-22 Design of Effective Emuent and Environmental Monitoring Programs SC 64-23 Cesium in the ~nviionment Biological Effects and Exposure Criteria for Ultrasound Radiation Protection in Mammography Guidance on Radiation Received in Space Activities Risk of Lung Cancer from Radon Radioactive and Mixed Waste SC 87-1 Waste Avoidance and Volume Reduction SC 87-2 Waste Classification Based on Risk SC 87-3 Performance Assessment SC 87-4 Management of Waste Metals Containing Radioactivity Fluence as the Basis for a Radiation Protection System for Astronauts Nonionizing Electromagnetic Fields SC 89-1 Biological Effects of Magnetic Fields

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SC 89-3 Biological Effects of Extremely Low-Frequency Electric and Magnetic Fields SC 89-4 Biological Effects and Exposure Recommendations for Modulated Radiofrequency Fields SC 89-5 Biological Effects and Exposure Criteria for Radiofrequency Fields SC 91 Radiation Protection in Medicine SC 91-1 Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides SC 91-2 Radiation Protection in Dentistry SC 91-3 Medical Radiation Exposure of the U.S. Population with Emphasis on Radiation Exposure of the Female Breast SC 92 Public Policy and Risk Communication SC 93 Radiation Measurement and Dosimetry In recognition of its responsibility to facilitate and stimulate cooperation among organizations concerned with the scientific and related aspects of radiation protection and measurement, the Council has created a category of NCRP Collaborating Organizations. Organizations or groups of organizations that are national or international in scope and are concerned with scientific problems involving radiation quantities, units, measurements and effects, or radiation protection may be admitted to collaborating status by the Council. Collaborating Organizations provide a means by which the NCRP can gain input into its activities from a wider segment of society. At the same time, the relationships with the Collaborating Organizations facilitate wider dissemination of information about the Council's activities, interests and concerns. Collaborating Organizations have the opportunity to comment on draft reports (at the time that these are submitted to the members of the Council). This is intended to capitalize on the fact that Collaborating Organizations are in an excellent position to both contribute to the identification of what needs to be treated in NCRP reports and to identify problems that might result from proposed recommendations. The present Collaborating Organizations with which the NCRP maintains liaison are a s follows: Agency for Toxic Substances and Disease Registry American Academy of Dermatology American Academy of Environmental Engineers American Academy of Health Physics American Association of Physicists in Medicine American College of Medical Physics American College of Nuclear Physicians American College of Occupational and Environmental Medicine American College of Radiology American Dental Association American Industrial Hygiene Association American Institute of Ultrasound in Medicine

THE NCRP

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American Insurance Services Group American Medical Association American Nuclear Society American Pharmaceutical Association American Podiatric Medical Association American Public Health Association American Radium Society American Roentgen Ray Society American Society of Health-System Pharmacists American Society of Radiologic Technologists American Society for Therapeutic Radiology and Oncology Association of University Radiologists Bioelectromagnetics Society Campus Radiation Safety Officers College of American Pathologists Conference of Radiation Control Program Directors, Inc. Council on Radionuclides and Radiopharmaceuticals Defense Special Weapons Agency Electric Power Research Institute Electromagnetic Energy Association Federal Communications Commission Federal Emergency Management Agency Genetics Society of America Health Physics Society Institute of Electrical and Electronics Engineers, Inc. Institute of Nuclear Power Operations International Brotherhood of Electrical Workers National Aeronautics and Space Administration National Association of Environmental Professionals National Electrical Manufacturers Association National Institute for Occupational Safety and Health National Institute of Standards and Technology Nuclear Energy Institute Office of Science and Technology Policy Oil, Chemical and Atomic Workers Union Radiation Research Society Radiological Society of North America Society of Nuclear Medicine Society for Risk Analysis United States Air Force United States Army United States Coast Guard United States Department of Energy United States Department of Housing and Urban Development United States Department of Labor United States Department of Transportation United States Environmental Protection Agency United States Navy

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THE NCRP

United States Nuclear Regulatory Commission United States Public Health Service Utility Workers Union of America The NCRP has found its relationships with these organizations to be extremely valuable to continued progress in its program. Another aspect of the cooperative efforts of the NCRP relates to the Special Liaison relationships established with various governmental organizations that have a n interest in radiation protection and measurements. This liaison relationship provides: (1)a n opportunity for participating organizations to designate an individual to provide liaison between the organization and the NCRP; (2) that the individual designated will receive copies of draft NCRP reports (at t h e time that these are submitted to the members of the Council) with an invitation to comment, but not vote; and (3) that new NCRP efforts might be discussed with liaison individuals as appropriate, so that they might have a n opportunity to make suggestions on new studies and related matters. The following organizations participate in the Special Liaison Program: Australian Radiation Laboratory Bundesamt f i Strahlenschutz (Germany) Central Laboratory for Radiological Protection (Poland) European Commission Health Council of the Netherlands Institute de Protection et de Surete Nucleaire (France) International Commission on Non-Ionizing Radiation Protection Japan Radiation Council Korea Institute of Nuclear Safety National Radiological Protection Board (United Kingdom) National Research Council (Canada) Russian Scientific Commission on Radiation Protection South African Forum for Radiation Protection Ultrasonics Institute (Australia) The NCRP values highly the participation of these organizations in the Special Liaison Program. The Council also benefits significantly from the relationships established pursuant to the Corporate Sponsor's Program. The program facilitates the interchange of information and ideas and corporate sponsors provide valuable fiscal support for the Council's program. This developing program currently includes the following Corporate Sponsors: Nycomed Arnersham Imaging Commonwealth Edison Consolidated Edison Duke Energy Corporation Florida Power Corporation Landauer, Inc.

New York Power Authority Nuclear Energy Institute Southern California Edison The Council's activities are made possible by the voluntary contribution of time and effort by its members and participants and the generous support of the following organizations: 3M Health Physics Services Agfa Corporation Alfred P. Sloan Foundation Alliance of American Insurers American Academy of Dermatology American Academy of Health Physics American Academy of Oral and Maxillofacial Radiology American Association of Physicists in Medicine American Cancer Society American College of Medical Physics American College of Nuclear Physicians American College of Occupational and Environmental Medicine American College of Radiology American College of Radiology Foundation American Dental Association American Healthcare Radiology Administrators American Industrial Hygiene Association American Insurance Services Group American Medical Association American Nuclear Society American Osteopathic College of Radiology American Podiatric Medical Association American mtblic Health Association American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists American Society for Therapeutic Radiology and Oncology American Veterinary Medical Association American Veterinary Radiology Society Association of University Radiologists Battelle Memorial Institute Canberra Industries, Inc. Chem Nuclear Systems Center for Devices and Radiological Health College of American Pathologists Committee on Interagency Radiation Research and Policy Coordination Commonwealth of Pennsylvania Consumers Power Company Council on Radionuclides and Radiopharmaceuticals

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Defense Nuclear Agency Eastman Kodak Company Edison Electric Institute Edward Mallinckrodt, J r . Foundation EG&G Idaho, Inc. Electric Power Research Institute Federal Emergency Management Agency Florida Institute of Phosphate Research Fuji Medical Systems, U.S.A., Inc. Genetics Society of America Health Effects Research Foundation (Japan) Health Physics Society Institute of Nuclear Power Operations James Picker Foundation Martin Marietta Corporation Motorola Foundation National Aeronautics and Space Administration National Association of Photographic Manufacturers National Cancer Institute National Electrical Manufacturers Association National Institute of Standards and Technology Picker International Public Service Electric and Gas Company Radiation Research Society Radiological Society of North America Richard Lounsbery Foundation Sandia National Laboratory Siemens Medical Systems, Inc. Society of Nuclear Medicine Society of Pediatric Radiology United States Department of Energy United States Department of Labor United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission Victoreen, Inc. Westinghouse Electric Corporation Initial funds for publication of NCRP reports were provided by a grant from the James Picker Foundation. The NCRP seeks to promulgate information and recommen-dations based on leading scientific judgment on matters of radiation protection and measurement and to foster cooperation among organizations concerned with these matters. These efforts are intended to serve the public interest and the Council welcomes comments and suggestions on its reports or activities from those interested in its work.

NCRP Publications

Information on NCRP publications may be obtained from the NCRP website (http~/www.ncrp.com),e-mail ( n c r p p u b ~ c r p . c o m )by , telephone (800-229-2652),or fax (301-907-8768).The address is: NCRP Publications 7910 Woodmont Avenue Suite 800 Bethesda, M D 20814-3095 Abstracts of NCRP reports published since 1980, abstracts of all NCRP commentaries, and the text of all NCRP statements are available at the NCRP website. Currently available publications are listed below.

NCRP Reports No.

Title Control and Removal of Radioactive Contamination in Laboratories (1951) Maximum Permissible Body Burdens and Maximum Permissible Concentrations of Radionuclides i n Air and i n Water for Occupational Exposure (1959) [Includes Addendum 1 issued in August 19631 Measurement of Neutron Flux and Spectra for Physical and Biological Applications (1960) Measurement of Absorbed Dose of Neutrons, arul of Mixtures of Neutrons and Gamma Rays (1961) Stopping Powers for Use with Cavity Chambers (1961) Safe Handling of Radioactive Materials (1964) Radiation Protection in Educational Institutions (1966) Dental X-Ray Protection (1970) Radiation Protection i n Veterinary Medicine (1970) Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Protection Against Neutron Radiation (1971) Specif~ationof Gamma-Ray Brachytherapy Sources (1974)

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NCRP PUBLICATIONS

Radiological Factors mecting Decision-Making in a Nuclear Attack (1974) Krypton-85 in the Atmosphere -Accumulation, Biological Significance, and Control Technology (1975) Alpha-Emitting Particles in Lungs (1975) Tritium Measurement Techniques (1976) Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 10 MeV (1976) Environmental Radiation Measurements (1976) Cesium-137 from the Environment to Man: Metabolism and Dose (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977) Protection o f the Thyroid Gland in the Event of Releases of Radioiodine (1977) Instrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook of Radioactiuity Measurements Procedures, 2nd ed. (1985) Operational Radiation Safety Program (1978) Physical, Chemical, and Biological Properties of Radiocerium Relevant to Radiation Protection Guidelines (1978) Radiation Safety Training Criteria for Industrial Radiography (1978) Tritium in the Environment (1979) Tritium and Other Radionuclide Labeled Organic Compounds Incorporated in Genetic Material (1979) Influence of Dose and Its Distribution in Time on Dose-Response Relationships for Low-LET Radiations (1980) Management of Persons Accidentally Contaminated with Radionuclides (1980) Radiofrequency Electromagnetic Fields - Properties, Quantities and Units, Biophysical Interaction, and Measurements (1981) Radiation Protection in Pediatric Radiology (1981) Dosimetry of X-Ray and Gamma-Ray Beams for Radiation Therapy in the Energy Range 10 keV to 50 MeV (1981) Nuclear Medicine -Factors Influencing the Choice and Use of Radionuclides in Diagnosis and Therapy (1982) Operational Radiation Safety - Training (1983) Radiation Protection and Measurement for Low-Voltage Neutron Generators (1983) Protection in Nuclear Medicine and Ultrasound Diagnostic Procedures in Children (1983) Biological Effects of Ultrasound: Mechanisms and Clinical Implications (1983) Iodine-129: Evaluation of Releases fmm Nuclear Power Generation (1983)

NCRP PUBLICATIONS

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Exposures from the Uranium Series with Emphasis on Radon and Its Daughters (1984) Neutron Contamination from Medical Electron Accelerators (1984) Induction of Thyroid Cancer by Ionizing Radiation (1985) Carbon-14 i n the Environment (1985) S I Units i n Radiation Protection and Measurements (1985) The Experimental Basis for Absorbed-Dose Calculations i n Medical Uses of Radionuclides (1985) General Concepts for the Dosimetry of Internally Deposited Radionuclides (1985) Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Fields (1986) Use o f Bioassay Procedures for Assessment of Internal Radionuclide Deposition (1987) Radiation Alarms and Access Control Systems (1986) Genetic Effects from Internally Deposited Radionuclides (1987) Neptunium: Radiation Protection Guidelines (1988) Public Radiation Exposure from Nuclear Power Generation i n the United States (1987) Ionizing Radiation Exposure of the Population of the United States (1987) Exposure of the Population i n the United States and Canada from Natural Background Radiation (1987) Radiation Exposure of the U.S. Population from Consumer Products and Miscellaneous Sources (1987) Comparative Carcinogenicity of Ionizing Radiation and Chemicals (1989) Measurement of Radon and Radon Daughters i n Air (1988) Guidance on Radiation Received i n Space Activities (1989) Quality Assurance for Diagnostic Imaging (1988) Exposure of the U.S. Population from Diagnostic Medical Radiation (1989) Medical X-Ray, Electron Beam and Gamma-Ray Protection for Energies Up to 50 MeV (Equipment Design, Performance and Use) (1989) Control of Radon i n Houses (1989) The Relative Biological Effectiveness of Radiations of Different Quality (1990) Radiation Protection for Medical and Allied Health Personnel (1989) Limit for Exposure to "Hot Particles" on the Skin (1989) Implementation of the Principle of As Low As Reasonably Achievahle (ALAR4) for Medical and Dental Personnel (1990) Conceptual Basis for Calculations of Absorbed-Dose Distributions (1991) Effects of Ionizing Radiation on Aquatic Organisms (1991) Some Aspects of Strontium Radiobiology (1991)

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NCRP PUBLICATIONS

111 Developing Radiation Emergency Plans for Academic, Medical or Industrial Facilities (1991) 112 Calibration of Suruey Instruments Used in Radiation Protection for the Assessment of Ionizing Radiation Fields and Radioactive Surface Contamination (1991) 113 Exposure Criteria for Medical Diagnostic Ultrasound: 1. Criteria Based on Thermal Mechanisms (1992) 114 Maintaining Radiation Protection Records (1992) 115 Risk Estimates for Radiation Protection (1993) 116 Limitation of Exposure to Ionizing Radiation (1993) 117 Research Needs for Radiation Protection (1993) 118 Radiation Protection i n the Mineral Extraction Industry (1993) 119 A Practical Guide to the Determination of Human Exposure to Radiofrequency Fields (1993) 120 Dose Control at Nuclear Power Plants (1994) 121 Principles and Application of Collective Dose i n Radiation Protection (1995) 122 Use of Personal Monitors to Estimate Effective Dose Equivalent and Effective Dose to Workers for External Exposure to LowLET Radiation (1995) 123 Screening Models for Releases of Radionuclides to Atmosphere, Surface Water, and Ground (1996) 124 Sources and Magnitude of Occupational and Public Exposures f i m Nuclear Medicine Procedures (1996) 125 Deposition, Retention and Dosimetry of Inhaled Radioactive Substances (1997) 126 Uncertainties i n Fatal Cancer Risk Estimates Used i n Radiation Protection (1997) 127 Operational Radiation Safety Program (1998) 128 Radionuclide Exposure of the EmbryolFetus (1998) 129 Recommended Screening Limits for Contaminated Surface Soil and Review of Factors Relevant to Site-Specific Studies (1999) 130 Biological Effects and Exposure Limits for "Hot Particles" (1999) Binders for NCRP reports are available. Two sizes make it possible to collect into small binders the "old series" of reports (NCRP Reports Nos. 830)and into large binders the more recent publications (NCRP Reports Nos. 32-130).Each binder will accommodate from five to seven reports. The binders carry the identification "NCRP Reports" and come with label holders which permit the user to attach labels showing the reports contained in each binder. The following bound sets o f NCRP reports are also available: Volume I. NCRP Reports Nos. 8,22 Volume 11. NCRP Reports Nos. 23,25,27,30 Volume 111. NCRP Reports Nos. 32,35,36,37 Volume IV. NCRP Reports Nos. 38,40, 41 Volume V . NCRP Reports Nos. 42,44,46

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Volume VI. NCRP Reports Nos. 47,49,50,51 Volume VII. NCRP Reports Nos. 52, 53, 54, 55, 57 Volume VIII. NCRP Report No. 58 Volume IX. NCRP Reports Nos. 59, 60, 61, 62, 63 Volume X. NCRP Reports Nos. 64, 65,66, 67 Volume XI. NCRP Reports Nos. 68, 69, 70, 71, 72 Volume X I . NCRP Reports Nos. 73, 74, 75, 76 Volume XIII. NCRP Reports Nos. 77, 78, 79, 80 Volume XIV. NCRP Reports Nos. 81, 82,83, 84,85 Volume XV.NCRP Reports Nos. 86, 87,88, 89 Volume XVI. NCRP Reports Nos. 90, 91,92, 93 Volume XVII. NCRP Reports Nos. 94, 95, 96, 97 Volume XVIII. NCRP Reports Nos. 98, 99, 100 Volume XIX. NCRP Reports Nos. 101,102,103, 104 Volume XX. NCRP Reports Nos. 105, 106, 107, 108 Volume XXI. NCRP Reports Nos. 109, 110, 111 Volume XXII. NCRP Reports Nos. 112,113, 114 Volume XXIII. NCRP Reports Nos. 115, 116, 117, 118 Volume XXIV. NCRP Reports Nos. 119, 120,121,122 Volume XXV.NCRP Report No. 1231 and 12311 Volume XXVI. NCRP Reports Nos. 124, 125,126, 127

(Titles of the individual reports contained in each volume are given above.)

NCRP Commentaries No.

Title

1

Krypton-85 in the Atmosphere - With Specific Reference to the Public Health Significance of the Proposed Controlled Release at Three Mile Island (1980) Guidelines for the Release of Waste Water from Nuclear Facilities with Special Reference to the Public Health S i g n i f ~ a n c eof the Proposed Release of Trealed Waste Waters at Three Mile Island (1987) Review of the Publication, Living Without Ldndfills (1989) Radon Exposure of the U.S. Population - Status of the Problem (1991) Misadministration of Radioactive Material in Medicine Scientific Background (1991) Uncertainty in NCRP Screening Models Relating to Atmospheric Transport, Deposition and Uptake by Humans (1993) Considerations Regarding the Unintended Radiation Exposure of the Embryo, Fetus or Nursing Child (1994)

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NCRP PUBLICATIONS

Advising the Public about Radiation Emergencies: A Document for Public Comment (1994) Dose Limits for Individuals Who Receive Exposure from Radionuclide Therapy Patients (1995) Radiation Exposure and High-Altitude Flight (1995) A n Introduction to Eficacy i n Diagnostic Radiology and Nuclear Medicine (Justification of Medical Radiation Exposure) (1995) A Guide for Uncertainty Analysis i n Dose and Risk Assessments Related to Environmental Contamination (1996) Evaluating the Reliability of Biokinetic and Dosimetric Models and Parameters Used to Assess Individual Doses for Risk Assessment Purposes (1998)

Proceedings of the Annual Meeting No. Perceptions of Risk, Proceedings of the Fifteenth Annual Meeting held on March 14-15, 1979 (including Taylor Lecture No. 3) (1980) Critical Issues i n Setting Radiation Dose Limits, Proceedings of t h e Seventeenth Annual Meeting held on April 8-9, 1981 (including Taylor Lecture No. 5) (1982) Radiation Protection and New Medical Diagnostic Approaches, Proceedings of the Eighteenth Annual Meeting held on April 6-7, 1982 (including Taylor Lecture No. 6) (1983) Environmental Radioactivity, Proceedings of the Nineteenth Annual Meeting held on April 6-7, 1983 (including Taylor Lecture No. 7) (1983) Some Issues Important i n Developing Basic Radiation Protection Recommendations, Proceedings of the Twentieth Annual Meeting held on April 45, 1984 (including Taylor Lecture No. 8) (1985) Radioactive Waste, Proceedings of the Twenty-first Annual Meeting held on April 3-4, 1985 (including Taylor Ledure No. 9) (1986) Nonionizing Electromagnetic Radiations and Ultrasound, Proceedings of the Twenty-second Annual Meeting held on April 2-3, 1986 (including Taylor Lecture No. 10) (1988) New Dosimetry at Hiroshima and Nagasaki and Its Implications for Risk Estimates, Proceedings of the Twenty-third Annual Meeting held on April 8-9, 1987 (including Taylor Lecture No. 11) (1988) Radon, Proceedings of the Twenty-fourth Annual Meeting held on March 30-31, 1988 (including Taylor Lecture No. 12) (1989)

NCRP PUBLICATIONS

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Radiation Protection Today-The NCRP a t Sixty Years, Proceedings of the Twenty-fifth Annual Meeting held on April 5-6, 1989 (including Taylor Lecture No. 13) (1990) Health and Ecological Implications of Radioactively Contaminated Environments, Proceedings of the Twenty-sixth Annual Meeting held on April 4-5, 1990 (including Taylor Lecture No. 14) (1991) Genes, Cancer and Radiation Protection, h c e e d i n g s of the Twenty-seventh Annual Meeting held on April 3-4, 1991 (including Taylor Lecture No. 15) (1992) Radiation Protection i n Medicine, Proceedings of the Twentyeighth Annual Meeting held on April 1-2, 1992 (including Taylor Lecture No. 16) (1993) Radiation Science and Societal Decision Making, Proceedings of the Twenty-ninth Annual Meeting held on April 7-8, 1993 (including Taylor Lecture No. 17) (1994) Environmental Dose Reconstruction and Risk Implications, Proceedings of the Thirty-first Annual Meeting held on April 12-13, 1995 (including Taylor Lecture No. 19) (1996) Implications of New Data on Radiation Cancer Risk, Proceedings of the Thirty-second Annual Meeting held on April 3-4, 1996 (including Taylor Lecture No. 20) (1997) Radiation Protection i n Medicine: Contemporary Issues, Proceedings of the Thirty-fifth Annual Meeting held on April 7-8, 1999 (including Taylor Lecture No. 23) (1999)

Lauriston S. Taylor Lectures No. 1

2 3

Title The Squares of the Natural Numbers i n Radiation Protection by Herbert M. Parker (1977) Why be Quantitative about Radiation Risk Estimates? by Sir Edward Pochin (1978) Radiation Protection - Concepts and Trade Offs by Hymer L. Friedell (1979) [Available also in Perceptions of Risk, see abovel From "Quantity of Radiation" and "Dose" to "Exposure" and "Absorbed Doseu-An Historical Review by Harold 0.Wyckoff (1980) How Well Can We Assess Genetic Risk? Not Very by James F . Crow (1981) [Available also in Critical Issues i n Setting Radiation Dose Limits, see abovel Ethics, Trade-offs and Medical Radiation by Eugene L. Saenger (1982) [Available also in Radiation Protection and New Medical Diagnostic Approaches, see abovel

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NCRP PUBLICATIONS

The Human Environment - Past, Present and Future by Merril Eisenbud (1983) [Available also in Environmental Radioactivity, see above] Limitation and Assessment i n Radiation Protection by Harald H. Rossi (1984) [Available also in Some Issues Important i n Developing Basic Radiation Protection Recommendations, see above] Truth (and Beauty) in Radiation Measurement by John H. Harley (1985) [Available also in Radioactive Waste, see abovel Biological Effects of Non-ionizing Radiations: Cellular Properties and lnteractions by Herman P. Schwan (1987) [Available also in Nonionizing Electromagnetic Radiations and Ultrasound, see above] How to be Quantitative about Radiation Risk Estimates by Seymour Jablon (1988) [Available also in New Dosimetry at Hiroshima and Nagasaki and its Implications for Risk Estimates, see above] How Safe is Safe Enough? by Bo Lindell(1988) [Available also in Radon, see above] Radiobiology and Radiation Protection: The Past Century and Prospects for the Future by Arthur C. Upton (1989) [Available also in Radiation Protection Today, see abovel Radiation Protection and the Internal Emitter Saga by J. Newel1 Stannard (1990) [Available also in Health and Ecological Implications of Radioactively Contaminated Environments, see above] When is a Dose Not a Dose? by Victor P. Bond (1992) [Available also in Genes, Cancer and Radiation Protection, see abovel Dose and Risk in Diagnostic Radiology: How Big? How Little? by Edward W. Webster (1992)[Available also in Radiation Protection in Medicine, see above] Science, Radiation Protection and the NCRP by Warren K. Sinclair (1993)[Available also in Radiation Science and Societal Decision Making, see above] Mice, Myths and Men by R.J. Michael Fry (1995)

Symposium Proceedings No. 1

2

Title The Control of Exposure of the Public to Ionizing Radiation in the Event of Accident or Attack, Proceedings of a Symposium held April 27-29, 1981 (1982) Radioactive and Mixed Waste -Risk as a Basis for Waste Classifiation, Proceedings of a Symposium held November 9, 1994 (1995)

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Acceptability of Risk from Radiation -Application to Human Space Flight, Proceedings of a Symposium held May 29, 1996 (1997)

NCRP Statements No. 1

2

3 4 5

6 7 8

Title "Blood Counts, Statement of the National Committee on Radiation Protection," Radiology 63, 428 (1954) "Statements on Maximum Permissible Dose from Television Receivers and Maximum Permissible Dose to the Skin o f the Whole Body," Am. J. Roentgenol., Radium Ther. and Nucl. Med. 84, 152 (1960) and Radiology 75, 122 (1960) X-Ray Protection Standurds for Home Tekvision Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (1968) Specification of Units of Natural Uranium and Natural Thorium, Statement of the National Council on Radiation Protection and Measurements (1973) NCRP Statement on Dose Limit for Neutrons (1980) Control of Air Emissions of Radionuclides (1984) The Probability That a Particular Malignancy May Have Been Caused by a Specified Irradiation (1992) The Application of ALARA for Occupational Exposures (1999)

Other Documents The following documents of the NCRP were published outside of the NCRP report, commentary and statement series: Somatic Radiation Dose for the General Population, Report of the Ad Hoc Committee of the National Council on Radiation Protection and Measurements, 6 May 1959, Science, February 19, 1960, Vol. 131, No. 3399, pages 482-486 Dose Effect Modifying Factors In Radiation Protection, Report of Subcommittee M-4(Relative Biological Effectiveness) of the National Council on Radiation Protection and Measurements, Report BNL 50073 (T-471) (1967) Brookhaven National Laboratory (National Technical Information Service Springfield, Virginia)

Index "Co in Stellites, 29 dosimetry calculations, 29 goSrPOyin fuel, 29 dosimetry calculations, 29 Absorbed dose, 16,33,34, 52 effects of field size, 52 from beta particle sources, 16 laboratory measurements, 34 measurements, 33 radiochromic dye films, 34 ACCEPT code, 20 Activation products, 14 cobalt, 14 hot particles, 14 Activation-type hot particles, 7 radionuclides in, 7 Activity of hot particles, 6 distribution of, 6 Age dating, 1 3 hot particles, 13 Antimony hot particles, 15 source of, 15 Approaches to limits, 181, 190, 191, 193 eye, 190 gastrointestinal tract, 193 hot particles, 181 respiratory tract, 191 Beta-particle sources, 16 absorbed doses from, 16 Body site, 45 skin thickness, 45 Boiling water reactors, 6 hot particles in, 6 Bronchi and bronchioles, 124 Brownian diffusion, 128 Calculation of absorbed dose, 16 Monte Carlo Method, 16

NISTKIN, 16 transport equation, 16 VARSKIN, 16 Chernobyl, 3, 12 hot particles, 3, 12 Cobalt hot particles, 14 activation of, 14 sources of, 14 Colon cancer, 172 induction by ionizing radiation, 172 Condensed history, 22 Monte Carlo calculations, 22 Cornea, 95, 107 schematized drawing, 95 CYLTRAN code, 20 Dermal thinning, 74 skin, 74 Deterministic effects, 47, 163, 165,184 large intestine, 165 limiting of, 184 skin, 47 small intestine, 163 Distribution of activity, 6 fuel hot particles, 6 Dose based on particle characteristics, 37 Dosimetric modeling, 177 gastrointestinal tract, 177 Dosimetry models, 16 for hot particles, 16 Dosimetry calculations, 27, 29, 30 60Coin Stellitea, 29 gOSrPOYin fuel, 29 hot-particle geometries, 27 VARSKIN and NISTKIN comparison, 30 Dosimetry codes, 19, 20, 21, 22, 23, 26, 27

INDEX

ACCEPT, 20,27 CYLTRAN, 20 EGS, 21 EGS4,26 ELTRAN, 19 ETRAN, 19 ITS, 19 MCNP4A, 20 new point kernel, 23 NISTKIN, 27 other Monte Carlo codes, 21 SADDE, 22 SANDYL, 19 VARSKIN, 22 VARSKIN MOD2,22,27 ZEBRA, 19 Dosimetry of hot particles, 16 models and calculations, 16 Ear, 45, 46, 88 anatomical structure and function, 45 diagrammatic representation, 46 radiation response, 88 EGS code, 21 Electrically charged particles, 129 Electron emission data, 24 for hot particles, 24 Electron micrograph, 6 hot particle, 6 ELTRAN code, 20 Epidermal thickness, 43 variation in adults, 43 Esophagus, 155 Esophagus cancer, 177 induction by ionizing radiation, 177 Esophagus irradiation effects, 158 summary of, 158 ETRAN dosimetry code, 19 Exoelectron dosimeter, 36 measurement of absorbed dose, 36 Extrapolation chamber, 35 measurement of absorbed dose, 35

1

255

Eye, 92, 93, 94, 96,98, 99, 100, 101,114,190 approaches to limits, 190 eyelids, 100 fibrous tunic, 93 large radiation fields, 101 lens, 98 retina, 96 schematic drawing, 92, 114 structure and physiology, 92 uvea, 94 vitreous, 99 Eye irradiation, 106, 107, 108, 112,113,116 cataractogenic dose, 108 cornea, 107 eyelids, 106 hot particles, 113 lens, 107 ocular effects, 116 retina, 112 Eyelids, 100, 106 Fibrous tunic, 93 Field measurements, 36, 37 absorbed dose, 36 survey instrument dose assessment, 37 Fuel cladding damage, 10 source of fuel particles, 10 Fuel fragments, 10, 11 cesium in, 10 radionuclides in, 11 source of, 11 Fuel hot particles, 6 distribution of activity, 6 Fuel particles, 10 source of, 10 Gas exchange airways, 125 Gastrointestinal tract, 148, 155, 168,193 approaches to limits, 193 radiation effects, 155 stochastic effects, 168 stomach cancer, 168 structure and function, 148

256

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INDEX

Gastrointestinal tract irradiation, 155, 157, 159, 160, 162, 163, 164, 165, 166, 167, 172, 177, 179 animal studies, 157, 160, 164, 167 by hot particles, 179 cancer of the small intestine, 177 colon cancer, 172 dosimetric modeling, 177 esophagus, 155 esophagus cancer, 177 large intestine, 167 patient studies, 159, 163, 166 small intestine, 163, 165 stomach, 159, 162 Hot particles, 1, 3, 5, 6, 7, 9, 11, 12, 13, 14, 16, 24, 25, 27, 56, 76, 113, 137, 143, 179, 181, 184 activity of radionuclides in, 9 age dating, 13 approaches to limiting deterministic effects, 184 approaches to limits, 181 Chernobyl, 12 description of, 1, 3, 5 distribution of radionuclides, 11 dose assessment, 3 dosimetry geometries, 27 dosimetry of, 16 electron emission data, 24 electron micrograph, 6 eye irradiation, 113 from activation products, 14 gastrointestinal tract risks, 179 in pressurized water reactors, 6 in boiling water reactors, 6 in reactor plants, 5 measurement of radioactivity, 13 nuclear rocket engines, 3 nuclear weapons test, 3 off the skin, 76 origin and nature of, 5 photon emission data, 25 primary types, 5

radioactive decay of, 1 3 radionuclides found in, 7 radionuclides in, 12 respiratory tract, 137 respiratory tract irradiation, 143 skin biological reactions, 56 sources of, 5 typical activities, 12 U.S.nuclear power plants, 7 Hot-particle measurements, 33 absorbed dose. 33 Impaction, 128 Interception, 129 Laboratory measurements, 34, 35,36 absorbed dose, 34 exoelectron dosimeter, 36 extrapolation chamber, 35 radiochromic dye films, 34 thermoluminescent dosimeter, 36 Large-field irradiation, 48 biological response of skin, 48 Large intestine, 165, 167 deterministic effects, 165 summary of radiation effects, 167 Larynx, 123 Lens, 98, 107 Lung, 141 Lymphatic system, 125 MCNP4A code, 20 Moist desquamation, 53 skin dose, 53 Monte Carlo calculations, 19,22 condensed-history, 22 single scattering, 22 solution of electron transport problems, 19 Nose, 120 Nuclear rocket engines, 3 hot particles, 3 Nuclear weapons tests, 3, 10

INDEX

gaseous ruthenium, 10 hot particles, 3 Particle deposition, 128 Brownian diffusion, 128 impaction, 128 sedimentation, 128 Pharynx, 123 Photon emission data, 25 hot particles, 25 Point-kernel-based calculations, 23 Point kernels, 17 empirical, 17 moments-method, 17 Pressurized water reactors, 6 hot particles in, 6 Pulmonary region, 132 Radioactivity, 13 measurement of, 1 3 typical hot particles, 13 Radiochromic dye films, 34 measurement of absorbed dose, 34 Radionuclides, 11, 12 distribution in hot particles, 11 in hot particles, 12 Reactor coolant, 10 cesium in, 10 Reactor plants, 5 distribution of hot particles, 5 Respiratory tract, 120, 123, 124, 125, 127, 129, 130, 132, 137, 140,146, 191 acute pneumonitis-syndrome, 137 approaches to limits, 191 bronchi and bronchioles, 124 deterministic effects, 132 electrically charged particles, 129 gas exchange airways, 125 hot particles, 137 interception, 129 large radiation fields, 132, 140 larynx, 123 lymphatic system, 125

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257

nose, 120 particle deposition, 127 pharynx, 123 pulmonary region, 132 radiation response, 132 retention and clearance of deposited particles, 129 stochastic effects. 140 structure and physiology, 120 summary of hot-particle irradiation, 146 trachea, 124 tracheobronchial region, 130 upper respiratory tract, 130 Respiratory tract irradiation, 133, 140,141, 143 hot particles, 143 large-field effects, 133 lung, 141 nasal cavity, pharynx, larynx and trachea, 140 Retention and clearance of deposited particles, 129 Retina, 96, 112 Ruthenium, 10 hot particles, 10 nuclear weapons tests, 10 SADDE code, 22 SANDYL code, 20 Sedimentation, 128 Single scattering, 22 Monte Carlo calculations, 22 Skin, 40, 48, 53,55, 57, 59? 61, 63, 64, 66, 73, 74, 78, 79,82, 83 acute ulceration, 59, 78 cancer lethality, 83 cancer risks, 82 damage with time, 64 dermal thinning, 55, 74 deterministic effects, 79 doses for acute ulceration, 73 effects of beta energy, 66 effects with time, 61 epidermis, 40 high-energy betas, 57 intermediate-energy betas, 57 large-field irradiation, 48

258

1

INDEX

low-energy betas, 63 moist desquamation, 53 photomicrograph, 40 Skin cancer, 84 radiation risk coefficients, 84 Skin dose, 52 effects of field size, 52 Skin and ear, 39,43,44,45,47 appendages, 44 dermis, 44 deterministic effects, 47 radiation biology, 39 radiation response, 47 structure and function, 39 variation in thickness, 45 variation in epidermal thickness, 43 Small intestine, 163, 165 deterministic effects, 163 summary of radiation effects, 165 Small intestine cancer, 177 induction by ionizing radiation, 177 Stochastic effects, 168 gastrointestinal tract, 168 Stomach, 159, 162 summary of radiation effects, 162

Stomach cancer, 168 induction by radiation, 168 Survey instrument dose assessment, 37 Thermoluminescent dosimeter, 36 measurement of absorbed dose, 36 Three-Mile Island, 11 distribution in hot particles, 11 Trachea, 124 Tracheobronchial region, 130 Transport equation, 16 solution of, 16 United States nuclear power plants, 7 comprehensive survey of hot particles, 7 Upper respiratory tract, 130 Uvea, 94 VARSKIN code, 22 VARSKIN MOD2,22 VARSKIN and NISTKIN, 30 comparison of dosimetry calculations, 30

ZEBRA dosimetry code, 19