Nuclear Medicine-Factors Influencing the Choice & Use of Radionuclics in Diagnosis & Therapy (NCRP report)

NCRP REPORT No. 70

NUCLEAR MEDICINE-FACTORS INFLUENCING THE CHOICE A N D USE OF RADIONUCLIDES IN DIAGNOSIS A N D THERAPY

Recommendations of the NATIONAL COUNCIL O N RADIATION PROTECTION AND MEASUREMENTS

Issued June 1, 1982

First Reprinting February 28,1992 National Council on Radiation Protection and Measuremen ts 7910 WOODMONT AVENUE / BETHESDA, MD 20814

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 reports. 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 thie 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.

Copyright O National Council on Radiation Protection and Measurements 1982 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 copyright owner. except for brief quotation in critical articles or reviews. Library of Congress Catalog Card Number 81-84121 International Standard Book Number 0-913392-57-x International Standard Serial Number ISSN 0083-209x

Preface

.

This report addresses the many factors which influence the choice of the proper radiopharmaceutical drug product for the diagnosis or treatment of a specific disease or condition in a human subject. The Report examines the historical factors that influence the choice of radionuclides, the factors that influence the localization of radionuclides in tissues, the factors that influence the choice of instruments, and includes an evaluation of the nuclear medicine procedures that could be selected and their clinical usefulness. In examining these factors the desirable characteristics of the radiopharmaceutical drug products and of the measurement systems are identified. The methods of dose determination and the assumptions used in determination of dose are developed. There is also a section on radiation effects. A chapter on guidelines for procedures in nuclear medicine and some general and specific recommendations for protection of patients conclude the body of the text. Guidelines for the clinical evaluation of radiopharmaceutical drugs which were developed by the Food and Drug Administration's Radiopharmaceutical Advisory Committee are set out in Appendix A. Appendix B provides radiation absorbed dose estimates for many radiopharmaceutical drug products. The Council has noted the adoption by the 15th General Conference of Weights and Measures of special names for some units of the Systbme International #Unites (SI) used in the field of ionizing radiation. The gray (symbol Gy) has been adopted as the special name for the SI unit of absorbed dose, absorbed dose index, kema, and specific energy imparted. The becquerel (symbol Bq) has been adopted as the special name for the SI unit of activity (of a radionuclide). One gray equals one joule per kilogram; and one becquerel is equal to one second to the power of minus one. Since the transition from the special units currently employed-rad and curie-to the new special names is expected to take some time, the Council has determined to continue, for the time being, the use of rad and curie. T o convert from one set of units to the other, the following relationships pertain: 1 rad = 0.01 J kg-' = 0.01 Gy 1 curie a 3.7 x 10108-I = 3.7 X 10'' Bq (exactly). iii

iv

/

PREFACE

Serving on Scientific Committee 32 on Administered Radioactivity during the preparation of this report were: A. Bertrand Brill, Chairman Medical Department Brookhaven National Laboratory Upton, LI, New York Members S. James Adelstein Harvard Medical School 25 Shattuck Street Boston, MA

Robert N. Beck The Franklin McLean Memorial Research Institute 950 East 59th Street Chicago, IL

Roger J. Cloutier Oak Ridge Associated Universities P. 0.Box 117 Oak Ridge, TN

Mary Rose Ford Oak Ridge National Laboratory P. 0.Box X Oak Ridge, TN

R. Eugene Johnston Division of Nuclear Medicine University of North Carolina Chapel Hill, NC

Paul Numerof 10 Ryan Road Edison, NJ

George V. Taplin (Deceased) Nuclear Medicine Research Lab UCLA Dept of Radiology Los Angeles, CA

Saul Winchell Medi-Physics Inc. 5855 Christie Avenue Emeryville, CA

Consultants Suresh Srivastava William G. Myers The Ohio State University Hospitals Brookhaven National LaboColumbus, Ohio ratory Upton, LI, New York

NCRP Secretariat, James A. Spahn, Jr. The Council wishes to express its gratitude to the members of the Committee for the time and effort devoted to the preparation of this report. Warren K. Sinclair President, NCRP Bethesda, Maryland 7 August 1981

CONTENTS Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Decision Making i n Nuclear Medicine . . . . . . . . . . . . . . . 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . - - . . . . . . . . . . 2. Decision-Making Considerations i n t h e Choice of Radiopharmaceutical D r u g Products . . . . . . . . . . . . . . . . 2.1 Historical Factors Influencing t h e Use of Radionuclides i n Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Desirable Characteristics of Radioactive Diagnostic ... . . . . . . . . . . . . Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 Optimum Radionuclide Characteristics Relative to Available Detection Devices and Intended Use . . . 2.2.2 Optimum Radiochemical Characteristics . . . . . . . . . .2.3 Optimum In Viuo Distribution . . . . . . . . . . . . . . . . . . . 2.3 esirable Characteristics of Therapeutic Radiopharmaceutical D r u g Products . . . . . . . . . . . . . . . . . . . - . . . . 2.3.1 Optimum Radionuclide Characteristics Relative to Desired Micro- and Macro-Radiation Dose Dis. . tnbution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 Optimum Radiochemical Characteristics . . . . . . . . . . 2.3.3 Optimum In Viuo Distribution Behavior . . . . . . . . . . 2.4 Factors Influencing Localization of Labeled Materials i n Tiesues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - . . . 2.4.1 General Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Discussion of Factors Influencing Distribution . . . . . 2.4.3 Specific Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 T h e Nature of Radionuclides Produced i n Reactors a n d Charged-Particle Accelerators . . . . . . . . . . . . . . . . 2.6 Acceptance Criteria for Radiopharmaceutical Drug Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1 Radionuclide Identity, Quantity and Purity . . . . . . . 2.6.2 Radiochemical Identity and Purity . . . . . . . . . . . . . . . ,

,

,

,

, ,

&

-.

,

vi

/

CONTENTS

2.6.3 Content and Toxicity of Non-Radioactive Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.4 In Vivo Distribution Behavior . . . . . . . . . . . . . . . . . . . 2.6.5 General Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.6 Sterility and Apyrogenicity . . . . . . . . . . . . . . . . . . . . . 2.6.7 Absorbed Radiation Dose . . . . . . . . . . . . . . . . . . . . . . 2.7 Regulations Regarding Production, Testing, Shipping, and Utilization of Radiopharmaceutical Drug Products for Human Use . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8 Choice of Radiopharmaceutical Drug Product for a Given Diagnostic Procedure or Treatment . . . . . . . . . 2.9 Management of Misadministration of Radiopharmaceutical Drug Products . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9.1 Administrative Responsibilities . . . . . . . . . . . . . . . . . 2.9.2 Medical Care Responsibilities . . . . . . . . . . . . . . . . . . . . 3 Factors in Choosing an Instrument for Nuclear Medicine Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Measurement Systems Used in Nuclear Medicine . . 3.2.1 Survey Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Dose Calibrators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3 Sample Counters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4 h b e Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 Imaging Syeteme Ueed in Nuclear Medicine . . . . . . 3.3.1 Rectilinear Scannexs . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2 Scintillation Cameras . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3 Tomographic Imaging Systems . . . . . . . . . . . . . . . 3.3.4 X-Ray Fluorescence Imaging Systems . . . . . . . . . . . . 3.4 Properties of Radiation Detectors for Measurement and Imaging Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2 Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3 Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Properties of Recording Devices Used in Nuclear . . . Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1 Count and Count Rate Recording Techniques . . . . . 3.5.2 Image Recording Techniques . . . . . . . . . . . . . . . . . . . . 3.6 Resolution Factors Affecting the Choice of Systems 3.6.1 Temporal Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2 Spatial Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.3 Energy Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Radiation Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Radiation Dose from Administered Radionuclides

.

.

CONTENTS

vii

4.1.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Dose Rate From Internal Emitters . . . . . . . . . . . . . . . 4.1.3 Absorbed Radiation Dose Calculations . . . . . . . . . . 4.2 Effects of Internally Administered Radionuclides in Man . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Sources of Information . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Review of Accidental and Unusual Occupational Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3 Medical Uses-Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.4 Medica4 Uses-Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 4.2.5 Summary of Findings from Historical Review . . . . . 4.2.6 Topics of Special Interest in Nuclear Medicine . . . . 5. Evaluation of Radionuclide Procedures and Their Clinical Ut~llty. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Evaluating the Role of New Nuclear Medical Procedures . . . . . : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1 A Priori Measures (of systems) and Figures of Merit for Imaging Procedures . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2 Evaluation of Non-Imaging Procedures . . . . . . . . . 5.2.3 Evaluation of Therapy Procedures . . . . . . . . . . . . . . . 5.2.4 A Posteriori Measures . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Measuring the Clinical Efficacy of Nuclear Medicine Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1 Nuclear Medicine Test Provides New Information . 5.3.2 Introduction of a Test lmproves Diagnostic Accuracy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.3 Introduction of a Test Leads to a Reduction in Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.4 Survival not Affected by Introduction of Nuclear Medicine Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Financial Costs and Cost Effectiveness . . . . . . . . . . . . 5.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Guidelines for Performing Nuclear Medicine Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Categories of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1 Patients Receiving Radionuclides for Diagnostic Purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2 Volunteer Subjects Receiving Radionuclides for Investigative Purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Methods of Patient Dose Reduction . . . . . . . . . . . . . . . . 6.3.1 Routine Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

..

.

viii

CONTENTS

6.3.2 Misadministrations . . . . . . . . . . . . . . . . . . . . .. .. . . . . 99 6.4 Radiation Protection Guides . . . . . . . . . . . . . . . . . . . . . . . 99 6.5 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 6.5.1 General Recommendation . . . . . . . . . . . . . . . . . . . . . . . 101 6.5.2 Thyroid Uptake of Iodine in Children . . . . . . . . . . . . 101 6.5.3 Radionuclides in Women in Reproductive Years . . . 102 6.5.4 Use of New Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 APPENDIX A-Guidelines for the Clinical Evaluation of Radiopharmaceutical Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 APPENDIX B-Radiation Absorbed Dose Estimates . . . . . 116 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .135 The NCRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 NCRP Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169

1. Decision Making in Nuclc:~r

Medicine 1.1

Introduction

The practice of nuclear medicine necessitates informed rlecision making in choosing the proper radionuclide, labeled compor~ud,;~trd instrumentation to be used in making a diagnosis or selecting the proper therapeutic radionuclide and dose. Practitioners of this branch of medicine must decide whether or not to perform a radioisotope procedure on a given patient, which radioisotope studies are indicated, and which are either not indicated or are contraindicated. Introduction of new radiopharmaceutical drug products (RDPs) and new indications for use of existing RDPs require decisions concerning the propriety of their proposed use. Such decisions are made by governmental regulatory bodies, institutional review committees, nuclear medical personnel performing routine clinical evaluations, clinical investigators, and finally, patients or experimental subjects themselves. Such decision making is most objective when it is based on the best data available a t the time, which must be weighed and analyzed objectively. While a number of source books are available that summarize present-day practice of nuclear medicine, there is a need for an information source organized around decision-making aspects for this discipline. The present report is directed toward this need. It is intended for use by all individuals and groups engaged in the decisionmaking processes in nuclear medicine including, but not limited to, personnel in government regulatory agencies, institutional committees overseeing the clinical use of radioactive agents both for routine and investigative purposes, and personnel in nuclear medicine laboratories concerned with acquisition and use of equipment and RDPs for routine and experimental purposes. It should also be of use to individuals who wish to familiarize themselves with the nuclear medicine decisionmaking process. This document does not provide guidance on the space, facility, and equipment requirements of a nuclear medicine laboratory, nor does it address itself to the personnel requirements and the training required to staff the laboratory. Neither is it concerned with the use of proce-

2

/

1. DECISION MAKING IN NUCLEAR MEDICINE

dures for safeguarding personnel and patients from hazards arising from storage, preparation, administration, utilization, and evaluation of radioactive materials, although familiarity with such information is a prerequisite for use with decision-making procedures in nuclear medicine. The reader should familiarize himself with these aspects of the discipline; such information will be found in general reference texts and in the following NCRP Reports whose titles indicate their contents. NCRP No. 30-Safe Handling of Radioactive Materials (1964) NCRP No. 37-Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) NCRP No. 39-Basic Radiation Protection Criteria (1971) NCRP No. 43-Review of the Current State of Radiation Protection Philosophy (1975) NCRP No. 48-Radiation Protection for Medical and Allied Health Personnel (1976) NCRP No. 57-Instrumentation and Monitoring Methods for Radiation Protection (1978) NCRP No. 58-A Handbook of Radioactivity Measurements Procedures ( 1978) NCRP No. 59-Operational Radiation Safety Program (1978) NCRP No. 65-Management of Persons Accidentally Contaminated with Radionuclides (1980) In addition to these sources, a World Health Organization report provides guidance on facilities and personnel required in performing nuclear medical procedures (WHO, 1976). The International Commission on Radiation Units and Measurements has published Report 32 Methods o f Assessment of Absorbed Dose in Clinical Use of Radionuclides (ICRU, 1979) which deals with the methods of evaluation of absorbed dose received by the tissues of persons to whom radioactive drug products have been administered. The Bureau of Radiological Health has produced a document containing information regarding the many recommendations and requirements for safe operation of a nuclear medicine laboratory (HHS, 1982).

Decision-Making Considerations in the Choice of Radiopharmaceutical Drug Products There are no ideal radiopharmaceutical drug products (RDPs) for use in diagnosis or therapy. There is only the best compromise at a given time between the physical and chemical characteristics of a particular substance plus various factors relating to instrumentation and RDP availability, quality control, and medical need. This section elaborates on these factors.

2.1

Historical Factors Muencing the Use of Radionuclides in Medicine

Radiations from decay of naturally-occurring radionuclides were used as encapsulated sources in therapy soon after the turn of the century. Radon gas, dissolved in saline, was used in classical flow studies in the late 1920s by Blumgart and Weiss (1927). Therapy with intravenous radium was also used in this era. But it was not until the charged-particle accelerators were used in the mid and late 1930s to make artificial radionuclides that significant quantities of a large number of radioactive species of elements became available for exploring their applications in medicine. In general, their availability was limited to investigators associated with the accelerators, and hence the early uses of radionuclides in medicine had a limited investigational character. After World War 11, the Congress of the United States created the U.S. Atomic Energy Commission (AEC) and charged it with the mission of developing peaceful uses for nuclear energy which included medical applications. A significant byproduct of nuclear technology has been the widespread availability of certain radionuclides generated as products of nuclear fission and others generated from bombardment of nuclei of stable elements by neutrons released during fission. 3

4

/

2.

CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

During the 1930s and 1940s, radiation detection devices were mostly based on the phenomenon of gas ionization, i.e., ionization chambers, gas proportional counters, and Geiger-Miiller counters. Medical uses of RDPs during this era were related largely to quantitation of volumespace distributions of labeled body constituents and evaluation of metabolic or cellular kinetics that could be deduced from data gathered by externally-placed collimated probes and by in vitro assay of activity in serial blood, urine, breath, or tissue samples. Even under the most favorable conditions, the gas ionization detectors provided only limited information on the two-dimensional localization of radioisotopes in patients. Development of the scintillation detector by Broser and Kallrnan (1947) in Germany was the key to in vivo detection. Cassen et al. (1951) invented the rectilinear scanner and Anger (1958) the singlecrystal scintillation camera-devices that generated two-dimensional spatial displays (images) of the in vivo distributions of gamma-emitting radionuclides. Their introduction made possible the present stage of nuclear medicine that is characterized by rapidly expanding clinical use of radionuclide imaging in the evaluation of the pathophysiology of local tissue disease processes. All of these latter devices use collimators made of lead or tungsten in conjunction with thallium-activated sodium iodide scintillation detectors [NaI(Tl)]. The characteristics of these devices are such that the higher the energy of the gamma-ray detected, the better the energy resolution of the scintillation detector and, therefore, the better the spatial resolution of the detector. Conversely, the higher the energy of the detected gamma ray, the lower is the detection efficiency of the scintillation crystal. Also, the characteristics of mechanical collimators are such that collimator transmission efficiency can be increased and septa1 penetration decreased with lower energy of the gamma-ray emission. Therefore, gamma-emitting radionuclides for use with the total gamma-ray imaging system (consisting of both the mechanical collimator and the NaI(T1) scintillation detector) must be chosen with regard to the energy of the gamma-ray emission(s). Moreover, the radionuclides to be used not only must possess the desirable characteristics outlined in the subsequent section but they must also be generally available. Since the only large-scale source of radionuclides available through the 1960s was the nuclear reactor, the choice of potential radionuclides for use with the new gamma-ray imaging devices was limited to neutron-excess nuclides. During the 1950s and the early part of the 1960s, reactor-produced I3'I was the principal radionuclide used in nuclear medicine. I t was available and

2.1

USE OF RADIONUCLIDES IN MEDICINE

/

5

inexpensive; and its 8-day physical half-life was long enough to minimize distribution logistics problems, especially since the small number and great dispersion of active nuclear medicine laboratories could not support a specialized rapid distribution network. During that time, l3'I was the "universal label"; it was bound to plasma, proteins, fats, and various other metabolites in addition to agents excreted by the kidney (e.g., '3'I-orthoiodohippurate)and the liver (e.g., '311-rosebengal). In fact, the first approved RDP under a New Drug Application (NDA) was '3'I-sodium iodide (November 23, 1951). I t became apparent that, although I3'I satisfied the principal radionuclide needs in the beginnings of nuclear medicine, the development of other agents was needed to serve the evolving requirements of the field. For reasons detailed in subsequent sections, searches began for short-lived radionuclides that emitted a minimum of non-penetrating radiation and a penetrating gamma-ray compatible with the capabilities of then-existing radiation detection devices. Such radionuclides were preferably nuclear reactor by-products, commercially available, and distributable through existing transportation channels without inordinate expense. Even with these requirements, solutions were found, embodied principally in the % O - ~ ~ Tand C the "3Sn-"3mIn generator systems. The relatively long-lived parent radionuclide in each of these instances could be produced in a reactor and the secondary generator system could be transported without undue haste, while the short-lived no-carrier-added daughter could be separated from the parent in the user's laboratory. While both of these generator systems received similar attention, the 99Mo-99nT~ system soon dominated and by 1972 approximately half of all clinical-nuclear medical studies performed in the United States utilized 99mTc(DHEW, 1968; 1970). A growing list of other generator produced radionuclides is available for research purposes, some of which will no doubt be found useful in clinical nuclear medicine. In the 1970s the development of low-cost cyclotrons and larger scale proton accelerators made a new source of proton-excess radionuclides available. By the beginning of the 1970s, the number of institutions practicing nuclear medicine had increased sufficiently to justify establishment of several specialized distribution networks capable of reliable daily delivery of short-lived radionuclides to nuclear medical laboratories. As a consequence, nuclear medicine no longer was as bound by the restricted availability of suitable radionuclides as was previously the case. At present there are several non-commercial isotope production facilities that provide hard-to-produce radionuclides for research applications. The facilities include BLIP (Brookhaven Linac Isotope

6

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

Producer), at the Brookhaven National Laboratory, LAMPF (Los Alamos Meson Production Facility) at Los Alamos National Laboratory, The TRIUMF (Tri University Meson Facility) in Canada, and the Oak Ridge National Laboratory. Improved facilities for radionuclide production are also being built by a number of radiopharmaceutical manufacturers which could improve the availiability of RDP's and contribute to the development of new agents. In spite of this, due to the continued development of pharmaceuticals labeled with *Tc, this radionuclide is stiU the most widely used at the present time. In this same period, several new radionuclides were introduced and accepted into routine clinical practice. Despite sub-optimal radionuclidic properties, gallium-67 citrate was used widely for tumor imaging, as well as abscess localization. The establishment of the potential utility of this NDA-approved RDP was based largely upon the results of coordinated studies involving multiple institutions using common protocols (Hayes, 1978). The availability of a long-lived generator system for production of 100 minute indium-113m from the 117 day parent tin-113, made it possible for institutions in remote locations and in developing countries to perform a wide variety of nuclear medicine procedures. Indium-111 (2.7 day) came into increasing use for blood cell kinetics and distribution studies and as a plasma protein label. Iodine-123 has been available commercially since the mid-19709. Its 159 keV principal gamma-ray emission is compatible with scintillation camera imaging devices and its physical half-life (-13 hr) and its relative freedom from emissions of other radiations ought to make it the radionuclide of choice for use in diagnostic studies of the thyroid gland. In spite of these advantages and the several conferences that have been sponsored to popularize the use of Iz3I (DHEW, 19764, the agent still receives only limited use in the U.S.A. presumably due to cost and logistic factors. Another example of a potentially useful short-lived nuclide that is not widely used because of logistics problems is fluorine-18 with a 110 min physical half-life. This nuclide is readily produced in high yield by existing charged particle accelerators and-while its requirements for rapid distribution pose substantial logistics problems-it clearly can be, and has, been, commercially produced and distributed throughout the U.S.A. Rapid, efficient chemical procedures for incorporating fluorine-18 into medically-useful compounds have been developed recently. Such compounds could be provided to the nuclear medical community from commercial sources once their unique utility has been established and adequate detection/irnaging devices have

2.2 CHARACTERISTICS OF RADIOACTIVE DRUGS

/

7

been placed in use. Radionuclides containing "C, 13N, and 1 5 0 , with physical half-lives of 30 minutes or less, will probably require on-site production by specialized charged-particle accelerators. A number of other radionuclides are finding new and increasing roles in clinical practice. Xenon-127 with its better imaging properties and longer shelflife could replace xenon-133 for blood flow and pulmonary ventilation studies if production and distribution problems are resolved. Several new short-lived generator systems are now available and promise to be of importance to future clinical practice because of favorable radionuclidic properties. Examples include the rubidium-81/ kryptonSlm generator (for blood flow and pulmonary studies-permitting sequential studies in the same patient) the osmium-19l/iridium191 generator (for first-pass angiography). A number of new radiopharmaceutical drug products which utilize the favorable properties of new nuclides, such as bromine-77, ruthenium-97 and tin-ll7m are under development. Present and future developments resulting in new and improved RDPs will certainly extend the usefulness of various nuclear medicine procedures. Their application must be considered as these agents become available for clinical use.

2.2

2.2.1

Desirable Characteristics of Radioactive Diagnostic Drugs

Optimum Radionuclide Characteristics Relative to Available Detection Devices and Intended Use

An optimum radionuclide for in vivo diagnostic use is one that results in the greatest diagnostic information with the lowest possible absorbed radiation dose in the tissues of the patient. The information content per unit radiation dose is often referred to as the Figure of Merit (FOM); and this concept is discussed more fully in Section 5.2.1. An optimized diagnostic strategy is achieved when a radionuclide is used that possesses a physical half-life most closely approximating the physiological half-time of the process being investigated (Myers, 1966, Wagner and Emmons, 1966). The emissions should have a minimum of non-penetrating components (i.e., a, P-, P', conversion or Auger electrons, low-energy gamma rays, or x rays) together with a maximum of penetrating emissions (gamma rays or high-energy x rays), the energy of which is matched to the detection device in a

8

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

manner that optimizes detection efficiency and spatial resolution. When single detector devices are employed, the best compromise is generally achieved by use of radionuclides decaying by electron capture or isomeric transition. When coincidence detectors for annihilation radiation are employed, the use of pure positron-emitting radionuclides is desirable. In addition to compatibility with available detection devices, it is necessary to choose radionuclides with penetrating radiations intended for detection that are appropriate for the study to be performed. Radionuclides intended for study of tissues or organs situated deep within the body, ideally should have hlgher energy gamma-ray emissions than those chosen to image structures close to the body surface. For example, other factors being equal, a radionuclide that is intended for evaluation of bone would optimally have a higher energy gamma-ray emission than a radionuclide intended for evaluation of the thyroid gland. Except for special applications where penetrating emissions of different energies are detected and analyzed in special ways, it is desirable for a radionuclide to have monoenergetic penetrating emissions. This requirement results from the fact that a particular combination of collimator and detector are matched optimally to detect and to quantitate primary photons of a given energy. Even when a detector device is capable of concurrent detection of several photopeaks, emission of photons of multiple energies is generally undesirable because the "lower energy" photons are inefficiently collimated by the "higher energy" collimator. If a collimator designed for the "lower energy" photon is used, then a significant number of the "higher energy" photons may penetrate the septa of the collimator without being scattered or absorbed. In addition, photons arising from scatter of the "higher energy" photons in the collimator or detector may contribute to the background for the "lower energy" photon peak. These considerations apply equally to photons arising from radionuclide contaminants in the preparations to be used. Such contamination results in a higher radiation dose to the patient than that from preparations having purified radionuclides. Also, when the energy of the emission of the contaminant is greater than that of the principal radionuclide for which collimation has been optimized, those photons are scattered principally in the patient and scintillation crystal, and contribute to the noise background of the photon under study. Special attention must be paid to avoidance of the presence of radiocontaminants in radionuclides separated from fission by-product materials. The presence of long-lived, alpha-emitting radionuclides in fission by-product material should be considered a significant contam-

2.2 CHARACTERlSTICS OF RADIOACTIVE DRUGS

/

9

ination problem since alpha-particles are difficult to detect and the presence of even miniscule alpha-emitting contaminants can contribute significantly to the absorbed radiation dose. When radionuclides are produced in a reactor by the (by)reaction, the presence of carrier nuclide may constitute a problem since, with this reaction, the radioactive product is chemically the same element as the non-radioactive target material and, generally, chemical separation of carrier from the radioactive moiety is not possible. With both neutron and chargedparticle activated radionuclides, radioactive contamination may be produced by activation of contaminants in the bombarded target. It is important to recognize that radioactive and non-radioactive contarninants may be present in a product and their levels will determine the usefulness of the material for specific applications. 2.2.2

Optimum Radiochemical Characteristics

The radiopharmaceutical drug product to be administered must be in a desirable, well-defined chemical form, stable in vitro, and must have a predictable stable (or unstable) behavior in uiuo. 99"rc-labeled substances provide examples of these requirements. -Tc has a variety of potential states of oxidation, and, presumably, the coordination compounds that it forms are functions of its oxidation state. A variety of radiocompounds becomes possible in any mixture of ""Tc with reducing agent and chelate, the form of the radiochemical achieved depending on the state of oxidation of the ""Tc, the reducing agent, the pH, the solvent and solute content, and the concentration of each of the constituents. Stability of the desired radiochemical form in vitro is essential.' However, there are cases where instability of the radiochemical form in uiuo actually may be a desired property. Examples of this are the -Tc-labeled agents for renal cortical imaging in which the -Tc label appears to be transchelated from its original compound to form RBmT~labeled complex moieties (presumably binding with -SH or other groups) during passage through the renal tubules. It is usually desirable to use radionuclides and radiochemicals that have minimum carrier (non-radioactive isotope of the radioactive element). When a carrier-free radiochemical is complexed with a suitable chelate and/or when additional agents are used to obtain a given oxidation state of the radionuclide, it is important to reduce as

' Stability refers to the lack of change in the chemical form of the RDP with time under various circumstances.

10

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

much as possible the concentration of all non-radioactive constituents in an effort to minimize possible toxic or adverse effects. 2.2.3

Optimum I n Vivo Distribution

The optimum in vivo distribution of a RDP should be such that, after its administration, mixing should be rapid and its kinetics simple and quantitatively interpretable. The rate of accumulation of tracer in, and its clearance from, the tissue or organ being studied should reflect physiological, pathophysiological, and biochemical processes that can be interpreted. If the intent is to image anatomical detail, the agent should rapidly accumulate in the organ or tissue of interest in patterns that reflect anatomical structure. Ideally, after a study is complete, the agent should be excreted rapidly and the tissues involved in the excretory process ought not receive undue radiation exposure. It should be noted that excretion of radionuclides in the urine involves radiation exposure to the kidneys and radioactivity in the bladder results in irradiation of pelvic organs. Excretion in the bile or intestine results in radiation exposure of intestinal mucosa, particularly that of the large bowel, where transit times are not normally rapid. In the former case, adequate fluid diuresis and frequent voiding and, in the latter case, enemas or cathartics minimize radiation doses to tissues related to the excretory routes. When long-lived radionuclides are employed, the apparent biological clearance of a radioactive drug from the body should not be relied on as a predictor of complete removal of the radionuclide from the body. Seldom is an agent cleared by a single rapid process, and even though apparently negligible, that fraction of an agent which is cleared slowly from the body may contribute more to the absorbed radiation dose than did the bulk of the agent that was cleared rapidly (Winchell, 1970).Thus, the 1percent of an administered quantity of a 14C-labeled compound cleared from the body with a mean time of 200 hours results in more than twice the radiation absorbed dose from the 99 percent of the administered quantity that cleared with a mean time of one hour. Similarly, use of the kinetics of clearance of a long-lived agent in a normal subject to calculate radiation absorbed dose may have little relevance to the actual radiation absorbed dose in the presence of abnormalities. Examples of this are radiation absorbed doses to the central nervous system when cisternographic agents, labeled with longlived radionuclides, are used in patients with sequestered cerebrospinal fluid or abnormally slow turnover of cerebrospinal fluid (Barbizet et al., 1972), or in the use of long-lived agents excreted by the kidneys or liver in the presence of renal or hepatic disease.

2.3 THERAPEUTIC DRUG PRODUCTS

2.3

2.3.1

/

11

Desirable Characteristics of Therapeutic Radiopharmaceutical Drug Products

Optimum Radionuclide Characteristics Relative to Desired Micro- and Macro-Radiation Dose Distribution

The desirable characteristics of RDPs intended for therapy are usually different from those described in Section 2.2.1. In general, radionuclides are chosen for which non-penetrating radiations (a,P-, p+, internal conversion and Auger electrons, soft x and gamma rays) are abundant and penetrating radiations (energetic gamma and x rays) infrequent. When radiation-induced damage of specific molecules or subcellular structures is desired, the radionuclides chosen are those that localize in such structures and produce damage due to recoiI energy, nuclide emission, or by change in nuclide identity after decay (i.e., transmutation). Local subcellular irradiation of structures in the immediate vicinity of the radionuclide can be accomplished by using radionuclides with a high Auger electron yield or a high yield of very weak /3- or internal conversion electrons. Irradiation of cells in the vicinity of the cell containing the radionuclide may be accomplished by using typical a,or high-energy 8- and B' emitters. More widespread radiation, diminishing approximately as the inverse square of the distance from the emission, can be obtained by using radionuclides emitting weak gamma or x rays. 2.3.2

Optimum Radiochemical Characteristics

These are comparable to those described for radioactive diagnostic drugs in Section 2.2.2.

2.3.3

Optimum In Viuo Distribution Behavior

Ideally, radioactive therapeutic drugs should localize selectively in the target tissues, cells, or subcellular structures.

2.4 2.4.1

Factors Influencing Localization of Labeled Materials in Tissues

General Kinetics

The rate of change of the content of radioactive material in a given tissue is equal to the difference between the influx or rate of entry of

12

/

2.

CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

the material into the tissue and its rate of exit. Consequently, the content of the material in the tissue a t any time following administration is equal to the difference between the integrals with respect to time of the influx and efflux. The influx of the material into the tissue is, for the most part, a function of tissue perfusion (blood flow) and the capillary or endothel i d permeability to the material in the form in which it exists in the microcirculation. The efflux of material from the tissue is a function of its probability of passing from the extracellular fluid space into capillary or lymphatic vessels and returning to blood. In turn, the probability of the material being found in the extracellular fluid space will depend upon (1)the probability of its being bound on surfaces bathed by extracellular fluid; (2) bidirectional transfer through the cell wall; and (3) the subsequent metabolic fate of the radioactive label. 2.4.2

Discussion of Factors Influencing Distribution

The general processes that influence the distributions of RDPs in the body subsequent to the intravascular administration of labeled material are illustrated in Figure 1. Various mechanisms influence the distribution of labelled compounds and a conceptual description of these processes is outlined in this section. After intravenous administration of a drug, the initial processes affecting its distribution relate to mixing in the intravascular

B. TRANSCAPILLARY A N D EXTRACELlUlAR FLUID (ECFj EQUILIBRATION

,

C. EFLUX IN LYMPHAT~C VESSELS

D A T T A C H M E N T T O OR DIFFUSION O R TRANSPORT ACROSS CELL M E M B R A N E

/

EQUllfBRATfON

. METABOLISM

OF TRANSLOCATED

fluid space

Surfaces

barhed

in ECF

Fig. 1. Processes affecting radionuclide concentration in tissues.

2.4

LOCALIZATION OF LABELED MATERIALS IN TISSUES

/

13

space from the point of injection to the first capillary bed reached by the agent. Certain highly water-insoluble drugs may adhere to the lining of the vein wall distal to the site of injection (Winstead et al., 1973a), while other agents may show an affinity for binding with plasma proteins (e.g., Ca[II] and Sr[II] for albumin and Fe[II, 1111, Ga[II, 1111, and In[III] for transfenin) or intracellular constituents (e.g., radiolabeled diisopropyl fluorophosphate). Upon reaching a capillary bed, the drug will mechanically lodge in the capillaries if the drug is in a particulate form whose effective diameter is greater than the lumen of the capillary (e.g., >10pm). If the drug is sufficiently lipidsoluble and inert, (e.g., 02, COz, and the monatomic inert gases Ne, Ar, Kr, Xe, and Rn) it will usually pass across the lipoprotein membranes of the capillary endothelium. If the lipid-soluble drug is a gas and the capillary endothelium under consideration is in the lungs, then the agent will accumulate in the gas contained in the alveoli and be expired in the breath. If the lipid-soluble drug contacts lipid-rich pools after passage across the capillary endothelium, it will equilibrate with such lipid pools (Winstead et al., 1973a; Winstead et al., 197313; Oldendorf, 1974). Its subsequent loss from such lipid pools will depend primarily on the partition coefficient between the lipid pool and the blood, plus the blood perfusion rate of the lipid pool. The surface membranes of the reticuloendothelial cells lining the sinusoids in the liver, spleen, bone marrow, and lymph nodes have the ability to extract particulate material from the blood flowing through the sinusoids. They behave this way to both organic particles such as microaggregated albumin and inorganic particles like polymeric hydrolyzed metals. Lipid-insoluble drugs, for example electrolytes, most carbohydrates, amino acids, and proteins, are unable to cross the lipoprotein barrier of the capillary endothelial membrane. Their route of egress from the intravascular space is through the tiny gaps (pores or canniculi) that exist at the junction between capillary endothelial cells. The size or effective diameters of these endothelial pores appear to vary widely among the various organs of the body. The reticuloendothelial lining of vascular sinusoids in the Liver and spleen, and possibly bone marrow and lymph nodes, appears to possess pores that are relatively large and allow passage of macromolecules such as albumin or transferrin. The pores between capillary endothelial cells in the intestine are smaller since they limit the rate of transfer of macromolecules from the blood to the interstitial fluid more than those of the liver; the pores in the intestinal epithelium allow appreciably greater passage of macromolecules than do the pores in the skeletal muscle and other somatic tissues (Winchell et aL,1964).The smallest endothelial pores probably exist in the vasculature of the brain, a situation accounting in part for

14

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

the so-called "blood-brain barrier." It should be added that the capillary walls in neovascularization processes may have abnormally large gaps or pores. Examples are seen in neoplasms, inflammatory reactions, and in certain phases of recovery from infarction. The electrostatic charge of a particle does not seem as important as its shape and size in governing the transcapillary and extracellular fluid kinetics of most materials. For example, the kinetics of movement of transferrin (molecular weight, 83,000 to 90,000) from the intravascular space is similar to that for albumin (molecular weight, 69,000) even though their electrostatic charges a t body pH are not identical (Winchell et al., 1964).Fibrinogen, on the other hand, with a molecular weight of 340,000,equilibrates much more slowly across the capillary endothelium and within the extracellular fluid space than does either albumin or transferrin. Except for vasculature of the central nervous system, small lipidinsoluble molecular species (e.g., hydrated electrolytes and molecules of less than a few thousand molecular weight) rapidly pass from the intravascular to the interstitial fluid space through the pores of the capillary endothelial membranes. Once low molecular weight molecules have entered the interstitial fluid space, they may re-enter the intravascular space through the same gaps or pores in the capillary endothelium that allowed their exit. However, high molecular weight molecules must return to the intravascular space by way of the lymphatic vessel pathways. Mechanical blockade of the lymphatic drainage from a tumor, plus delays in the new growth of lymphatic vessels to match the growth of the neoplasm or development of inflammatory processes, all may contribute to the increased concentration of macromolecules in these abnormal tissues. Molecules in the interstitial fluid space may adhere or be bound to surfaces bathed by extracellular fluid. Such surfaces include cell membranes and the apatite crystal of bone. When the bonding site has a high specificity and affinity for a particular ligand, it is considered a receptor site. The possibility of using radiolabeled ligands directed toward these receptor sites is receiving attention currently with a view toward diagnostic and therapeutic applications (Eckelrnan et al, 1979). Diffusion and transport across the cell membrane represent the ratelimiting step in the distribution kinetics of many substances. Many small organic molecules rapidly equilibrate within the extracellular fluid space and either diffuse rapidly or are actively transported across the cell membrane so that the largest pool of these molecules in the body is within the intracellular space. Amino acids are examples of such molecules (Lin and Winchell, 1970). For them, the kinetics of intracellular metabolism is the most important factor determining the changes in concentration of radioactivity in various tissues. If the

2.4 LOCALIZATION OF LABELED MATERIALS IN TISSUES

/

15

material exists in various forms within the cell, the intracellular kinetics may be complicated because the tracer may cycle and recycle from one form to many others, each with its own kinetics. An example of such a process is the fixing of free intracellular amino acids into intracellular protein moieties which, upon degradation, feed the labeled amino acid back into the free amino acid pool. Evaluation of the complex concentration changes for such compounds in different tissues requires information concerning the fraction in the extra-cellular fluid pool that enters cells contained in a unit mass of the tissue as well as the intracellular kinetics of the labeled material once it enters the cells. If the label is translocated to another molecular species subsequent to its metabolism, the distribution kinetics of this translocated label must be considered. The metabolism of such translocated labels becomes quite complex for very long-lived nuclides such as carbon-14 or tritium, particularly when the label can be cycled through a large number of metabolic pools before its excretion from the body.

2.4.3

Specific Examples

Since the generalizations given above are not comprehensive, the factors determining the distribution of intravenously administered drugs are best considered in relation to specific groups of drugs. The tissue distribution of well-mixed particulate material having sizes greater than the width of capillary beds is evidence of the relative distribution of blood flow to these capillary beds. Similarly, the distribution of particulate material small enough to pass through capillary beds, but of a nature to be nearly totally removed by reticuloendothelial cells lining blood vessel walls, reflects relative blood flow to such reticuloendothelial cells. Since the apatite crystal of bone acts as a non-specific ion exchange medium toward certain molecules found in the extracellular fluid of bone, the relative perfusion and transcapillary movement of radioactive tracers that are adsorbed and exchanged on the apatite crystal determine the relative uptake of such molecules in bone. The fluoride ion is a small ionic species not bound to macromolecules when it is present in the microcirculation and thus freely diffuses across the pores in the capillary walls. Consequently, the principal factors influencing uptake of radiofluoride in bone are the blood flow to that region of bone, the concentrations of the radiofluoride in the blood, and the affinity of bone crystal or its osteoid matrix for it. Calcium and strontium are cations that are bound principally to plasma proteins, but only the unbound cation present as a small fraction of the total concentration is free to interact with the apatite crystal. Consequently, although blood flow to an area of bone is the

16

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

principal factor in influencing the regional bone uptake of radiocalcium and radiostrontium, the relative rate of such bone uptake is considerably slower than that seen with non-protein-bound radiofluoride. intermediate between these two examples is the case of the phosphates, pyrophosphates, polyphosphates, and phosphonates labeled with various radioelements. This latter group generally shows binding to plasma proteins but not to the extent seen with calcium and strontium. Here, too, their relative uptake in normal bone is principally determined by the blood flow, but the rate of bone uptake is intermediate between the non-protein-bound fluoride and the strongly proteinbound calcium and strontium. The kidneys and the liver, between them, excrete nearly all nonmetabolizable foreign materials from the body. Polar water-soluble moieties in general are cleared from the blood by the kidneys and excreted in the urine, while lipid-soluble non-polar moieties are cleared by the liver and excreted in the bile. Radiolabeled lipid-soluble materials excreted in the bile include radioiodine-labeled rose bengal, bromsulphalein, toluidine blue, fluorescein, and other dyes, and certain technetium-labeled lipid-soluble compounds. Totally inert freely diffusible water-soluble materials, for which there is no renal tubular excretion or reabsorption mechanism, are cleared from the blood in their passage through the renal glomerulus (glomerular filtration). Examples are chelates of EDTA and DTPA and the inert polysaccharide inulin. Inert diffusible materials for which an active renal excretory mechanism exists will be cleared actively from the blood while passing through the renal tubules. Examples of compounds that are excreted by the tubules are hippuric acid and its derivatives; their plasma clearance is a measure of renal plasma flow. Most water-soluble nonmetabolizable materials excreted by the kidney appear in the urine after having been exposed to a combination of glomerular filtration, tubular excretion, and tubular reabsorption more or less specific for a given substance, e.g., H+ or K+. Certain materials that are handled by tubular excretion or reabsorption are either retained in the tubules or the radioactive label is removed by the tubules to result in its longterm retention there. Such is the case for organoradiomercurial agents, radiochromium and technetium-labeled saccharides, polypeptides, and certain water-soluble mercaptocarboxylates (Lin et al., 1974a). Neoplasms, areas of inflammation, and certain phases of infarct healing are characterized by an increased permeability of their capillary beds to macromolecules. This increase is related to neovascularization and the large intercapillary pores associated with new growth of capillary beds in these circumstances. Thus, in all three clinical conditions, the flow of macromolecules from the intravascular space into

2.5 REACTOR AND ACCELERATOR PRODUCED NUCLIDES

/

17

t.hc interst.itia1fluid space is increased above that seen in normal tissue. Moreover, in the case of neoplasms and inflammatory processes, there may be blocked lymphatic drainage plus a delay in new lymphatic vessel growth that add to the residence time of the macromolecules in the interstitial fluid space. In all three conditions, the increased macrophage activity associated with tissue necrosis leads to phagocytosis of the labeled macromolecule; pinocytosis may result in ingestion of the labeled macromolecule by still other cells in the lesion; and there may be specific receptor sites on the cell membranes to which the labeled macromolecules b i d , followed by the label passing into the intracellular space. Radio-labeled macromolecules such as albumin, fibrinogen, or gamma globulins, and radionuclides that bind to macromolecules such as radiogallium, radioindium, and other radioelements, localize in tumors, inflammatory lesions, and in healing infarcts. In the case of radiogallium and radioindium, the binding macromolecule is transfenin (Weiner el al., 1979) and it is known that some cells have specific receptor sites for transferrin on the cell membrane (Idarson el al., 1979). The in uit~odistribution of most currently used radiopharmaceutical drug products is explained by the processes described in this section. 2.5

The Nature of Radionuclides Produced in Reactors and Charged-Particle Accelerators

A large number of radioactive nuclides result from nuclear fission. l'o use such fission products, chemical techniques are employed that separate the desired radionuclide from all other contaminating elements. This procedure limits the radioelements that can be obtained from f ~ s i o nproducts to those with half-lives long enough to survive the time required for the separation process. Neutrons released during nuclear fission are used to activate stable elen~c!nts.Bombardment of stable nuclei with low-energy neutrons rc!sult.s in the formation of product nuclei that have a neutron excess and t.hat dccay by beta-gamma emissions. Moreover, since the chemical identity (Znumber) of the radioactive nuclide is identical to that of the stable target nucleus, the radioactive product usually contains con~iderablequantities of carrier that can limit its medical applicability. When neutron-activated radioactive species decay to a different chemical element, the daughter product is essentially carrier free (e.g., ~)roduc.tiot~ of wMo by the "Mo(n, y ) *Mo reaction, followed by wMo - , "'""l'c, or production of ''Xe by the '"Xe(n, 7 ) '"Xe reaction, folluwc~tlby '"Xe -, 'zJl). (!hargc.d-particle accelerat.ors (linear accelerators, cyclotrons, Van

18

/

2.

CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

de Graaff generators, etc.) can accelerate the nuclei of elements, usually hydrogen, deuterium or helium, which can then react with the nuclei of stable elements to create new radioactive forms. The product radioactive nuclide resulting from charged-particle bombardment is a different chemical species and usually has a proton excess (neutron deficiency). Thus, radionuclides produced by use of charged-particle accelerators typically are carrier-free and decay by electron capture or positron emission. Many of them also possess the desirable characteristic of being short-lived. High-energy photons can be used to bombard target nuclei with a resultant loss of neutrons or protons from the target nucleus. When neutrons are lost from the target nucleus, the product nucleus is neutron deficient and, if unstable, will generally decay by electron capture or positron emission, e.g., '2C(v,n)"C. Because the product nuclei have the same chemical identity as the target nuclei, the specific activity of the product is usually very low. When protons are lost from the target nuclei, the product nuclei generally have a neutron excess and decay by beta-gamma emission, e.g., 44Ca(y,p)'". Since the product nuclei have a different chemical identity than the target nuclei, the product can be obtained in an essentially "carrier-free" state. Primarily due to governmental underwriting of nuclear reactors for research purposes, radionuclides formed from fission processes or from neutron activation have been less expensive and more readily available than radionuclides generated otherwise. Recent development of compact, relatively inexpensive cyclotron accelerators has made many proton excess" radionuclides available for use in medicine. Only a limited number of radionuclides for medical application have been produced that use photonuclear reactions, but these reactions may be more useful in the future. 44

2.6

2.6.1

Acceptance Criteria for Radiopharmaceutical Drug Products

Radionuclide Identity, Quantity, and Purity

The identity and quantity of the radionuclide, as well as the identity and quantity of contaminating radionuclides, must be known prior to administration of a drug to a patient (Tubis, 1978). Since the ultimate responsibility for the welfare of patients relative to the administration of a radionuclide must reside with the attending nuclear medical physician, he must assure himself that this information is known and proper at the time of administration of the agent to the patient.

2.6 CRITERIA FOR RADIOPHARMACEUTICAL PRODUCTS

/

19

Manufacturers or suppliers information on assay of RDPs should be verified in the nuclear medicine laboratory. This should be a normal quality assurance procedure. Performance of quality assurance tests by the end user is mandatory when the integrity of the radioactive drug in its final packaged form has been breeched in any significant way prior to use. Gross confirmation of radionuclide identity and purity can be performed by analyzing samples with several types of instruments: 1) single channel analyzers and NaI(T1) scintillation detection devices and 2) multichannel analyzers used in conjunction with NaI(T1) or Ge(Li) detectors. Once radionuclide identity and purity have been checked, the activity of the radionuclide present (in the absence of significant radiocontaminants) can be checked by use of calibrated ionization chambers (dose calibrator) and other simple devices. Each patient dose should be measured prior to its administration regardless of the source of the radioactive agent.

2.6.2

Radiochemical Identity and Purity

The chemical identity of RDPs should be known prior to administration and the presence of all chemical forms of the radionuclide other than that which is desired (radiochemical purity) must be assessed. Currently, this is most simply done by using radiochromatographic techniques (paper, thin-layer, and column chromatography). These methods are applicable a t the no carrier-added level, require inexpensive equipment and are easy to perform. For ascertaining radiochemical purity, use of a t least two chromatographic systems is recommended. Both systems should be chosen to provide concordant or complimentary information. A number of solvent and eluting systems for paper, thin-layer and column chromatography have recently been developed and find use in the analysis of a variety of RDPs including technetium radiopharmaceuticals (Eckelman, and Levenson, 1978). Simple chromatographic procedures do not have the resolving power or the sensitivity that is necessary for a complete characterization of multicomponent preparations. Many RDPs are complex mixtures and not single homogeneous compounds. A new technique, high-performance liquid chromatography (HPLC), offers the prospect for rapid, high resolution analysis of the multicomponent mixtures which constitute many RDPs, and should find increasing use in research and routine screening of compounds used in clinical nuclear medicine (Pinkerton, et a1 1980, Srivastava, et al, 1981). Assurance of proper radiochemical identity and purity is best achieved by validating a production procedure and carefully duplicat-

20

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

ing this production procedure each time the material is made. Even when the drug is purchased in final dosage form, the nuclear medicine laboratory should use the best techniques available to verify the radiochemical identity and purity prior to administering any radioactive drug to a patient. 2.6.3

Content and Toxicity of Non-Radioactiue Constituents

Some radionuclides produced by the (n, y) reaction contain variable quantities of the stable element (carrier) from which the radionuclide was produced. Similarly, non-radioactive elements may contaminate a radionuclide after their introduction during target processing or radionuclide purification. Furthermore, no radioisotope is ever truly "carrier-free" since minute quantities of carrier are always present in solutions and materials used in processing. Non-radioactive materials may be introduced deliberately to change the valence state of a radioelement or to form a coordination or covalent compound with it. Non-radioactive materials may also be added to adjust pH or tonicity and to stabilize or preserve the radionuclidic material of interest. AU of these non-radioactive constituents must be evaluated relative to potential toxicity and their content in the final product should be minimized without compromising the useful functions they are intended to peform. 2.6.4

In Vivo Distribution Behavior

The single most important quality of an RDP is that its distribution and metabolism be predictable in uiuo. At present, however, few in vivo experimental evaluation procedures can provide the predictive basis for estimating precisely the in viuo distribution in man. Few radiopharmaceuticals, if any, localize in the specific organs with complete selectivity. Upon injection into the blood, the normal processes of absorption, distribution, and excretion take place; the nature and rate of these is determined by the chemical characteristics of the agent, its affinity for and the extent of its interaction with biological molecules including proteins, the relative kinetics of uptake and elimination processes involved, and the changes in pharmacokinetics brought about by patient pathophysiology. RDPs can be divided into two broad classes based upon their biological behavior. Those belonging to one category include agents in which the radionuclide functions as a true tracer, that is, the n o d biological distribution of the labeled

2.6 CRITERIA FOR RADIOPHARMACEUTICAL PRODUCTS

/

21

substance is not perturbed significantly by the presence of the nuclide. These include labeled particles, proteins, cells, and certain other bioactive molecules including drugs. For example, injection of colloidal material into the circulation is followed by its near compIete removal by the reticuloendothelial system, regardless of whether the particles are radio-labeled or not. The second category includes labeled compounds the biological fate of which are to a large extent determined by the presence of the radionuclide. The biodistribution of this class of compounds is usually markedly different from that of the unlabeled substrate. In other words, the distribution is governed by the nature of the resultant radionuclide-ligand complex, and the properties of the non-labeled ligand contribute insignificantly to the overall distribution pattern of the activity. Examples include 99mTc-HIDA,various kidney function agents, and compounds that localize in the infarcted mycardium. The in-vivo mechanisms involved, however, are so far poorly understood. Validation by measurement of the in vivo distribution of an RDP in a suitable animal test system (model) is essential. When a relationship has not been established between the distribution of a radionuclide in uivo and the metabolic kinetics in an animal model, such studies need to be performed prior to qualifying an RDP for human use. I t seems reasonable to expect that when the ability to characterize the different chemical constituents in the RDP is improved, the in vivo behavior will be easier to predict. 2.6.5

General Safety

"General safety" of a diagnostic drug is evaluated by administering very large doses of the material intended for human use to a normal animal (10-100 times the amount used in man in pCi/kg) and observing the animal over a period of time to determine whether the animal becomes sick or dies. While clearly crude and non-specific, such "general safety" tests do provide some protection against the introduction of non-specific toxic materials that may not be detected in tests for specific anticipated contaminants. The most realistic application of general safety tests is in qualifying non-perishable raw materials, "kits", or "reagents" used in radiopharmaceutical drug manufacture. These tests are most applicable for use by primary pharmaceutical manufacturers, but under certain circumstances they may be of direct service to the nuclear medicine physician in whose laboratory new procedures are being developed.

22 2.6.6

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

Sterility and Apyrogenicity

Sterility must be assured for all drugs intended for parenteral administration. It is achieved through filtration, chemical treatment, exposure to high intensity radiation fluxes of appropriate wavelength, or through a combination of heat and pressure. Sterility is evaluated by testing for the presence of ~ i a b l eorganisms (USP, 1980). The presence of viable organisms is evaluated by noting visible growth of colonies of microorganisms on suitable growth media, but new methods, such as the utilization of I4C-labeled sugars that directly test metabolic activity of viable organisms before colony growth can be seen, may be employed in the future (De Blanc et al., 1971; Hetzel and Ice, 1975). With currently accepted techniques for assessing sterility, the short time interval between production and use of short-lived radioactive drugs requires after-the-fact assurance of sterility. Thus, sterility testing in practice consists of having an assured procedure that has internal controls rather than qualifying each specific product batch. Pyrogenic reactions are rare to non-existent in most present day radiopharmaceutical products. This is so largely because sources of bacterial endotoxin are now known and proper procedures for precluding pyrogen introduction or inactivation in products are now employed during parenteral pharmaceutical manufacture. Reactions have been recorded after administration of radioactive drugs by inhalation, after intrathecal injection of radiolabeled human serum albumin, and after intravenous injection of radioactive drugs containing gelatin. It is doubtful, however, that significant patient reactions have occurred from the presence of pyrogens in radioactive drug products since the reported reactions are not attributed to pyrogens. Nevertheless, FDA regulations require pyrogen testing for many RDPs and the testing procedure (USP, 1975) formerly employed was rigidly defined in terms of sex, weight, species, and management of the animals to be used in the test. This test was complicated, expensive, and difficult to conduct. A new procedure (lirnulus amebocyte lysate coagulation) has now been approved to test for the presence of bacterial endotoxin. It is believed to be the most sensitive, convenient method available for detecting pyrogens. The test procedure is defined in the U.S. Pharmacopeia (USP, 1980) and test kits are available commercially.

2.6.7

Absorbed Radiation Dose

The absorbed radiation dose to all critical organs or tissues shall be calculated for each RDP and each radiocontaminant in it by use of accepted methods (see Section 4.1). Such calculations should be re-

2.7 REGULATIONS & UTILIZATION OF RDPS FOR HUMAN USE

/

23

vised as newer, more accurate calculation methods or more reliable in vivo distribution data become available for that drug. Knowledge of the absorbed radiation dose relative to recognized and suspected radiobiological effects must be balanced against the potential benefits to the patient receiving the radioactive drug. An elaboration of this risk vs. benefit concept is presented in Section 5.

2.7

Regulations Regarding Production, Testing, Shipping, a n d Utilization of RDPs Intended for Human Use

Prior to the formation of the Atomic Energy Commission (AEC) in 1947, there were virtually no government regulations or regulatory bodies supervising the production, testing, shipping, and utilization of radioactive drugs intended for administration to human subjects. Responding to a Congressional mandate to monitor the safe production, distribution, storage, disposal, and use of reactor by-product material, the Division of Materials Licensing of the AEC in the late 1940spromulgated regulations designed to protect the American public from needless radiation exposure from radioactive drugs. Since the AEC was given authority by Congress only for reactor by-product materials, radioactive drugs incorporating accelerator produced products were exempted from these regulations. These regulations sought to control distribution, storage, disposal, and use of the agent by "authorizing" physicians to use these drugs. To accommodate institutions possessing considerable in-house expertise and exercisingsuitable in-house controls, the Division of Materials Licensing of the AEC issued "Authorizations" (subsequently known as "Broad Licenses") that permitted physicians within such institutions to use reactor byproduct materials in human subjects as long as such use received institutional review and approval. Other institutions and individual practitioners could apply for specific "authorizations" allowing them to administer reactor by-product materials to patients in performance of procedures for which the licensee demonstrated prior adequate experience and training and possession of facilities to perform the procedure adequately. As the number of clinical procedures using byproduct materials in the routine practice of medicine increased, the Division of Materials Licensing of the AEC formulated a Routine Medical Use list that contained those by-product materials that were deemed suitable for routine medical practice. From time to time, additions were made to this list. Physicians possessing specific product licenses were allowed to receive, store, use, and dispose of by-product materials that appeared on this routine medical use list, in conformity

24

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

with published restrictions on such use, without submitting detailed justification for this to the AEC. After passage of the Harris-Kefauver sponsored legislation in the early 1960s, responsibility for monitoring the safety and efficacy of all drugs, including radioactive drugs, was delegated to the U. S. Food and Drug Administration (FDA). The FDA then issued a temporary exemption relating to reactor by-product radioactive drugs that allowed for the distribution of these agents under the aegis of the AEC. In August of 1975 this exemption was withdrawn with respect to reactor by-product radioactive drugs on the Well-Established AEC medical use list so that all radioactive drugs, regardless of production method, were placed directly under FDA jurisdiction. The successor to the AEC2continues to exercise regulatory authority over the receipt, possession, use, and disposal of radioactive drugs as it relates to the radiation safety of the public and personnel who may be exposed to the by-products. The Nuclear Regulatory Commission (NRC) carries out its regulatory function by licensing directly or delegating the authority to a state governing body (Agreement State) to license the nuclear medicine user. Further, it checks the nuclear medicine user periodically to see that the specific requirements of such licensure are maintained. The Department of Transportation (DOT) exercises regulatory authority over the shipment of radioactive drugs, and this is done by licensure of distribution agents and by restrictions placed on the drug manufacturer. The framework of basic regulations has been formulated that will guide radioactive drug development during the next few years. This framework is the same as that used in the development of nonradioactive drugs. When the available information justifies evaluation of safety and efficacy of a radioactive drug for purposes of possible clinical use, a "Notice of Claimed Exemption for Investigational New Drug" application (IND) is fled with FDA. Such an application requires details on the manufacturing processes employed to assure conformity with Good Manufacturing Practices (GMP), quality control procedures to assure radionuclidic and radiochemical identity and purity, basic research data to establish claims of safety and efficacy, and biokinetic data indicating acceptable radiation dose to subjects in whom such studies are performed (CFR, 1981a). Under an IND, a small number of patients are studied intensively to establish the pharmacology and "ow divided into the U.S. Department of Energy (through October 1977 known as U.S. Energy Research and Development Administration) and the U.S. Nuclear Regulatory Commission, the latter being the regulatory body.

2.9

MANAGEMENT OF MISADMINISTRATION

/

25

kinetics of the radioactive drug (Phase I studies), followed by an expanded but controlled clinical study to establish safety and indications for use (Phase 11), typically followed by a larger, less well controlled clinical study to establish a broader basis for evaluating safety and efficacy (Phase 111). A more detailed description of the "Guidelines for the Clinical Evaluation of Radiopharmaceutical Drug Products" is presented in Appendix A. It should be noted that the majority of INDs are submitted by individual practitioners rather than by radiopharmaceutical manufacturers. Human metabolic research studies utilizing new RDPs can be monitored within an institution if the institution has an FDA approved Radioactive Drug Research Committee (RDRC). Such in-house Committees are empowered to approve human metabolic research studies after they determine that the pharmacologic dose is within certain specified limits, the radiation dose is within the limits specified in Part 361.1 of 21 CFR (CFR, 1981a),and the radiation exposure is justified by the quality of the study being undertaken and the importance of the information sought. By definition, such research studies can have no immediate diagnostic or therapeutic value to the research subject. Typical studies approved by such RDRC review are limited to evaluations based on a small number of patients. A New Drug Application (NDA) must be filed with the FDA by the manufacturer if (1) an RDP is intended for widespread use by many clinicians; (2) its use is to be promoted; or (3) it is intended for sale. It is required that a thorough review of all of the preclinical and clinical data obtained during the IND phase of the drug's development be included in the NDA. Such data are the basis for establishing the safety and efficacy of the drug. Detailed information on the RDP's manufacture, quality control, and labeling is also required. The average time taken for a NDA approval for a RDP by the FDA is 31.5 months (Halperin, et al., 1979). In the time period from 1951 to 1978, 129 NDAs were approved for radioactive drugs (Halperin, et al., 1979). The physician practicing nuclear medicine must employ practices consistent with all regulations adopted by FDA, NRC, DOT, and Agreement States. In order to administer investigational RDPs to a patient, a clinician must be an FDA-approved clinical investigator for use of that agent. Radiopharmaceutical Drug Products which are approved new drugs as determined by the FDA theoretically may be used by any physician licensed to practice medicine. However, in order to possess, store, use, and dispose of the agent, the physician must be certain that the radioactive materials license from the NRC or delegated state authority allows for such use or is amended to allow for such use.

26

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

2.8

Choice of RDP For A Given Diagnostic Procedure o r Treatment

Maximizing patient benefit while minimizing patient risk and discomfort is the goal of the decision-making process in choosing an RDP for a given diagnostic procedure or treatment. The first issue to be considered in choosing an RDP for a given procedure is efficacy. Efficacy translates into: (a) degree of target (organ, tumor, etc.) to non-target (other tissues or background) accumulation, retention, or clearance in a manner that will provide the information or treatment required (target to non-target ratio and kinetics of uptake and clearance); and (b) the compatibility of the radiations emitted from the radioactive drugs with the available detection devices (detection efficiency and rate and spatial resolution of the device for the emitted radiations), or the treatment effect desired. Given that the highest degree of efficacy has been established, the second consideration is patient risk. Risks arise from adverse reaction to the chemical properties of the agent and include direct chemical toxicity of the agent, sepsis due to microbial contamination, and pyrogenic responses principally due to contamination of the product with certain microbial by-products. Another patient risk factor derives from the absorbed radiation dose (see Section 4). Production delays or shipping problems cause patient distress when RDPs are unavailable a t scheduled times for administration. The question of patient cost is complex and should not be limited to cost of the RDP. Use of an expensive drug that is readily available and hence reduces patient time in the hospital or that requires less expensive equipment may result in a lower cost of the study to the patient than the use of a less expensive agent. Since the cost of the RDP is usually a small part of the procedure cost, it is difficult to justify not using new or improved drugs that increase patient benefit and decrease patient risks simply because of the lower cost of the commonly used agents. An additional consideration which limits the choice of RDPs for clinical use is the status of licensing or approval by governmental agencies of new agents. A discussion of the methods available for choosing the best combination of RDP and instrumentation for diagnostic tests is presented in Section 5. 2.9 Management of Misadministration of Radiopharmaceutical D r u g Products

The preceding sections of this chapter have dealt with decisionmaking factors involved in the choice of RDPs for use in patients. In

2.9 MANAGEMENT OF MISADMINISTRATION

/

27

spite of considerable attention to the choice of an RDP, the final drug chosen may be misadministered and such misadministration may prove to be harmful to the patient. A diagnostic misadministration, as defined by the Nuclear Regulatory Commission, is one that differs from the prescribed dose by more than 50 percent (10 CFR 35.41). A therapeutic misadministration is one that differs from the prescribed dose by more than 10 percent (10 CFR 35.41) (CFR, 1981b). Faced with the prospect of managing a patient who has received a misadministration of an RDP, the managing physician should immediately obtain whatever expert opinion is available. While reliance should be placed on such guidance, the responsible physician needs to be aware of the therapeutic options and their rationale. In the majority of misadministrations reported there has been no harm and no need for intervention. This is due to either the short half-life of the RDP or the rapid elimination of the RDP from the body, or both. One consequence related to misadministration of a radioactive drug is radiation injury. In the history of reported misadministrations, a very small number (less than 10) have resulted in detectable radiation injury. Since radiation injury, by its nature, is an episodic, unprogrammed event, there are no truly established medical protocols for its therapy; nor are there NDA-approved, commercially available therapeutic agents for such application. Nonetheless, it is useful to summarize the consensus of expert opinion on methods of treatment of misadministrations. It is the responsibility of the physician managing such patients to use his best judgment and to take such action as he deems necessary despite the absence of well established therapy protocols. The need for prompt initiation of treatment requires the physician to be familiar with the general principles of such therapy. The following discussion is intended as an aid in orienting a physician given the responsibility for managing such a case and the current opinions on therapy. Further guidance is provided in NCRP Report No. 65, Management of Persons Accidentally Contaminated with Radionuclides (NCRP, 1980).Techniques are described in that report for reducing the biological effects of administered radioactivity, including: (1)increasing the rate of excretion; and (2) altering the pattern of biological distribution. 2.9.1

Administrative Responsibilities

In the event of a misadministration resulting in radiation overexposure, the licensee is responsible for reporting the event. The requirements for notification are published in the Code of Federal Regulations as 10 CFR 35.42 and 35.43 (CFR, 1981b).

28

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

An adverse reaction (reaction to the drug product) (Ford et al., 1978) observed by an investigator during the course of study covered under an IND application shall be reported to the IND sponsor who shall then report the reaction to the FDA. Similar reporting also is in order after a drug has received NDA approval.

2.9.2

Medical Care Responsibilities

The importance of very early recognition of a misadministration can hardly be over-emphasized. Delayed recognition leaves the physician with only supportive treatment. It is very desirable to know the dosage of the misadrninistration as a guide to treatment, but therapy should not be withheld until precise dosimetric data are established. The first one or two hours after a misadministration may be the crucial time for effective treatment. First aid following internal contamination, analogous to fvst aid following a traumatic injury, may determine the prospects for the success of a total treatment program. After oral administration, there is a variable time period before the radionuclide has been absorbed, transported, and taken up by tissue cells. Absorption from the intestine can sometimes be reduced by chemical manipulation in the GI tract or by hastening passage of the material through the body. Alkalinizing the stomach may cause the formation of relatively insoluble hydroxides or at least will keep the pH high enough to reduce solubility of some metal salts, while rapid administration of nonabsorbable ion exchangers or adsorbents (e.g., charcoal) may limit systemic absorption of the radionuclide. The administration of a cathartic will shorten the intestinal transit time and will thereby reduce absorption and radiation exposure of the intestinal wall and nearby tissues. Once absorbed, uptake by tissues can be reduced by the use of blocking agents, isotopic dilution, or chelating agents. In the case of misadministration of radioisotopes of certain elements, the incorporation of the radionuclide can be "blocked" by administering large doses of the stable element. Atom for atom, the stable element is many times more numerous and successfully displaces the radioactive form, which then is excreted more rapidly. Thus, stable iodine taken by mouth diminishes thyroid uptake of circulating '"I. With isotopic dilution, it is desirable to get the stable isotope into the system quickly and, if possible, in a chemical form that is more easily absorbed and incorporated than the radioisotope. A special form of dilution therapy, sometimes called displacement therapy, refers to the use of a non-radioactive element of a different atomic number to

2.9 MANAGEMENT OF MISADMINISTRATION

/

29

compete with the radionuclide. Examples would be the use of calcium

to compete with radiostrontium and stable iodine to reduce the thyroidal uptake of technetium. When misadministration of a radionuclide results in systemic distribution of an ionic species of the radionuclide, chelating agents may be useful in patient management. In practice, the available chelates are limited to those that can interact with multivalent cations. Diethylenetriamine pentaacetic acid (DTPA) and ethylenediamine tetraacetic acid (EDTA) have been the chelating agents most frequently used for this purpose, largely because of their strong sequestration of most metal cations and rapid clearance from the body primarily by glomerular filtration. However, for selected radioactive cations, other chelates should be considered. Thus, dimercaptosuccinic acid has been used in mercury poisoning in China (Wang et al., 1965) and its propensity for arsenic and antimony might recommend its use for radionuclides of these elements. Moreover, the strong interaction between mercury and thiol groups could be used to advantage in clearing mercury from the liver by use of mercaptoisobutyric acid (Lin et al., 1974b) or dihydrothioctic acid (Tonkin and DeLand, 1974), agents that concentrate in the liver and are excreted in the bile. Similarly, other thiol-containing chelates, such as dimercaptopropanol (BAL) or penicillamine, which are cleared largely by the kidney, should be considered to promote the excretion of radioactive cations that localize in the kidneys, but show affinity for thiol groups (NCRP, 1980). Other radioactive cations that localize in the liver might similarly be mobilized by use of the newer imidodiacetic acid derivatives, which are extracted from the plasma by the liver and are excreted in the bile (Loberg et al., 1976). Inherent in treatment of accidental overexposure to systemically absorbed cations by using chelates is the consideration that the chelate employed must not only form strong interactions with the radioactive cations in question, but the chelate should be one that concentrates in the same tissues as the radioactive cations. The recent development of chelates that slow tissue localization should be useful in extending treatment possibilities in the event of radionuclidic misadministration (see above). However, it must be emphasized that use of such relatively organ specific chelates in treatment of such misadministration is purely conjectural at present and requires experimental verification. The choice of drug in these circumstances will depend largely on agent availability and status as an approved therapeutic modality. If it has been determined that the patient will receive a very large and possibly lethal radiation absorbed dose, the use of free-radical scavengers could be considered since some radiation effects on tissues are believed to be caused by formation of free radicals and peroxides.

30

/

2. CHOICE OF RADIOPHARMACEUTICAL DRUG PRODUCTS

In this circumstance, it is possible that biological effects could be diminished by administering free-radical and peroxide scavengers. The use of these so-called radiation protection compounds is associated with a high degree of toxicity and, hence, has not been recommended for use in man. In the event of such an overexposure, a rapid assessment of the utility of this class of radiation protection agents should be obtained promptly through expert consultation.

3. Factors in Choosing an

Instrument for Nuclear Medicine Procedures 3.1 General Rapid developments have occurred since the 1960s in instrumentation used in nuclear medicine. These have been closely coupled t o radiopharmaceutical and procedural requirements. The Anger type of scintillation camera and 99mTc-labeledcompounds have revolutionized the practice of nuclear medicine. Many collimators are now available for use in specific studies and strongly influence the kind and quality of results derived from the study. Decisions regarding instrumentation depend upon the clinical problem and are modified by the need to minimize patient radiation exposure. The importance of choosing proper instrumentation is well accepted, but the fundamental considerations that influence this decision are not always well understood. This section of the report enumerates the types of instruments used in nuclear medicine for sample measurement and for imaging spatial distribution of radioactivity. The properties of these systems are described to provide a foundation for the discussion of the factors affecting choice of a particular instrument for particular purposes. In Section 5 these ideas are extended to include radiopharmaceutical factors in the establishment of figures of merit to guide the conduct of nuclear medicine procedures and to assess their clinical utility.

3.2

Measurement S y s t e m s Used i n Nuclear Medicine

Many different types of radiation detectors are used in nuclear medicine and each detector system is designed for a limited range of applications and specific purposes. There is usually a single "best instrument." In some cases, the differences may not be large and 31

32

/

3.

CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

personal preference determines the instrument of choice. T o select the best instrument for a given task, it is necessary to consider: (1)the characteristics of the radiation to be detected, i.e., photon or particletype, and energy; (2) the amounts, and half-life of different radioactive species present; (3)the type of sample, i.e., in vitro or in vivo; (4) the nature of the clinical or other problem; and (5)the time available for the measurements.

3.2.1

Survey Instruments

Survey equipment is used to monitor the level of radioactivity in the laboratory, usually the background level. Such equipment typically consists of a portable or semiportable battery operated Geiger-Muller (G-M) or scintillation detector with a count-rate meter; it may include a count-rate audio output. These are used mainly to detect and monitor low to moderate levels of beta and gamma radiation. For monitoring high levels of radioactivity, the survey meter may incorporate an ionization chamber. An end-window or pancake G-M detector, preferably shielded on the side walls, is the detector of choice for measurements of surface contamination in the presence of high-level sources, e.g., Mo/Tc generators. For further details, see NCRP Report No. 57, Instrumentation and Monitoring Methods for Radiation Protection (NCRP, 1978a).

3.2.2

Dose Calibrators

These are typically well-type ionization chambers, with direct digital display of the output calibrated in pCi or mCi. They are used to measure radioactivity in a syringe prior to injection. Such devices are discussed in detail in A Handbook of Radioactivity Measurements Procedures (NCRP, 1978b). Ionization chambers operate on the principle that the amount of ionization produced is proportional to the energy absorbed and thus to the amount of radioactivity present. They are employed to measure moderate to high levels of radioactivity under conditions where detection of individual photons and energy discrimination are not required. These instruments are calibrated by use of sources directly or indirectly traceable to the National Bureau of Standards (NBS). These standard sources have photon energies and geometry comparable to the unknown activities to be measured (NCRP, 1978b).

3.2 MEASUREMENT SYSTEMS IN NUCLEAR MEDICINE

3.2.3. Sample Counters

/

33

.

A detailed discussion of the following devices appears in Hine (1967) and Fenyves and Haiman (1969). (a) G-M counters are an inexpensive widely used class of detectors for gamma rays and high-energy beta particles (>I00 keV) although the detection efficiency is low for gamma rays. Since all detected radiation events produce pulses with essentially the same amplitude, energy discrimination is not possible with these detectors. (b) Liquid scintillation detectors are the most sensitive class of detectors for low levels of low-energy beta emitters and in some cases for low energy x- and y-ray emitters. In this case, the sample to be counted is incorporated in the detection medium, a liquid scintillation material usually viewed by two photomultiplier tubes operated in coincidence to reduce the background noise level. (c) Gas-flow proportional counters are operated under voltage conditions that produce an output pulse that is proportional in amplitude to the energy absorbed. They are typically used to detect beta and low-energy gamma rays. For these radiations, the energy resolution of proportional counters may be superior to that of a scintillation detector. (d) NaI(Tl) crystal well-type scintillation counters provide excellent geometry, efficient detection of gamma rays, and a mean pulse amplitude that is proportional to the energy absorbed. These counters are used to measure low to moderate levels of radioactivity when some energy discrimination is required (Birks, 164). (e) Ge(Li) and high purity germanium (HPGe) semiconductor detectors provide photon energy resolution superior to any of the above detectors. They may be used to advantage in identifying and quantitating low levels of gamma-ray emitting radionuclidic impurities in radioactive drugs. They may also be used to analyze the radionuclidic composition of samples and mixtures that emit multiple photon energies. The value of the detectors for spectral analysis is due to the high peak to background (valley) ratios that can be achieved. The relatively s m d size of these detectors limits their usefulness for efficient detection of high-energy photons. In addition, they must be kept cold with liquid nitrogen to prevent migration of Li, which would ruin the detector. HPGe detectors overcome this last problem and may be more useful for certain applications in nuclear medicine (Hoffer et al., 1971). (f) Si(Li) semiconductor detectors provide excellent energy resolution for low-energy photons (less than 30 keV). Above this energy they have much lower sensitivity than Ge(Li) detectors of the same size

34

/

3. CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

because of the lower value of Z. These, detectors must be operated at liquid nitrogen temperature to reduce noise, but are less sensitive than Ge(Li) detectors to destruction by warming to room temperature (Hoffer et al., 1971).

3.2.4

Probe Systems

(a) NaI(T1) scintillation detectors utilizing a "flat field" collimator that has essentially uniform sensitivity over the field of view are used for thyroid uptake and other similar external measurements of gammaray emitters (IAEA, 1973). (b) Surgical probes, consisting of tiny G-M counters, or Si(Li) or CdTe semiconductors may be used during surgical procedures to detect low-energy gamma or high-energy beta radiation (Sasaki et al., 1971). (c) Intravascular and intracavitary probes employing semiconductor materials such as Si(Li), CdTe, and HgJ, together with fiber optic viewing systems to facilitate probe placement may ultimately be useful in detecting beta particles and low-energy photons in vivo. These applications are being investigated for diagnostic procedures in nuclear medicine (Sasaki et al., 1971).

3.3 3.3.1

Imaging Systems Used i n Nuclear Medicine

Rectilinear Scanners

Single and dual crystal scanning systems utilizing 3 inch to 8 inch diameter NaI(T1) scintillation detectors with focused collimators are used to perform total body scans and for selected diagnostic imaging procedures in nuclear medicine. In addition, scanning systems employing Anger-type scintillation cameras and one and two dimensional arrays of NaI(T1) crystals have been developed. Generally, these systems incorporate photographic and/or digital recording systems.

3.3.2

Scintillation Cameras

(a) Single crystal scintillation cameras of the Anger-type are used to perform most of the high spatial resolution imaging examinations in nuclear medicine and for most dynamic studies in which a rapid sequence of images is required (Anger, 1967).

3.3 IMAGING SYSTEMS USED IN NUCLEAR MEDICINE

/

35

(b) Mosaic crystal cameras, such as those based on the autofluoroscope (Bender, 19641, provide higher count-rate potential than the conventional Anger-type cameras by virtue of the possibility of parallel processing of simultaneous events. For this reason they may be the instruments of choice for certain rapid dynamic function studies. However, the relatively poor energy resolution of these devices does not permit effective rejection of scattered radiation. High resolution semiconductor cameras are being developed that may overcome this limitation, although they are limited by relatively poor sensitivity (Kaufman et al., 1975; Gerber et al., 1977; McCready et al., 1971). (c) Camera systems employing single and mosaic arrays of scintillation crystals viewed by an image intensifier tube have high countrate capabilities and produce images with excellent spatial resolution (Muehllehner et al., 1976).The use of new electro-optical devices, such as charge-coupled devices (CCDs), makes it possible to obtain digital as well as analog information from this type of imaging device (Barbe, 1975). (d) Gas-filled multi-wire proportional counters have been developed (Borkowski and Kopp, 1972; Kaufrnan et al., 1972) that provide excellent spatial resolution. However, even when used with special y-ray converters, the efficiency for detection of y rays above 100 keV is low, less than 25 percent. Drift chambers are now being used that provide equal or better position information and may be useful in medical applications (Charpak, 1977; Jeavons et al., 1981). 3.3.3

Tomographic Imaging Systems

Longitudinal tomographic imaging systems have been developed that provide in-focus views of a radionuclide distribution at selected depths within the patient (Anger, 1969). These techniques rely on the collimator apertures to view the distribution of activity from different directions. In this case, the techniques used to form the images do not discriminate against detected photons originating throughout the volume. Thus, images formed for the desired plane of interest are reduced in contrast by the superposition of out-of-focus images from all planes. Computational techniques (Myers et al., 1973; Chang et al., 1976) have been shown to be effective in reducing these distortions. Positron imaging systems (Brownell et al., 1969; Brownell and Bumham, 1974) can provide similar longitudinal tomographic images but also suffer from superposition of events from all planes. With the development of adequately fast electronics, positron images may be formed in principle by time-of-flight measurements. At the present

36

/

3.

CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

level of technology, the spatial resolution of such images is not satisfactory for practical use in clinical nuclear medicine (Wagner et al., 1977). The use of cesium fluoride as a fast scintillator (Allemand et al., 1980) with rotational tomography (Mullani et al., 1981) promises to improve the spatial resolution and accuracy of positron emission tomography (PET) imaging (Ter Pogossian et al., 1981). The fact that many positron emitting radionuclides are short-lived and require onsite production has limited the widespread use of positron emitters for clinical diagnosis. The transverse section tomographic imaging technique was introduced by Kuhl (Kuhl, 1964) to provide cross-sectional images of a gamma ray emitting radionuclide distribution. Since the usual thickness of each section is of the order of a centimeter, several serial crosssections must be obtained to cover a thick region of interest adequately. New developments in instrumentation and mathematical reconstruction algorithms provide systems that can be used to obtain quantitatively accurate images of radionuclide concentrations in multiple cross-sections (Ter-Pogossian et al., 1977). Because nuclear medicine procedures are primarily measures of some physiologic function, quantitative transaxial tomographic imaging will continue to be an important factor in biomedical research and nuclear medicine. Computers are used with many of the imaging devices listed in this section. With traditional scanners and cameras, they provide the opportunity for distortion correction and for parameter extraction and thereby augment the information derived from the study. With tomographic instrumentation, the computer is an essential element for construction of the image and the extraction of physiologically significant information. 3.3.4

X-Ray Fluorescence Imaging Systems

X-ray fluorescence imaging systems utilize an external photon source to excite x-ray emissions from stable elements and are currently used almost exclusively to image the non-radioactive I2'I in the thyroid gland (Hoffer et al., 1968 and Patton and Brill, 1978). In this case, a 10-20 Ci source of "'Am is used for excitation. The advantage of this technique is a greatly reduced radiation dosage to the thyroid gland (and no exposure to other areas and organs). There is some hope of extending the fluorescence imaging procedure to other high-Z materials, e-g., the imaging of bismuth in the brain, gold and mercury in other organs. However, in view of the toxicity of these materials, their potential usefulness for diagnostic studies is uncertain (Patton et al., 1971). T h e ability to measure high levels of lead (Bloch et al., 1977) in

3.4 DETECTORS FOR MEASUREMENT A N D IMAGING

/

37

teeth and copper in .the eye (Loewinger et al., 1975) has been demonstrated and these techniques should be of increasing utility because of their measurement specificity and low patient radiation exposure.

3.4

3.4.1

Properties of Radiation Detectors for Measurement a n d Imaging Systems

General

System performance is determined by the electronic counting circuits employed, the detector sensitivity, detector resolution (spatial, temporal, and energy), and the characteristics of the recording and readout devices. 3.4.2

Sensitivity

The sensitivity of a measurement system is expressed in terms of the number of photons counted by the detection system relative to the number of photons emitted from the radiation source to which the system is exposed. (a) Inherent Detector Efficiency (commonly known as intrinsic efficiency). The stopping power of the detection medium material determines the probability of occurrence of an interaction of the incident radiation in the detector. To be detected, radiation must interact with, and transfer energy to, the detector material. The probability of energy deposition is a function of the atomic number (or effective atomic number) of the material and its density, together with the type and energy of the radiation and its path length through this material. The curves in Figure 2 summarize the relationship between probability of interaction per unit path length and photon energy for several solid detector materials, which typically are two orders of magnitude more efficient than gas-filled detectors (Hoffer et al., 1971). (b) Geometrical Efficiency.The sensitivity of a detector is a function of the cross-sectional area of the detector or the fractional solid angle that is exposed to incident radiation and may approach unity for well counters. For collimated detectors, the exposed area depends upon the diameter of the detector and the fraction of the area unshielded by the collimator. Two different means have been used to express the geometrical efficiency of collimated radiation detectors. These are system sensitivity to a point source and to an extended plane source located at different distances from the collimator face (MacIntyre et al., 1969). Point source sencitivity is useful for describing the properties of

38

/

3.

CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

Photon ENERGY, keV Fig. 2. Attenuation coefficient (i.e., the interaction probability per cm path length) plotted vs. gamma ray energy for five detector materials-Silicon (Sc), Germanium (Ge), Cesium Fluoride (CSF),Sodium Iodide (NaI), and Bismuth germanate (BGO). (Hubbell, 1969; Plechaty et al., 1978).

detectors employing focused collimators, but it is difficult to measure directly (Beck et al., 1973b). Response to plane sources, ones that are large with respect to the field of view, can be used for comparisons between scintillation cameras and scanners and is more easily mea-

3.4

DETECTORS FOR MEASUREMENT AND IMAGING

/

39

sured. In general, response to a plane source is independent of distance intervening between the detector and the source when attenuation is negligible, as in air, and when the photons do not penetrate the septae of the channels in the collimator (Tsialas and Psarrakos, 1973). (c) Energy Selection ("window") Efficiency. A pulse height analyzer is usually used in conjunction with detectors that produce pulses whose amplitudes are proportional to the energy absorbed. By setting the "window" of the pulse height analyzer to bracket the entire total absorption peak, the signals due to background and scattered radiation can be reduced. A somewhat narrower window, which rejects more pulses from scattered than unscattered photons, maximizes the signalto-noise ratio (Beck et al., 1969; 1973a; Atkins et al., 1977).The fraction of the total absorption peak due to unscattered photons that lies within the window is called the window efficiency. The degree to which the window can be narrowed without significant loss in efficiency depends upon the energy resolution of the detector, as described below.

3.4.3

Resolution

The resolution of a system describes its capability for distinguishing various characteristic features of the source that may be distributed with respect to space, time, or energy. (a) Energy Resolution. The discrete energy spectra of radionuclides used in nuclear medicine procedures provide access to information that the investigator may use to advantage. In sample counting, the ability of the instrument to select well-defined energy levels and reject others allows simultaneous counting of more than one radionuclide. In external measurements of in vivo radionuclides, the ability to distinguish scattered and unscattered photons is important in achieving maximal spatial information and minimal loss in contrast. The relationship between incident gamma-ray energy and scattered photon energy in tissue for various scattering angles is shown in Figure 3, computed by Compton's equation. High-energy photons lose a relatively large amount of energy even when scattered through small angles. In that case, a detector with even modest energy resolution can easily distinguish scattered from unscattered photons. At low energies, t200 keV, the amount of energy lost by a photon when it scatters becomes small; and a detector with excellent energy resolution is required to distinguish between scattered and unscattered photons. A common measure of the energy resolution, RE, is given by the fill Wldth of the pulse amplitude distribution a t its Half Maximum

40

/

3. CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

I

I

$

I

ANGLE

I

"oo~~ZLz

W

0

ENERGY OF INCIDENT GAMMA 400 RAY 500 (keV)

Fig. 3. Relationship between incident gamma ray energy and scattered photon energy in tissue for various scattering angles.

height (FWHM), divided by the mean position of the peak a t the pulse corresponding to gamma-ray energy, E, expressed as a percentage; that is

RE =-FWHM x 100 percent. (For example, see Fig. 4.) E The width of the distribution of pulse amplitudes is related to the random fluctuations in the number of statistical units3 comprising a pulse which, in turn, is proportional to the gamma-ray energy, E; experimentally it is observed that FWHM is approximately proportional to A,and that

fi

RE a -x 100 percent = E

100 percent

Jz

Clearly, a large percent energy resolution corresponds to a broad pulse amplitude distribution and thus poor ability to distinguish between scattered and unscattered photons. Figure 4 illustrates how energy resolution (percent) varies with incident gamma-ray energy for a

'' For scintillation detectors, this is the number of photoelectrons collected at the first dynode of the photomultiplier tube per gamma ray detected. For semiconductor detectors, this is the number of electron-hole pairs collected per gamma ray detected.

3.4 DETECTORS

FOR MEASUREMENT AND IMAGING

/

41

Gamma-Ray Energy (MeV)

Fig. 4.

Plot of detector resolution (RE)as a function of gamma-ray energy (Heath,

1964).

typical NaI(T1) scintillation detector. Thus, at low energies, where good resolution is required to separate scattered and unscattered radiation, the energy resolution becomes worse. For semiconductor detectors, the energy resolution likewise becomes larger a t lower energies, but is an order of magnitude smaller than for NaI (typically FWHM 5 2 keV a t 140 keV or RE 5 1.4 percent) (see Figure 5). (b) Spatial Resolution. Spatial resolution is a measure of the capability of a system to produce an image in which details of the object can be distinguished. A commonly accepted measurement of resolution is the minimum separation that line sources must have to be distinguished (Brownell, 1964; Gottachalk and Beck, 1968). This distance has been found to be approximately equal to the width of a single line source response curve at half maximum amplitude (FWHM) and is termed "index of resolution" (MacIntyre et al., 1969) (see Figure 6). The FWHM provides a simple description of the resolution of a collimator. However, it is relatively insensitive to the effects of scatter and septal penetration, which contribute to the tail of the total collimator response function and degrade image contrast while increasing FWHM only slightly (Beck et al., 1969).

42

/

3.

CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

The modulation transfer function, MTF(v), is a mathematical entity that expresses the response of the imaging system or system component to sinusoidal inputs as a function of varying spatial frequency (Beck, 1964; Beck, 1972). The rationale for using the modulation transfer function is based on the fact that every object and its image can be resolved into a continuous spectrum of sinusoidal components, each having a certain frequency, amplitude, phase, and orientation. Images that exhibit fine detail have a spectral content in which the amplitude of high frequency components is large compared with images that have only coarse structures. Thus, the ability of a system to faithfully reproduce the spatial variations of a radioactive source would be indicated by the MTF(v), which is a measure of the efficiency with which the amplitudes of object sinusoids are transferred to the image. For an ideal detector, MTF(v) = 1 for all object sinusoids. Fortunately, the modulation transfer function can be expressed rather simply as the normalized Fourier transform of a line source response function and is sensitive to the shape of the entire function, not just its width. This more general measure of spatial resolution of an imaging system can be computed from the measured response curve to a line source. An example of line source response functions for a small high resolution focused collimator is shown in Figure 7 along with the measured MTF(v) curves. The effect of scattered radiations in degrading the MTF is seen in the mid spatial frequency range. The influence of improved energy resolution on lesion perceptibility is illustrated in the liver phantom images ( m r e 7d). The high resolution Ge detectors (HPGe) provide better delineation of voids when a scattering medium is present. A number of parameters are needed to describe a collimator com-

ENERGY IN keV Fig. 5. Pulse amplitude spectra obtained from a distributed source of ""Tc with a scintillation detector and lithium drifted germanium detector having energy resolutions of 17 percent and 0.5 percent, respectively, for 140 keV gamma rays. (Patton, 1978).

3.4 DETECTORS FOR MEASUREMENT AND IMAGING

/

43

Fig. 6. Calculated response curves for two-line sources separated by a distance, a, and for a resolution distance, d, which may be defined as the effective system resolution. (Brownell, 1968).

pletely. Figure 7a shows a diagram of the collimator and the values for these parameters. The desirable qualities of a collimator, good spatial resolution and high sensitivity, compete in that if the parameters are selected to achieve high sensitivity, the collimator will generally have low resolution; conversely, high resolution generally results in poor sensitivity. The selection of the best collimator for a particular use depends upon the specific needs for each procedure. Thus, knowledge of the line spread function or MTF at different depths in tissue from the face of the collimator is useful in determining which collimator should be used for a particular study. Spatial resolution and sensitivity requirements play an important role in making this judgement (Tsui et al., 1977, 1978; Metz et al., 1977). (c) Temporal Resolution. If the time interval between two gamma rays that interact with the detector is less than some value, 7, the second gamma ray will not be counted. Thus, 7 can be thought of as the resolving time or as the dead time per detected gamma ray. Real detectors can be described, approximately, by one of two idealized

44

/

3. CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

SMALL HIGH RESOLUTION 19 HOLE COLLIMATOR

AIR

SCATTER LSF

lbl MTF

IcJ

Na l

HPGe

Nal

HPGe

Fig. 7. Comparison of NaI and HPGe detectors. The Collimator used is defined in (a). Line spread functions (LSF) are shown in (b) and modulation transfer functions (MTF) in (c) for 99"Tc. Images of a *Tc filled liver slice phantom obtained with these two detectors are shown in (d), with and without scatter media between the phantom and detector. (Patton, 1978).

3.4 DETECTORS FOR MEASUREMENT AND IMAGING

/

45

forms or a combination of these (Adams and Zimmerman 1973; Adams et al., 1978; Sorenson, 1975, 1976). (1) Non-paralyzable Detectors. If the second gamma ray interacts with the detector at any time t following the first, such that for 0 5 t I7 , the dead time is not extended beyond T if the detector is nonparalyzable. Such detectors are also described as non-extendable or non-cumulative (Evans, 1955). In this case, if R,, is the expected number of gamma rays that are observed per unit time, the number R that interact with the detector is

and the number lost due to dead time is

With such a detector, the observed count rate increases monotonically 1

and approaches a limit R, + - as R + m. 7

(2) Paralyzable Detectors. If the second gamma ray interacts with the detector at any time t following the fmt, such that for 0 s t 5 7, the dead time is extended to t + 7, the detector is paralyzable. Such detectors are also described as extendable, cumulative, or updating (Evans, 1955). In this case

With such a detector, the observed count rate passes through a R maximum value (R,),,, = -, then decreases as R + m. e In either case, a t low count rates the observed rate R, is very nearly equal to the true rate R, and the detector is said to be linear. At high rates, however, both types of detectors become nonlinear and no longer provide an accurate measure of radioactivity, unless properly calibrated. (Procedures for calibration and use of these detectors are described in NCRP Report No. 58, A Handbook of Radioactivity Measurements Procedures.) (3) System with Combined Paralyzable and Non-Paralyzable Detectors. Anger-type scintillation cameras are prone to both types of dead time losses. The maximum count rate a t which these systems perform adequately has been increased almost ten-fold in recent years. Above a maximum count rate, several factors are encountered that strongly influence image quality. First, the spatial resolution becomes degraded and then, at somewhat higher count rates, spurious images

46

/

3. CHOOSING AN INSTRUMENT

FOR NUCLEAR MEDICINE

are obtained. These show blurred outlines of true sources plus spurious images located in between the true objects (Strand and Larsson, 1978). These spatial artifacts can be avoided by using lower doses. Count rate losses a t lower count levels can be corrected by using computational techniques (Budinger, 1974).

3.5

3.5.1

Properties of Recording Devices Used in Nuclear Medicine

Count and Count Rate Recording Techniques

A microammeter is normally employed to indicate the output current from an ionization chamber used to measure radioactivity. A comparable effect is achieved from detectors that produce a pulse for each detected event by use of a count-rate meter that integrates the counts observed for some preset interval, designated the "time constant," and displays the result as a meter reading in counts/unit time. For a permanent record, the output from such a device can be fed to a strip chart recorder, as is commonly done in renal clearance studies utilizing multiple probe-type scintillation detectors. Different detectors may be aimed a t each kidney, the bladder, and blood pool or "background" regions. T o store the number of counts observed in some preset time, or to measure the time required for some preset number of counts, a scalertimer with a suitable number of electronic decade indicators or mechanical registers is used. 3.5.2

Image Recording Techniques

To record selected pulses from the detector, early scanning systems utilized a mechanical tapping device and carbon paper, or an arcing stylus and teledeltos paper. Both devices have a limited dynamic range, are noisy, and tend to become paralyzed or saturated a t high count rates. These disadvantages are reduced by using a pulsed light source to project a spot on photographic film. The amount of image smoothing introduced by the recording device increases with increasing size of the projected spot. Smoothing in the recording device reduces recorded image noise (Metz and Beck, 1974; Pizer and Todd-Pokropek, 1976),

3.5

RECORDING DEVICES USED IN NUCLEAR MEDICINE

/

47

but excessive smoothing reduces image contrast for structures of interest. Image contrast may be increased by techniques such as "background erase" in which no spots are recorded unless the count rate exceeds a certain preset minimum level, and by contrast enhancement in which the intensity of the recorded spot is increased with increasing count rate. For scintillation camera systems, a common recording technique employs a cathode-ray tube and a Polaroid camera. It is common practice to expand the limited dynamic range of Polaroid film by employing three lenses with different aperture settings to record images from an oscilloscope. Transparency film recording systems are being used increasingly when wider film latitude or faster framing rates are required. To store the quantitative data that characterize the image formed by a scanner or camera system, magnetic core, tapes, discs, and drums have been used. Even when the spatial resolution of the detector may warrant only a digital matrix of 64 x 64 elements, it is generally accepted that a matrix of 128 x 128 or 256 x 256 elements should be generated by interpolation for image display so as to reduce the visually disturbing effect of obvious image elements. Digitized images are especially convenient and desirable for further analysis or image processing by computer. Digital image recording techniques are being used increasingly in dynamic function studies and flow studies in order to derive quantitative information (Larson and Cox, 1974). Data from these studies can be displayed in black and white or in color. Color coding provides obvious advantages for comparing multiple curves in a single image when each curve reflects a different characteristic. Similarly, when the image contains different objects, these can be assigned different colors and the extent of overlap can be determined. The ability to perceive small differences in count intensity in the image limits threshold detection of small, low contrast objects. The optimum assignment of display driving intensity levels to scintillation count rate depends on the range of values in the recorded image and on the characteristics of the display device itself. Procedures for optimizing contrast detection with real devices have been proposed (Pizer et al., 1982).They show that properly linearized gray scale video displays allow the preception of approximately 90 just noticeable differences (JNDs) and that natural pseudocolor scales can be created which reveal 140 JNDs. T o maximize the information transmitted from a recorded image to an observer, an appropriate assignment of

48

/

3. CHOOSING AN INSTRUMENT FOR NUCLEAR MEDICINE

displayed intensities to represent the recorded intensities must be made (Pizer, 1981).

3.6

3.6.1

Resolution Factors Affecting t h e Choice of Systems

Temporal Factors

Information regarding the quantity of radioactivity in an organ such as the thyroid or an image of the static distribution of the radioactivity can be obtained with probes and scanning systems. This is sometimes limited in time by the patient's clinical condition. Information regarding dynamic processes must be obtained in 'a sequence of measurements or frames during a period that is determined primarily by the speed of the process. For blood flow studies through the heart, frame rates of 0.05 to 0.5 sec/frame may be required, whereas for kidney blood flow studies with -Tc04-, frame rates of 0.25 to 1.0 sec/frame are usually adequate. In general, gamma ray scintillation camera systems are required for studies requiring images and involving frame rates higher than about 1min/frarne. For images formed in such brief periods to be useful, it is necessary that the random fluctuation, or noise, be low. Random fluctuations in the image are due almost entirely to fluctuations in the count density, which are described by Poisson statistics. Thus, if the expected number of counts recorded in a given region is N, then on repeated imaging procedures, the standard deviation a, about N will be f i and the fractional standard deviation" will be I/&.

N

In general, the number

of counts required to reduce random fluctuations to a negligible level, compared with the signal to be detected, determines the time required for the imaging procedure and is a function of the amount of radioactivity injected, the uptake ratio in the structure to be detected, as well as its size and depth and the sensitivity of the detector. In order for the observed counts in the image to represent an accurate measure of the amount of radioactivity present, the count losses due to dead time of the detector and recording system must be low, or known and corrected, and the effects of attenuation and scatter must be taken into account. Scintillation cameras of the Anger-type generally provide the best compromise between sensitivity and resolution needed for dynamic studies.

3.6

3.6.2

FACTORS AFFECTING THE CHOICE OF SYSTEMS

/

49

Spatial Factors

To ensure that the spatial resolution of the imaging system will be adequate to resolve structures of interest a t various distances from the collimator, it is necessary that the FWHM of the system for the linespread function at those distances be comparable to or smaller than the structures. Superficial structures are best resolved by camera systems that have the best resolutions at the collimator face; deeper structures are sometimes best resolved by scanners employing focused collimators.

3.6.3

Energy Factors

In spite of the effects of attenuation and scattering within the patient, it appears, on the basis of the signal-to-noise ratio (S/N) achieved per unit of observation time, that the optimum y-ray energy for many imaging procedures is below 200 keV. In evaluating particular radionuclides, the Figure of Merit (FOM) should be normalized with respect to absorbed dose to the critical organ or the whole body, whichever is limiting. The FOM is fully discussed in section 5. In any case, improved energy resolution permits increased scatter rejection and increased image contrast.

4.

Radiation Dose 4.1

4.1.1

Radiation Dose from Administered Radionuclides

General

Good estimates of absorbed radiation dose can be made when information on radionuclide properties and decay scheme, amount injected, and its biological fate and distribution are available. Today's knowledge of radionuclide properties is adequate but biological data are often very limited. Most approaches to radiation dose estimates assume the following: (a) that the tissue material is homogeneous throughout the region of interest and (b) that the radionuclide is uniformly distributed. These assumptions usually result in a dose value that may be considered to be an average value for the tissue. When gross non-uniformities of radioactive material distribution exist in the tissues, the radiation dose in the immediate vicinity of the radionuclide may be one or more orders of magnitude greater or less than the average calculated dose. Biological effects data do not indicate, however, that non-uniform doses carry a greater risk of late effects, such as cancer, than that from the same quantity of radioactive material spread uniformly throughout the organ. Non-uniform radionuclide distributions are known to occur in the thyroid with iodine, within the kidney with chlormerodrin, and in the lungs with iodine-labeled macroaggregates. Similar problems occur in evaluating the radiation dose to the walls of the stomach and intestines from radioactivity in the luminal content of these organs. Local deposition of energy from charged-particle radiation can also cause radiation doses several orders of magnitude greater than what might be calculated as an average value. However, risks of exposure depend on the size of the exposed mass or number of cells irradiated-often expressed as an integral dose in kg-rad-so large local doses may not entail more biological risk than the same integral dose spread more uniformly through the tissue of interest. Other factors that can influence the biological distribution of radio50

4.1 RADIATION FROM ADMINISTERED RADIONUCLIDES

/

51

active materials within the patient are alterations of organ size, uptake, and excretion in the diseased state (Kaplan and Zimmerman, 1976). Radiation doses received by the patient from diagnostic and therapeutic procedures are presented in this report (Appendix B). Very much smaller doses are received by medical, and paramedical personnel managing the patient, other nearby patients, or family. Even lower doses are received by persons collecting and processing blood, urine, and tissue samples. Doses from such exposures are not tabulated in this report. A consideration of these sources of exposure and estimated doses are included in Castronovo, et al., 1982. Specific guidance for similar exposure circumstances following therapeutic procedures is presented in NCRP Report 37 (NCRP, 1970). 4.1.2

Dose Rate from Internal Emitters

The rate a t which radiation is absorbed by tissues is an important factor in determining the extent of damage to irradiated cells. Most radionuclides deliver their total radiation dose over many days. The total radiation dose, although relatively small from short-lived radionuclides such as 99mTc,is delivered in a few hours at high dose rates. Radionuclides with short physical or biological half times, such as 133 Xe, deliver their total radiation dose in seconds. At present, only limited data exist by which to evaluate the effect of high dose rate from internal emitters that deliver relatively low total doses, but it is a factor that must be further evaluated. Conservative risk factors are available based on extrapolation of biological effects observed at high dose rates (NAS/NRC, 1972,1980; UNSCEAR, 1977). An additional factor of potential importance is transmutation. When an administered radiolabeled material decays by charged particle emission, the chemical nature of the labeled compound is changed, 32 e.g., P-labeled positions in labeled compounds, DNA for example, become 32S-containingsites. The observed biological effects may result from the radiation and/or the transmutation (NCRP, 1979). 4.1.3

Absorbed Radiation Dose Calculations

(a) Methods and Assumptions Mathematical Formulation. The radiation dose depends upon the physical parameters of each radionuclide, the fraction of energy ernitted that is absorbed in the tissues of interest, and the biological distribution and retention of the radionuclide. Physical data for most radionuclides are available in the literature, and from these the fraction

52

/

4.

RADIATION DOSE

of available energy absorbed in various organs can be determined mathematically for defined geometrical shapes and configurations. The absorbed fraction data are calculated by using a phantom simulating a reference man (Snyder et al., 1978; Snyder et al., 1974). The assumptions used in dose calculations are: (a) calculation of dose for a reference man and reference organs (consequently there is uncertainty about the agreement between the calculated dose and the true dose because the phantom only approximates the geometry of the actual human under consideration and statistical and computational errors are inherent in the results); (b) homogeneous distribution of radioactivity in a homogeneous organ or part of organ; and (c) validity and generality of simplified or inadequate biological parameters derived from the literature. Much of the biological information needed for dose calculations is inadequate or non-existent, especially for man. When data are unavailable or available data are unreliable, conservative dose estimates are in order. For radionuclides with short physical half-lives, the retention time in the organ is often assumed to equal the physical halflife. For radionuclides with long physical half-lives, this assumption can result in large overestimates. The fraction of activity contained in an organ is generally estimated from quantitative observations, but if no quantitative information is available, a "best guess" is made. Thus, it becomes obvious that radiation dose estimates may be reasonably accurate only if adequate data are available for the distribution and retention of the activity. The radiation dose estimates from newly available radiolabeled materials often serve only as crude estimates of the radiation dose to a "standard patient" rather than being estimates of dose to a particular patient. Dose Calculations. Some examples of dose estimates are presented below to provide a guide to the use of the dose estimates in Appendix B. They have been selected to demonstrate the differences in radiation dosimetry associated with variations in physical and biological properties of radiopharmaceuticals. The dose is calculated by using techniques adopted by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine (Loevinger and Berman, 1976) as follows: =

A

ZA@/rn =

2.s

(1)

where = mean absorbed dose (rad) in target organ

A

= cumulated activity in the source organ (pCi-h) m = target organ mass (g) A = mean energy emitted per unit cumulative activity (g-rad/pCi-h)

53

/

4.1 RADIATION FROM ADMINISTERED RADIONUCLIDES

4 = absorbed fraction (dimensionless)-fraction of energy emitted from cumulated activity in source organ that is absorbed in target organ S = absorbed dose per unit cumulated activity. Computer calculations of S have been tabulated (Snyder et al., 1975). The S values are based upon the assumptions that radioactivity is uniformly distributed throughout the source organ. The geometrical size and location of organs are those of the MIRD mathematical phantom. Charged-particle radiations are included in the S values where is unity if source and target are the same, CP is zero if source and target are different except for walled organs and skeletal regions. The radiation doses to the thyroid from radioactive iodine-123, -125, and -131 were selected as examples to illustrate how a radiation dose is calculated as a hnction of the physical properties of the radionuclide. The scientific literature contains a great many papers about radioactivity and the thyroid gland. For the dosimetrist, however, the questions are which literature data should be used, are there distribution data for other regions of the body, and to what degree does extrathyroidal activity contribute to the thyroid dose? The example of radiation dose to the thyroid (page 58) illustrates the simplest type of radiation dose estimate. Illustrative data for this example are presented in summarized form in Tables 1 through 3. Based upon these data, equation (1)was used to calculate the radiation dose to the thyroid gland, but there is no consideration of iodine in other organs. Table 4 is a summary of the radiation dose values. It should again be pointed out that the examples are illustrative only and that the radiation dose values are based upon hypothetical biological values presented in Table 1. The biological information used is the maximum thyroid uptake value with a single exponential turnover function (Table 1);for this example, a 24-hour uptake value of 27 percent and a biological half-time of 68 days is assumed. With this approximation of the biological turnover of iodine in the thyroid gland, one can estimate the cumulative activity, A", for the thyroid from the following equation: TABLEI-Typical biological values for radioiodine in the thyroid gland Example of

Euthyroid (Adult) Hypothyroid (Adult) Hyperthyroid (Adult) Newborn (0years)"

" Wellman et al., 1970

Biologeal life (d)

68 136 34 11

24 h

~ ~ (~ercent)

27 5 54 67

Thpid ~ ~Mass~ (g)

20 20 40 3.4

-

i @Cid h, jul

5 0.94 10 12

v2..,l

I:II~

298 67 72 13 405 122 215 108

54

/

4.

RADIATION DOSE TABLEF S u m m a r y of nuclear data for ""I, ""I and '"I 1251

Characteristic

Mode of Decay Physical Half-Life Decay Constant A for charged particle radiation (g-rad/pCi - h)

Electron Capture 13 hours 0.0533 h-' 0.06

Electron Capture 60.2 days 0.0115 day-' 0.0434

1:III

Beta Minus 8.06 days 0.860 day-' 0.4085

Principal Photons: E (MeV) A (g-rad/pCi-h)

"Weighted mean energy of K x rays ' The summed A for a span of photon energies represented by the energy of the major contributor. Derived from material presented in MIRD Dose Estimate Report No. 5 (MIRD, 1975~)

where fo = extrapolated activity in thyroid a t t = 0; Tb = biological half time; T , = physical half life. Similar approximations can be made for radioactive distributions in any selected tissue. Frequently, the information available in the literature is limited to estimates of peak times and values for radioactive retention at a few points determined by clinical interest, e.g., the optimal scanning times. Since these data are usually available only for short time periods after administration, possible long-term retention of small amounts of radioactivity may be missed. The error in radiation dose value introduced by assuming instantaneous uptake by the tissues of interest is usually relatively small and often negligible, whereas errors in radiation dose values attributable to the neglect of long-term retention of small amounts of radioactivity can be large. The physical data required for calculating A for the thyroid example are available from several literature sources (Lederer et al., 1968; Dillman, 1969; Dillman, 1970; Dillman and Von der Lage, 1975).4 Tables, as published in MIRD Pamphlet 10 (Dillman and Von der Lage, 1975), show a detailed enumeration of the emitted radiations. Table 2 is a summary of the physical data for the radionuclides lZ3I, lZ5I,and 13'I.All emitted radiations must be taken into account for a complete radiation dose estimate. The summary of radiation absorbed dose to the thyroid shows that charged-particle radiation is the major

56

/

4.

RADIATION DOSE

TABLE4-Mean radiation dose to the thyroidper pCi of administered activity (for the biological parameters shown in Table I ) Radionuclide

12'1

1251

Radiation absorbed dose (rad) Example

C p h s &

Photon

Total

Euthyroid (Adult) Hypothyroid (Adult) Hyperthyroid (Adult) Newborn Euthyroid Hypothyroid Hyperthyroid Newborn Euthyroid Hypothyroid Hyperthyroid Newborn

contribution to the thyroid dose for all nuclides in Table 4. Thus, even though 1251and 12=1have no direct charged-particle emanations, secondary radiations result in the largest fraction of the absorbed dose being delivered by charged particles for each of the tabulated nuclides. The remaining quantity required for dose calculations is the amount of energy deposited by the various radiations in the tissue of interest. The absorbed fraction of energy emitted depends upon the type of radiation, the energy of the radiation, the relative location of emitting source and absorbing target, and the mass of the target. Usually, the absorbed fraction for charged-particle radiation is assumed to be unity if the emitting source and target region are the same, and zero if the emitting source and target region are widely separated. These assumptions are not justified when the source and target regions are adjacent, such as is the case when the radioactivity is in the contents of the organ and the target is the organ wall. In this situation, the absorbed fraction is assumed to be 0.5 to calculate the surface dose to the organ wall. Where the radioactivity distribution is non-uniform and the charged-particle range in tissue is less than the distance separating the areas of concentration of radioactivity, then the use of @ = 1 to calculate an "average" radiation dose to the organ may not be a good assumption. The second example (page 59) illustrates a circumstance involving short-range radiations where microdosimetric evaluations are needed to provide an accurate description of the radiation dose distribution.

' These sources are compilations from data published in the physical literature such a~ Physical Review and others.

4.1

RADIATION FROM ADMINISTERED RADIONUCLIDES

/

57

Absorbed fractions have been determined for a variety of photon energies and geometrical shapes (Brownell et al., 1968; Ellett and Humes, 1971; Snyder et al., 1974). A complete phantom with a configuration representing a reference man has been designed and absorbed fractions for photons of 12 energies have been estimated by Monte Carlo type calculations for selected source target combinations (Snyder et al., 1978; Snyder et al., 1974). Unfortunately, the statistical nature of the Monte Carlo calculations often results in large uncertainties in q5 for small target organs that are distant from the source, as is the case for the gonads when the source is in the thyroid. Consequently, this method of estimating genetic dose is imprecise. However, the results usually have the desired precision where source and target organs coincide and this is the case with the values in Table 3 (Ford et al., 1975) where the coefficient of variation does not exceed 2.5 percent of the estimate in any instance. In some cases, where the Monte Carlo method has not yielded precise estimates of the absorbed fraction, these have been calculated by analytical methods. The reader therefore needs to be aware that not all estimates of absorbed fractions have equal accuracy and should take this into account when deciding on the validity of an estimate of dose. Since the size, mass, and location of organs of individual patients may vary from those used in the computation of absorbed fractions based on a reference man configuration, corrections for individual variations may be necessary. Corrections for absorbed fraction of photon energy for masses different from those used for reference man can be made by correcting the photon absorbed fraction, @,by the formula

where is the absorbed fraction of mass M I and & is the absorbed fraction for mass Mz.Although strictly accurate only for energy absorption in a small spherical organ, and generally valid only for photon energies greater than 100 keV, this approximation is, as yet. the best available. A more detailed discussion is found in the literature (Snyder, 1970 and Poston, 1976). One area of concern to the clinician is the radiation dose to children who receive radioactive materials. Common practice is to determine the amount of radioactivity to be administered to a child by multiplying the quantity of radioactive material given to the adult by the ratio of the child's body weight to the adult's weight. The assumption is that the radiation dose to the child will be the same as that estimated

58

/

4. RADIATION DOSE

for the adult because the concentration of the radionuclide in the organ will be approximately the same. This is not entirely true, however, since the ratio of organ weights may not be the same as the ratio of body weights and, furthermore, the shape of the child's organs may differ from that of the adult and other parameters such as the uptake may differ. Recommendations concerning the calculation of radiation dose in children is the subject of a forthcoming NCRP Report concerned with pediatric nuclear medicine. (b) Examples of absorbed dose calculations Radiation Dose to the Thyroid from Radioactive Iodine-123, -125, -131 in the Thyroid Gland. The method used to calculate radiation dose is that developed by Loevinger and Berman (1968, 1976), where the dose is given by

is the dose in rads to the target v from a radioactive where D(,,,, source r, A, is the cumulative activity in the source region, m, is the mass of the target, A ; is the mean energy emitted per unit cumulated is the fraction of ilh type of energy activity for radiation i, and $i(,,,, emitted from source r and absorbed in target v. In this example, r and v coincide. Contributions to the radiation dose to a particular target come from radioactivity within the target itself as well as from photon irradiation from other regions. Detailed radiation dose calculations are better exemplified in the literature (Lathrop et al., 1975; ICRU, 1979) whereas the examples presented here are simplified and intended to be illustrative only. To calculate the radiation dose to an organ, the following data are required: (a) Distribution and retention information for the radioactive material throughout the body. (b) Physical parameters for the radionuclide. (c) Fractions of energy emitted from source region that are absorbed in the organs of interest. The example summarized in Table 4 illustrates the importance of considering the physical properties of the radionuclide by presenting the mean values for the radiation doses to a 70 kg adult and a newborn child for the three iodine radionuclides. Although the physical half-life of lz5I is 8 times longer than that of 1311,the smaller amount of chargedparticle radiation from 1251results in a smaller dose. The very short physical half-life of 1231becomes the predominant factor in radiation

4.1 RADIATION FROM ADMINISTERED RADIONUCLIDES

/

59

dose to the thyroid, but may be a disadvantage if long-term measurements are wanted. Likewise, the low-energy photons of '=I, although producing low doses, are difficult to measure and may not be desirable for imaging with scanners or cameras. As demonstrated in the example, the radiation dose rate is directly proportional to the concentration (~Ci/g)of radioactivity in the gland, but it is modified by the combined biological and physical half-time. Thus, in the case of '*I, the very short physical half-life dominates and the effective retention time remains essentially the same regardless of biological variations. Microdosimetry in the Thyroid Gland For Radioactive Iodine. The need for knowledge concerning microdosimetry is illustrated by the inhomogeneous dose distribution from radioactive iodine used to treat patients with hyperthyroidism. Non-homogeneous dose distributions reflect anatomical and physiological features of the thyroid gland plus physical properties of the different radioactive iodine isotopes employed. The biokinetic sequence starts when the iodide ion is trapped at the surface membranes of the thyroid follicle cells and then moves through these membranes and cells toward the luminal end. Incorporation into thyroid hormones occurs rapidly and preferentially a t the colloidfollicle cell interface. The process of absorption, transport, hormone synthesis, and release is increased in rate and amount in hyperthyroid patients. In Graves disease, these processes are increased diffusely throughout the gland, while in nodular glands, the different follicles may vary greatly in degree of functional activity. Table 5 indicates typical values of gland and follicle sizes that affect radiation dose distribution. Radioactive emanations that travel long distances would result in relatively uniform dose distributions, even if asymmetrically localized in the thyroid follicles. The low energy electron radiations from '=I deposit their energy in very short distances. TABLE5-Values

for typical gland and follicle values which affect radiation dose distribution Normal

Gland weight (gm) Follicle diameter (pm) Follicular cell Length bun) Width (pm) Nucleus (distribution from lumen-pm) Iodine in cells (5%) Colloid content (fraction of gland volume)

Thyrotoxic

15-25 50-300

25-150 20-150

2.7-7.5 5.

10-30 c5. 5-15 >lo. .lo-.15

3.

10. c.3

60

/

4.

RADIATION DOSE

""

The principal conversion electron emissions from deposit their energy in c l p m (3.7 keV-K conversion) to a maximum of 23pm (34.5 keV-M conversion). If one assumes a 70pm spherical follicle in a 20 gm gland, with 90 percent of the Iz5Iin the colloid, the mean dose rate to the foUicular cell nuclei (taken to be 10pm for the colloid-follicularcell interface) is generdy less than the mean total gland dose and is typically 50 to 70 percent of it (Gillespie et al., 1970) (See Table 6). If 131 I is employed, with its longer range radiations, the cell nucleus and the cell-colloid interface would receive more nearly the same dose. Thus, it has been suggested that the probability of cell death and the induction of hypothyroidism following radioiodine therapy could be minimized by the use of Iz5I in therapy of hyperthyroidism. Such an effect has been sought in clinical studies, but has yet to be demonstrated (Ben-Porath et al., 1970; Lewitus et al., 1971). Nonetheless, TABLE6-Dose

rate (rad/dayper mCi

''9in the thyroid gland)

Site

rad/day-mCi

Mean dose rate to whole gland At colloid-cell interface At 1 pm from colloid-cell interface At 10 pm from colloid-cell interface Gland mass = 20 g 90 percent of iodine in colloid

75 253 98 38

--

this example illustrates the potential significance of microdosimetric considerations for treatment planning and radiobiology calculations. Radiation Dose to the Kdney. An illustration of a larger complex of variables is encountered in estimating radiation dose to the kidneys. In the kidney, the residence time of radiotracers in the renal cortex, medulla, and collecting system can be distinctly different. Radioactivity tends to become concentrated selectively within these structures. Generally, the administered materials are concentrated first in the renal cortex, followed by a concentration in the outer medulla, inner medulla, papillae, and calyceal system. Clinical studies using 13'1 iodohippuric acid demonstrate this sequence. A few substances, including mercury ions, do not filter readily into the urine, but accumulate progressively in the cortex and are distributed non-uniformly in the kidney. In the kidney model used for dosimetry, the organ is divided into three regions (Figure 8 ) , the cortex, medulla, and a collection region (calyces) which have masses of 93.5 g, 51 g, and 6 g, respectively. The biokinetic data for 203Hg-chlormerodrin are summarized in Table 7 (Dose Estimate Report No. 6, MIRD

4.1 RADIATION FROM ADMINISTERED RADIONUCLIDES

/

61

Fig. 8. Anatomic model of human kidney used for absorbed dose calculations. Shaded area represents renal collecting system. A-coronal plane; B-sagittal plane. (Dose Estimate Report 6 - MIKD 1975d).

TABLE 7-Biological retention data--for chlormerodrin ---

Region

Renal cortex, 187 g Renal medulla, 102 g

Praction of administered

Biological half-Lirne

activity

0.38 0.12 0.006

8 hours 30 days 40 days

1975d). Radiation dose estimates based on the data in Table 7 are shown in Table 8, where values for the cortex and medulla of the kidney are compared with values based on the assumption of a uniform distribution throughout the kidney. In some cases, biological retentions can be shortened by administration of appropriate agents. For example, stable mercurial diuretics can be administered to diminish the retention of radioactive mercury in the kidneys. The effect of 1 ml meralluride with 39 mg of organicallybound mercury is to reduce the longterm retention of mercury in the cortex by a factor of two. The effect on radiation dose to the kidney is shown in Table 8. Radioiodinated iodohippuric acid is another agent used to study kidney function. Unlike mercury, there is no marked accumulation of the radioiodine in the cortex and therefore an average radiation dose estimate based on a uniform distribution throughout the kidney is assumed. However, different rates of excretion of '"I iodohippuric acid

62

/

4. RADIATION DOSE

TABLE 8-Radiation dose (mrad/pCi) to the kidney from radioactivity administered as mHg-chlormerodrin Site

Renal cortex Medulla Total kidney"

No blocking agent

100

20 69

With blocking agent

55 15 38

" Uniformdistribution throughout the kidney assumed

from the kidney that are representative of clinical situations can be used to illustrate how alterations in organ function can affect the radiation dose considerations. Consider three different hypothetical states of kidney function: Normal kidney function where 96 percent of the administered activity passes through the kidneys with a half-time of 15 minutes and the remaining 4 percent is excreted with a half-time of 12 hours: The radiation dose to the total body from 1311 iodohippuric acid in the kidneys is on the order of 0.005 m a d per pCi of administered activity. Severe uremia where 50 percent of the administered activity passes through the kidneys with a half-time of 1.5 hours and the remaining 50 percent is excreted with a half-time of 12 hours. The radiation dose to the total body per pCi of I3'I administered activity is on the order of 0.04 mrad. A non-functioning kidney transplant with no excretion: Assume that 100 percent of the radioactivity is distributed in the extracellular spaces with an effective half-time clearance equal to the physical halflife of 13'I. The radiation dose to the total body from 1 pCi 13'1uniformly distributed in the total body is on the order of 0.3 mrad. These examples illustrate how the radiation dose to the total body can be modified by presence of disease. In the cases shown, the total body dose is increased by a factor of nearly 10 when the kidney is severely damaged and by a factor of 60 if there is no kidney excretion.

Radiation Dose to Various Body Organs from the Administration of ""Tc Sulfur Colloid. An example is presented here to describe a dose calculation in more detail. The example is for a patient administered 1 mCi of -Tc sulfur colloid. After intravenous administration, 89"'Tc sulfur colloid is rapidly cleared from the blood by the reticuloendothelial system with a nominal clearance half-time of approximately 2.5 minutes. Uptake of the radioactive colloid by organs of the reticuloendothelial system is dependent upon both their relative blood flow rates and the functional capacity of the phagocytic cells. In the average normal patient, about 85 percent (Dose Estimate Report No. 3, MIRD, 1975a) of the injected colloidal particles are phagocytized by the Kupfer cells of the liver, 7

4.1 RADIATION FROM ADMINISTERED RADIONUCLIDES

/

63

percent by the spleen, and 5 percent by the bone marrow. Since the biological turnover in these organs is considerably longer than the 6.0 hour radioactive half-life of -Tc, the effective (retention) half-time is equivalent to the 6 hour half-life of the ""Tc. The biological dsumptions are summarized below: Effective -. .. ... .

Half-Time

Organ

(Ten)

Liver Spleen Red Bone Marrow Rest of Body

85 percent 7 percent 5 percent 3 percent

6 hours 6 hours 6 hours 6 hours

Organ Mass 1830 g 176 g ~~ g

The cumulated activity, A, for each source organ is the area enclosed by the time-retention curve of radioactivity within that organ. Figure 9 is an example of the radioactive content of %"Tc in the liver as a function of time. For a single exponential curve, mathematical integration is quite simple: area = fo/A where f, is the activity at zero time in the organ and X is the effective decay constant given by X,U = 0.693/ T,rr. Thus, in this example: Source in liver f, = 850 pCi/mCi administered Xen = 0.693/6 h = 0.1155 h-' ALIv = 850/0.1155 = 7359 pCi-h

Source in spleen fo = 70 pCi/mCi administered hen = 0.1155 h-' ASP!.= 70/0.1155 = 606 pCi-h

TIME (hours)

Fig. 9. Radioactivity in the liver as a function of time after administration of !'!""Tc sulfur colloid.

64

/

4. RADIATION DOSE

Source in red bone marrow f, = 50 pCi/mCi administered h = 0.1155 h-' A l m M = 50/0.1155 = 433 pCi-h For more complex retention functions, the area under the curve may be determined by other mathematical expressions or perhaps by direct measurement with a planimeter or computerized coordinate digitizer. The radiation dose to a target region, r, from source volumes, v, can be calculated from the following equation:

In this example S values are employed in lieu of

Ai+i The S

xi-.

m

values used in this example are shown in Table 9. The use of S tables simplifies the arithmetic, but one must be aware of the assumptions used in compiling the S tables: (1) The absorbed fractions for chargedparticle radiations are unity when source and target are the same, zero when they are different except for walled organs and skeletal subregions. (2) Absorbed fractions for photon radiation have been calculated by using Monte Carlo or integration methods. (3) Uniform distribution of activity is assumed throughout the source organ, and the size and relative location of organs are those of the phantom (Snyder et al., 1975). TABLE 9-Values for S, the absorbed dose (rad)per 1 pCi-h of technetium-9%. Radioactive half-life 6.03 hours Source Organ Target Organ

Liver Spleen Red marrow Ovaries Testes

Liver

Spleen

Red bone manow

4.63-05 9.2347 1.63-06 4.53-07 6.2348

9.83-07 3.33-04 1.7E-06 4.OE-06 4.83-08

9.23-07 9.23-07 3.13-05 3.2346 4.5347

When the sources for this example are liver, spleen, and red bone marrow, the radiation dose to target organs is then calculated by the following method: Dose to liver

-

DLIV= ALIV-SLW-LIV + ASPL-SLIV~SPL + A'RBM'SLIV-RBM = 7359 x 4.6 x lo-" 606 x 9.8 X + 433 X 9.2 X lo-' = 0.34 rad/mCi administered

lose to Spleen

4.2

EFFECTS OF ADMINISTERED RADIONUCLIDES IN MAN

/

-

65

Dsp~ = 0.21 rad/mCi administered

Dose to Red Bone Marrow

-

-

DRBM = ALIV-SRBM-LIV + &PL-sRBMcSPL = 7359 x 1.6 x + 606 x 1.7 x = 0.026 rad/mCi administered

Dose to Ovaries

-

-

+ ARBM-SRBM-RBM

+ 433 x 3.1 x

-

Dov = XLIV-SOV-LIV + XSPL-SOV~SPL + ARBM-SOV-RBM + 433 x 3.2 X lo-" = 7359 x 4.5 x + 606 x 4 x = 0.005 rad/mCi administered

Dose to Testes

-

DTES= AIV-STES-LIV + XSPL-STES~SPL + ARBM-STES-RBM = 7359 X 6.2 X + 606 X 4.8 X + 433 X 4.5 X = 0.0007 rad/mCi administered. 4.2 4.2.1

Effects of Internally Administered Radionuclides in Man Sources of Information

A summary of the fundamental information on the genetic and somatic effects of ionizing radiations in man is found in recent reports from the United Nations Scientific Committee on the Effects of Atomic Radiations (UNSCEAR, 1966, 1969, 1972, 1977); the National Academy of Sciences (NAS/NRC 1972, 1980); and Reports Nos. 39 and 43 (NCRP 1971, 1975). These reports also evaluate both the acute and chronic (late) effects of a wide range of doses of ionizing radiations in man and animals and lower forms, deriving these evaluations by insight into the mechanisms of injury and the attendant risks to life. This section summarizes those effects that have been observed in man after exposures to radioactive materials taken internally. 4.2.2

Review of Accidental and Unusual Occupational Exposures

(a) Effects of &-particleemitters The earliest data that alerted scientists to the hazards of these radiations were obtained from the radium dial painters who were exposed to mixtures of radium and thorium compounds (aemitters) in the course of their work (Evans, 1981). The late effects of radium exposures in these and in medical subjects have been studied extensively by groups in the U.S. in Boston (Evans et al., 1969) and Chicago (Rowland and Stehney, 1978; Polednak et al.,

66

/

4.

RADIATION DOSE

1978) Medical patients (children and adults) given therapeutic doses of '24Ra (ThX) in Germany have also been studied a t Gottingen (Spiess, 1969; Mays et al., 1978). The results of all studies show that various tumors are increased in frequency after substantial exposures to '"Ra, 226Ra,and 22RRa.These tumors include osteogenic sarcomas, osteochondromas, and carcinomas of the mastoid and paranasal sinuses (Mays, 1973; NAS/NRC, 1980). A possible increase in leukemia, aplastic anemia, and lung cancer has also been reported (Finkel et al., 1969). The radiation dose depends on the nature of the mixture of materials absorbed by the patient, the uniformity of the biological distribution, and the retention time involved, and consequently computations of dose are imprecise. As of 1978, no bone sarcomas had been noted in the large number of subjects studied in Boston and Chicago who had accumulated alpha radiation exposures of less than 888 rad of skeletal average dose (Rowland and Stehney, 1978). Uranium and pitchblende miners have been the subject of intensive studies for many years. I t seems well established that there is an increased incidence of lung cancer from "'Rn inhalation in uranium miners (Mays, 1973), but the number of miners is relatively small, they tend to be itinerent, and the doses are poorly chronicled (Archer et al., 1973; NAS/NRC, 1980; Cohen, 1982). Thorotrast (colloidal thorium dioxide) was widely used as an x-ray contrast medium from 1928 through the mid-1950s. When it was found to be carcinogenic, it was no longer approved for use in patients and was removed from the U. S. Pharmacopeia. Tumors a t the site of the intravenous injection, liver malignancies (bile-duct carcinomas, angiosarcomas, and hepatic-cell carcinomas) (NAS/NRC, 1980), bone tumors (Mays and Spiess, 1979), and leukemia (Mole, 1978) were increased in frequency in patients who received this agent. Liver cancer rates projected to the end of the subjects' life spans were approximately 300 per lo6 person-rad of alpha particle radiation and the average tissue absorbed dose rate is about 25 rad per year (NAS/ NRC, 1980). The excess leukemia risk calculated through 30 years after the dose was administered is estimated as 40 cases per lo6 personrads (Mole, 1978). In 1945 and 1946, plutonium was administered to 17 human subjects who were presumed to have short life expectancies. Unexpectedly, six of these subjects survived more than 10 years-two were still alive 20 years later (Rowland and Durbin, 1976). No cancers have appeared in these persons. In view of the small number of persons exposed, it is not possible to conclude from these data that the risk is nil. However, if the risk had been 10 times higher than that observed following Thorotrast administrations, 4 liver cancers would have been expected,

4.2

EFFECT OF ADMINISTERED RADIONUCLIDES IN MAN

/

67

and the chance of having no liver cancers would have been very small ( P = 0.02) (NAS/NRC, 1980). Twenty-six male subjects who worked with plutonium during World War I1 under extraordinarily crude conditions have been followed medically for a period of 32 years. Inhalation was the primary mode of plutonium exposure. Eleven of the individuals have depositions greater than the maximum permissible body burden for workers. Two individuals have died; one due to myocardial infarction and the other due to injuries sustained in an automobile-pedestrian accident. There is no evidence in this study to suggest that adverse health effects have resulted from the 32 years of exposure to the intemally-deposited plutonium (Voelz et al., 1979).

(b) Effects of fission products (including radioactive iodine) Radioactive iodine is commonly used in medicine, but may also find its way into people from products of nuclear fission in the environment. In March 1954, persons living on islands downwind of the Bikini Atoll hydrogen bomb test site were exposed to fallout that contained relatively large amounts of different radionuclides of iodine and to other radionuclides as well. Estimated whole body doses of 175 rads were received by the most heavily irradiated adults, while the heavily exposed children may have received thyroid doses recently estimated to be as high as 1150 rad. Within 25 years, 30 out of 127 children were found to have developed thyroid nodules and seven were found to have developed thyroid cancer. In this size population 5.1 malignancies would be expected based on risk estimates for Japanese A-bomb survivors (Conard et al., 1980), and less than one naturally occurring malignancy would have been expected. The latent period varied between 11 and 22 years after exposure, and it appears that the higher doses led to earlier appearance of neoplasms. All of the thyroid cancers occurred in females, and the data do not reveal significant differences in cancer risks between exposed children and exposed adults (NAS/ NRC, 1980; UNSCEAR, 1977; Conard et al., 1967, 1970,1975, 1980). 4.2.3

Medical Uses-Therapy

Acute symptoms are seen after internal deposition of large doses of internal emitters. The time course of the events and their intensity depend upon the nuclide and amount used. As in other toxicity experiences, the larger the dose, the earlier and more severe the signs and symptoms. Late effects have also been seen after the large doses used in treating the following conditions.

68

/

4.

RADIATION DOSE

(a) ""I Therapy-Thyrod Cancer Large doses of radioactive iodine have been used in the treatment of many patients with thyroid cancer. A 100 mCi dose of '"I is commonly employed, and many patients are treated repeatedly. Bone marrow and lymphoid organ damage is the most frequent early complication. A prompt fall in WBC count (lymphocytes predominantly) is usually seen and occurs together with cytogenetic changes in cultured circulating lymphocytes. Some patients treated with multiple doses may receive as much as several curies of '"'I over a period of many years. Late effects, e.g., a significantly increased incidence of leukemia, have been reported: 4 observed vs. .08 expected (Pochin, 1969). Fatal cases of radiation pneumonitis and pulmonary fibrosis may occur after treatment of patients with diffuse pulmonary metastases who retain 100 mCi or more of '"I in their lungs (Rall et al., 1957). The progeny of patients treated as children for thyroid cancer show no evidence of genetic defects (Sarkar et al., 1976). (b) ""I Therapy-Thyrotoxicosis Radioactive isotopes of iodine have been used since 1939 for the treatment of thyrotoxicosis, and radioiodine continues to be the preferred treatment for most patients. T h e dose administered depends on various biological factors, as well as treatment objectives. T h e reduction of thyroid function is based on interphase killing of thyroid cells to the degree that the residual thyroid cell population can maintain normal circulating levels of thyroid hormone. Because the successfully treated patient has a normal life expectancy, a low dose to noninvolved tissue is required. Thus, treatment depends upon a very high dose of radiation to the thyroid and an acceptable low dose to other tissues. In contrast, the palliative treatment of metastatic thyroid malignancies requires a smaller absorbed dose to the tumor tissue because control is achieved by mitotic death and, in view of the prognosis, a greater allowable whole body dose (lower target-to-non-target ratio) may be accepted. Many patients have received I3'I treatment for thyrotoxicosis. The usual patient receives 5-10 mCi of I3'I, which is calculated to deliver 7.000 rads to the thyroid. Fearful that there might be late complications, leukemia or thyroid cancer in the subjects and genetic damage to their offspring, early recommendations restricted treatment to patients in the older age groups. Follow-up of 18,400 patients given '"I and a comparison group of 10,700 treated with anti-thyroid drugs and/ or surgery has shown no difference in leukemia incidence between the different treatment groups (Saenger et al., 1968). T h e only observed late effect of '"'I therapy of adult thyrotoxic patients has been an

4.2

EFFECT O F ADMINISTERED RADIONUCLIDES IN MAN

/

69

increased incidence of hypothyroidism caused presumably by the mitotic sterilization of precursor cells required to maintain the normal cell population (Becker et al., 1971). Children who were treated with 1U I I and not maintained on thyroid replacement medication thereafter have an increased incidence of benign nodules (Sheline et al., 1962). No presently available evidence suggests that thyroid cancer is induced by I3'I a t therapy dose levels (Seydel, 1973). Cytogenetic studies of lymphocytes from patients treated with '"'I (Cantolino et al., 1966) and '"1 (Boyd et al., 1974) for thyrotoxicosis revealed an increased frequency of chromosome abnormalities within 24 hours of exposure. Dicentric and acentric fragments were the most frequent anomalies and these aberrations, plus cells with ring formations, continued to be observed two months after '"I administration. Several patients have been treated inadvertently during the first trimester of pregnancy. While this is clearly undesirable, it is important to note that the offspring have been normal in all cases reported to date (Chapman and Maloof, 1955; Volpe et al., 1961). I n order to evaluate the possibility of genetic damage occurring in offspring subsequent to treatment, records a t the Massachusetts General Hospital were reviewed. Approximately 200 women became pregnant after '"I therapy without an increased incidence of abnormal offspring being observed (Stanbury and Chapman, 1976).

(c) "P Therapy-Polycythemia Vera Large numbers of patients with polycythemia Vera have been treated with 32Psince it was first introduced for this purpose in 1940. A dose of 4 mCi delivers up to 60 rad to the bone marrow compartment (Osgood, 1965). Patients usually receive multiple treatments in order to control, not cure, their disease. The average total injected activity was about 20 mCi in a large retrospectively studied series of patients treated a t major centers in the U.S. (Modan and Lilienfeld, 1965). The data showed a significantly increased incidence of leukemia in "P-treated patients above that expected in untreated polycythemia vera, but it is known that there is an increased incidence of leukemia in patients with polycythemia vera. The question that has been difficult to resolve is whether the increased incidence observed after '9 treatment is due to the direct effect of radiation from or to an "indirect effect." The latter suggestion has been based on an increased survival time of '"'Ptreated patients, thereby unmasking a heightened leukemia expectancy associated with the disease itself. Mays (1973) in a reanalysis of Modan's data suggests that the incidence of leukemia in treated patients is 60 leukemias per year per 10"erson-rad; this is approxi-

70

/

4.

RADIATION DOSE

mately 60 times higher than the leukemia induction rate observed in the Japanese A-bomb survivors. In the decision to use 32P,the possible risk of leukemia has to be weighed against the increased survival of the patients treated with 32Pand the quality of life they enjoy due to the improved control of clotting disorders by this form of therapy. 4.2.4

Medical Uses-Diagnosis

Millions of patients annually receive tracer doses of radioactive agents in diagnostic studies (Quinn, 1975). Almost all of these patients have diseases or symptoms that suggest disease, and it is difficult to design and conduct follow-up studies to identify late effects, if any, of these exposures. No pattern suggesting the existence of late effects has been observed to date, although all users of radioisotopes keep the possibility in mind. Follow-up of children who received diagnostic doses of 13'1 is being conducted in the United States (HHS,1980). Since only selected children received these tests, an adequate epidemiologic design is not readily established. However, because thyroid doses of 1-2 rad/pCi administered are received from these studies, large surveys are being conducted in other countries also. A Swedish study (Holm et al., 1980) reports results based on study of 10,000 patients who received I3lI in medical diagnosis and therapy. Based on a 17 year mean follow-up period, the following results were obtained: total number of thyroid cancers detected-9 expected number of spontaneous thyroid cancers-8.3. The thyroid cancer risk factors published by UNSCEAR (1977) were based on review of epidemiologic data from external high doserate exposures. Using those risk factors, the expected number of radiation-induced thyroid cancers in the Swedish study was 47-127 (Roedler, 1980). The fact that no increase was detected was taken to indicate that these risk estimates may be 10-100 times too high, and consistent with observations (Maxon et al., 1977) that I3lI is 1/70 as effective as external radiation in inducing thyroid cancer. 4.2.5

Summary of Findings from Historical Review

1. Based on available radiobiological data, no detectable effects are expected from administration of diagnostic doses of radionuclides. 2. Late somatic effects have been observed in man after significantly high internal deposition of a-particle emitting radionuclides (high-LET

4.2

EFFECT OF ADMINISTERED RADIONUCLIDES IN MAN

/

71

radiations). These agents are not used in the U.S. in nuclear medicine a t the present time. 3. I t is generally believed that the fetus is more sensitive than the adult with respect to the radiation induction of malignancies. This conclusion is based on findings in animal studies and is supported by some epidemiologic follow-up studies of human children exposed in utero to diagnostic x rays (NCRP, 1977). 4. An increased incidence of human thyroid cancer has been observed in the Marshallese after exposure to high doses of fallout radionuclides concentrating in the thyroid. These doses are intennediate between those used in diagnosis and therapy with 13'I.This result is numerically consistent with the increased incidence of thyroid cancer observed after external irradiation of the head and neck in children. 4.2.6

Topics of Special Interest in Nuclear Medicine

(a) Dose Rate The low linear energy transfer (LET) radiations (e.g., gamma and x rays) from radionuclides commonly employed in nuclear medicine are less likely to produce irreparable biological damage than high-LET radiations (UNSCEAR, 1977). The best data on biological effects of ionizing radiation are derived from studies of human populations exposed to high doses delivered a t high dose rate. As documented in Report No. 64 (NCRP, 1980a), there is a 2 to 10 fold reduction in effect observed when low-LET radiations are delivered a t low dose rates. Thus, a 2- to 10- fold safety factor is included when risk factors are derived directly from high dose, high dose rate observations of biological effects in human populations.

(b) Exposure of Gonads With the exception of unusual agents, such as iodocholesterol, radiopharmaceuticals used in nuclear medicine do not become localized in the gonads. Gonadal exposure, in most cases, is closely approximated by the whole-body dose. However, prolonged retention of radionuclides in the recto-sigrnoid bowel or the urinary bladder, especially in therapy of the female, is a potential source of gonadal exposure.

(c) Non- Uniform Tzssue Distribution of Dose Selective localization of radionuclides in specific tissues and organelles provides the basis for the radiotracer method and also leads to asymmetric dose distribution patterns. When a large fraction of the

72

/

4. RADIATION DOSE

energy is from low energy Auger electrons or conversion electrons, such as from 1-125, grossly asymmetric dose distributions and high local doses can result. [See page 59.1 Fortunately, relatively few of the radiopharmaceuticals used in nuclear medicine for diagnostic procedures become localized selectively in the more radiobiologically sensitive locations.

(d) High-LET Materials. High linear energy transfer (LET) radionuclides such as cw-emitters are not used in the U.S. in current nuclear medicine practice. Care must be taken to avoid contamination of materials intended for human use with high-LET radionuclides such as those derived from separated fission products (e.g., separation of 9 4 0 from fission products in preparation of some ""Tc generators). (e) Concentration in Sensitive Tissues Because of the differing radiosensitivity of various tissues, radionuclides that localize in high sensitivity tissues deserve particular attention. These sensitive tissues include: erythroid and myeloid bone marrow, thyroid, intestinal mucosa, and lymphatic and gonadal tissues. In particular, the increasing use of radiopharmaceuticals that are distributed within cells (e.g., '8F-fluorodeoxyglucoseand "'TI), as well as in extracellular compartments, requires that attention be paid to the microscopic distribution of energy in relation to the cell nucleus. For radionuclides, such as thallium-201, that decay by electron capture with the emission of significant short-range Auger and Coster-Kronig electrons, this can be of considerable importance when the radionuclides are concentrated by cells of these radiosensitive tissues (Bloomer and Adelstein, 1982).

(f) Transmutation Effects The transmutation of radionuclides that occurs during radioactive decay results in daughters of different atomic numbers. When the nuclide is contained in a radiosensitive site, the biological effect may be due chiefly to the deposited energy. If the nuclide is contained in an essential molecule, however, the transmutation results in an altered chemical moiety in addition to the deposited energy. For example, 32P decays by beta emission to 32Swhich, if located in DNA, would result in altered genetic information (NCRP, 1979). The radiation effects from the 32Pbeta particles however, outweigh effects from 32Ptransmutation in DNA (IAEA, 1968).

5. Evaluation of Radionuclide Procedures and their Clinical Utility 5.1

General

Physicians and medical scientists engaged in the practice of nuclear medicine are required to make many decisions with regard to radionuclide administration. These include: (1)the evaluation of the potential role of new nuclear medical procedures; (2) the evaluation of the benefits and risks to be encountered by the exposure of patients, normal volunteer (human) subjects, and personnel in the nuclear medicine laboratory to ionizing radiations; and (3) the determination as to which of the specific procedures available might best be employed in a particular patient or group of patients for improving diagnosis and treatment. The very rapid emergence of nuclear medicine as a discipline has resulted in part from the frequent introduction of new radionuclide procedures of demonstrated clinical utility. For each useful procedure there has been concomitant development of procedures with less than optimal clinical usefulness. The rapid pace with which new procedures are introduced makes it mandatory that those engaged in the practice of nuclear medicine be able to make a priori judgments as to whether a new procedure is likely to provide new diagnostic information or therapeutic effectiveness and whether it should replace an already established one. In addition, once a procedure has been introduced, a measure of its clinical utility should be obtained as rapidly as possible. Evaluation of the relative merits of different systems in medicine has been approached in various ways. Classically, clinical trials are conducted, and from the results obtained in one or more clinics, judgments are made on the relative merits of new agents or instruments. As the system's complexity increases and the questions become more searching, it has become necessary to devise new approaches, since all factors cannot be subjected to testing in the clinical setting. Section 5.2 presents some methods for evaluating new procedures and for judging their clinical utility. 73

74 5.2

5.2.1

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

Evaluating t h e Role of New Nuclear Medical Procedures

A Priori Measures (of Systems) and Figures of Merit for Imaging Procedures

One of the most difficult problems in nuclear medicine is that of evaluating in advance the myriad alternative procedures provided by the available imaging devices and radiopharmaceuticals in terms of the accuracy of physician performance (see Section 5.2.3) under realistic clinical conditions. Physical system models have been used by designers of systems (collimators, detectors, arrays) for many years. More recently, these models have increased in complexity and are used to estimate the expected system behavior in terms of known biological and physical factors. In addition, as the physical systems become more complex, probabilistic models, e.g., Monte Carlo techniques, are used for dosimetry (Brownell et al., 1968)and system design (Brownell, 1964).Various simple test objects are used to gain insight into system performance and these can be useful in evaluating and monitoring the performance of instruments (DHEW, 1976a, b). Experiments to test observer performance are sometimes conducted with realistic simulated test objects (Schulz et al., 1971; Schulz et al., 1973; Tsui et al., 1979); although difficult to conduct, they have provided important information. Methods of analyzing data from such trials include standard statistical tests used to evaluate multiple factors such as analysis of variance and factor analysis. The receiver operating characteristic (ROC) curve is an empirical approach that is often used in the evaluation of observer performance. This method may help to establish optimum values of system parameters as well as the relevant utility or importance of different diagnostic considerations (Lusted, 1968, 1971; Metz et al., 1977). Although reai images suffer from a variety of imperfections that affect observer performance in ways that are not predictable at present, it is nevertheless possible to make rough estimates of the effects of statistical noise and contrast on the basis of simple models of threshold detection, and, thereafter, to test predictions from these models experimentally.

(a) Simple Mathematical Model of Threshold Detection. From a theoretical point of view, what is needed is not only an adequate theory of the imaging process so that the image of any object can be computed, but also an objective criterion for diagnostic image quality

5.2

ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

/

75

that is known to correlate highly with observer performance and can be expressed in terms of parameters used to describe the imaging system and procedure (Tsui et al., 1979). A number of such criteria have been proposed, although the correlation with accuracy of diagnosis has not been determined for any. Criteria such as signal-to-noise ratio, S / N , and information content, IC, have been used most widely. Such criteria are usually formulated in terms of the magnitude of the relevant quantity (S/N or IC) that can be achieved in the image per unit of measurement time and per unit of absorbed radiation dose to the patient, to either the whole body or a critical organ, whichever is regarded as limiting. To some extent, such criteria have been used for the comparison of existing as well as hypothetical imaging systems (Beck, 1961; Dewey and Sinclair, 1961; Lathrop et al., 1970; Brownell, 1964; and Tsui et al., 1979). Alternative criteria that may be equally useful are those based on some measure of the correspondence between the image and the object, such as minimum squared deuiation, where deviations between image and object may be due to both random and non-random phenomena, i.e., noise and distortion (Linfoot, 1964; O'Neill, 1963; and Hart and Farrell, 1968). While all of the above criteria have some intuitive appeal, each can be formulated in a variety of ways. Consequently, their usefulness may be more critically dependent on the particular formulation than on the underlying basic concept. Measures of the signal-to-noise ratio in the numerical image can be formulated in various ways (Tsui et al., 1978), depending on what is taken to be the signal. Examples include the expected difference in: 1) the event or count densities at two points (one over the lesion to

be detected and the other over normal tissue); 2) the numbers of events in two regions of equal area; 3) the mean count densities in two regions of unequal area, e-g., the area of the lesion and the surrounding normal region; or 4) the nonuniformly weighted estimatesof the signal plus background and background count densities in two regions of equal or unequal area.

It should be noted that there are many other criteria that could be employed that are more dependent upon object shape than counts, character of the border, and similar factors. A commonly used formulation that serves to illustrate the relevant concepts is described in 2) above, i.e., the number of counts from two regions with equal areas. A more elegant and predictive formulation not based on equal areas is found in Tsui et al. (1978). Briefly, if NL = TCLand NN= TCNare the expected numbers of counts accumulated

76

/

5. EVALUATION

OF RADIONUCLIDE PROCEDURES

in time T[sec] over a lesion (or some other structure to be detected) and over a normal region having the same area, respectively, CL and CNbeing the associated count rates, then is regarded as the signal to be detected. Observed values will be distributed about (NL N N )with a standard deviation

-

which is regarded as the noise accompanying this signal. The signalto-noise ratio, SIN, is

Although this quantity can be used directly as a criterion, it is more convenient to introduce the concept of the figure of merit, Q, defined by

where cis the average count rate over these regions, and the last quantity in parentheses is a measure of image contrast. Thus, Q is a measure of the value of (SIN)' that can be achieved per unit of measurement time. The quantity

can be thought of as an index of confidence for lesion detection that can be achieved in T[sec]. Equation (9) depends upon characteristics of the object and the imaging system. These include: the concentration of activity and photon energy of the radionuclide in the lesion and surrounding tissues; the size, shape, and location of the lesion within the body and the relevant attenuation factors; and the sensitivity and spatial resolution of the instrument. In principle, Equation (9) can be applied to any object and imaging system. Analysis of this expression into separate factors for the object and imaging system is simplified by considering a sinusoidal object in a uniform sea of radioactivity. If CLand CNare interpreted as the maximum and minimum count rates registered by an instrument in response to this sinusoidal distribution, then (CL- C N / C I ,+ CN) can be interpreted as the image modulation, nr,or contrast. The quantity €can be interpreted simi-

5.2 ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

larly as the average count rate

/

77

CN and can be expressed as the 2 detector sensitivity to a uniform sheet distribution, SD, times the average effective emission rate of the sinusoid, 5. Similarly, the image contrast or modulation can be expressed as the product of the object contrast or modulation, m,, times the modulation transfer function, MTF, of the imaging system. (The MTF can be thought of as a measure of spatial resolution of the detector system.) Thus, for a sinusoidal object with frequency v cycles per cm cL

+

In order to consider the properties of the object and imaging system separately, the terms in Equation (12) may be arranged as follows: Q(v) = 25(m,(v))' x S ~ ( M T F ( V ) ) ~

(13)

Q(v) = 2Qo(v) x Q D ( ~ ) .

(14)

Here, Q, can be thought of as the effective detectability of the object structure, which is proportional to the average intensity, 6, and to the square of the object modulation contrast, m,(v); and similarly, QDcan be thought of as the detector figure-of-merit (FOM), which is proportional to sensitivity, So, and to the square of the detector modulation transfer function, MTF(v) (Beck et al., 1973b). In addition to these considerations, the absorbed radiation dose should also be taken into account. Thus, Q / D or the FOM normalized for the absorbed dose, D, can also be calculated in comparing two radiopharmaceuticals. In order to use this formulation, the quantities that must be measured are the line spread function, effective object modulation, biological distribution with time, and organ counts per minute per cm2 per injected mCi. Each of these measurements is sensitive to operational decisions concerning how the instrument is used, e.g., the pulse height analyzer window setting and the collimator used. These quantities relating to the object and detector can be measured or calculated approximately to determine Q(v). For a more complete discussion of one approach, see Lathrop et al. (1970). (b) Examples (i) Evaluation of radiopharmaceuticals. Radiopharmaceuticals that are to be used in uivo for diagnostic purposes should maximize

78

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

the number of detected photons for a given (acceptable) absorbed radiation dose to the patient. For example, the important variables in tumor localization studies are: the amount of activity in the lesion; the amount of activity in the tissue surrounding the lesion; the absorbed dose to target organs, including the source organ, from the radioactivity in those organs; the energy of the penetrating and non-penetrating radiations; and the effective accumulated activity in the organ (with attention to the biologic distribution and time course as well as the physical half-life). In such cases, three factors are of major importance: the difference in activity between the lesion and its background (proportional to contrast); the amount of activity in the lesion and its background (the statistical factor); and the energy of the photopeak as a determinant of the measured contrast from lesions at different depths. A practical example is provided in Table 10. TABLE 10-Parameters used for a comparison of the relative merits ofgold-198 colloid with indium-ll3m hydroxide and technetium-99m sulfur colloid for the detection of liver lesions (disease)

!:'"In

-"rc

393 0.67

140 0.92

6h 0.08

I

ImAu

Parameter

E, (keV) Abundance (photons/decay)

412 0.96

%ye4

2.7d

1.7h

ZA@, (g-rad/pCi-h)

0.83

0.45

From the physical half-life (TphySical, assumed to equal the effective haif-life since the biological retention is very long) and the integral absorbed dose per unit time (g-rad/pCi-h) for a 1500 gram liver, the administered dose to provide an absorbed dose of 1 rad can be calculated 1500

For lg8Au: 1.44 X 2.7

X

24 X 0.83

=

19.4 &i

Assume that the ratio of activity in the normal liver and in the lesion is ten-to-one for all of these agents. Then, by analogy with Equation (9), an intrinsic Figure of Merit can be defined for the radiopharmaceuticals (Q,) which is independent of the geometry of the lesion and surrounding tissues

5.2

ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

/

79

where AN = activity in normal liver (photons per minute per g ) AL = activity in lesion (for these lesions, A,/AL = 10) Qpld =

radiopharmaceutical Figure of Merit per unit absorbed dose.

For l9'A~:AN =

19.4 X 0.96 X 2.22 X 10' = 2.75 X lo4AL = 0.275 1500

X

lo4

Then,

This difference of more than 100 between gold-198 and technetium99m is due entirely to the fact that 100 times the activity of *"Tc can be administered than of lg8Auwhile providing the same absorbed dose to the critical organ. Some of the advantage for technetium-99m is lost in the detection of deeper lesions because its principal photon energy is low compared with that of lg8Au.For example, at 1 inch, 76 out of 100 "'Au photons reach the surface compared with only 69 out of 100 from 99"'Tc;whereas a t 3 inches, 44 out of 100 IwAu photons reach the surface and only 32 out of 100 -Tc do. In the calculation of the intrinsic Q,, the size, shape, and location of the lesion and the consequent effects of attenuation have not been taken into account. When this is done (Beck, 1961), the effective object figure of merit (Q,) can be expressed approximately as:

where a~ is the effective sheet distribution of activity over the lesion when attenuation is taken into account, while a~ is the corresponding value over the normal tissue. Here it is assumed that the lesion is large

r

5

$ c

TABLE11-Figures of Merit (FOM) for one-inch thick lesions* containing '*ALC.''-In, or *Tc located in a 1500g liuerphantom, 8 inches thick and with a lesion-to-surroundingactivity ratio of one to ten. Overall FOM

Effective FOM

Intrinsic FOM

'"Au

2

l lJmxn

98

-"I'c

2 16

Pp,d (photons x lo-')

g-rad-rnin

Surface

1 inch

3 inch

0.58 29 72

0.46

0.17 7.7 12

23 51

5

3

Qold y o X 10 crnz-rad-min

5 Inch Scanner

Scintillation Camera

Surface

l

inch

3 inch

Surface

l inch

3 inch

0.92 71 540

0.22 17 172

0.11 8 42

0.32 25

0.12 10 16

0.07

Qo

x Q,I photons

Q1d 6 T

The area of one lesion is assumed to be large enough to cover uniformly the sampled image area.

27

(=)

6 2

2 ?!

8 Z

C C)

c g

8

5.2 ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

/

81

enough to cover the full width of the detector point spread function uniformly. These effective Figures of Merit are given in Table 11 for a lesion located at the surface and at 1 inch (2.5 cm) and 3 inches (7.5 cm) in an organ 8 inches (20.3 cm) thick. Based upon the Figure of Merit calculations, the favored radiopharmaceutical for the detection of a liver metastasis would be a technetium colloid. The near-infinite biologic half-time in the liver of radiocolloids simplifies this choice. Where different rates of excretion occur in normal and diseased subjects, biological factors must be considered along with physical and statistical factors (see Section 2).

(ii) Evaluation of instruments. Thus far only the intrinsic and effective object properties have been discussed as they relate approximately to the first term of Equation (14). In order to evaluate the entire procedure, the second term, which incorporates the sensitivity and resolution of the detector system, must also be determined (MacIntyre et al., 1969). In Table 11, the Figures of Merit for gold colloid, indium hydroxide, and technetium sulfur colloid are presented for a liver lesion at different depths for an Anger scintillation camera or a 5-inch rectilinear scanner. These results are displayed pictorially in Figure 10, which shows a liver phantom with seven circular cold lesions surrounded by differing amounts of -Tc, 'ln"In, and ISsAu.The amounts of radioactivity used provide the same absorbed dose (1rad) and the phantom is viewed by an Anger camera for the same period of time. It is instructive to examine the source of the differences between the three agents and the two instruments. First, the advantage of the technetium sulfur colloid versus the indium and gold colloid derives not from a more favorable target-to-nontarget distribution; indeed, the target-to-nontarget distribution of the sulfur colloid can even be less favorable than that for gold colloid. Rather, the ""Tc yields a greater number of counts over the normal liver than does ISsAu per unit of absorbed dose. Second, with regard to the Anger scintillation camera, the thin crystal of the camera is more efficient for the 140 keV gamma rays of -Tc than for the 391 keV gamma rays of Il3"In or the 412 keV gamma rays of IgeAu.The energy resolution for the lgeAuand the 'IhIn gamma rays permits a better separation of scattered and unscattered photons than for -Tc. However, this effect is offset in part by the improved collimation that can be achieved for the 140 keV photons due to decreased septa1 penetration and increased sensitivity. Thus, the first step in the evaluation of a new in vivo procedure for the location of disease can be taken with ~ o ~ d e n given c e knowledge of the physical characteristics of the emitter, the biologic distribution,

82

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

Fig. 10. Liver phantom containing 3.5 mCi ""'Tc, 2.2 mCi """In, and 31 pCi IwAu calculated to produce 1 rad of absorbed dose. The exposure time was 70 seconds for each; the cathode ray tube was adjusted to provide images of equal intensity.

5.2 ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

/

83

the residence time of the radiopharmaceutical, and the characteristics of the detector system to be employed. This formulation, based primarily on physical and biological factors, does not take into account the quantitative visual response of a human observer. The implications for observer performance are not evident and must be validated empirically. It has been shown that the simple lesion detectability index (QT) derived above is consistent with observed data. This simple model predicts that the threshold for detectable contrast should be inversely proportional to the lesion diameter, w, and the square root of the count density, L5 This prediction has been tested empirically with computer generated images and trained observers (Schulz et al., 1971; Schulz et al., 1973) and good agreement has been found, particularly at low count density and with small lesions. There are several factors that limit image quality. These include: (i) Noise: due to random fluctuations in the number of y rays recorded per unit area a t each point in the image. Noise can be reduced by increasing the examination time, the injected dose, or the detector sensitivity. (ii) Reduction of image contrast: due to collimator septum penetration and scattering within the patient as well as "background" counts %n

page 76, it was shown that:

where T = the total observation time, and = the average number of counts. From this it is pa~sibleto determine the associated threshold of detectable contrast. For low contrast lesions NL = NN,then

Assume that there is a threshold of detectable contrast- NL - NN for which QT is greater NN than some value ( Q T ) T ~ Rearranging . Equation (18)gives

For a lesion with diameter, w, the average count density, ii, can be expressed as ri = 41J 7 Substituting in Equation (19)

nw

84

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

from the detector. These effects can be reduced by increasing septa1 thickness, improving the energy resolution of the detector, and irnproving shielding. (iii) Blur distortion (smoothing): due to the imperfect spatial resolution of the imaging device for properly collimated y rays. Such distortion can be reduced by decreasing the width of the geometrical point spread function of the collimator. In the case of positron (P') emitters, additional blur distortion is due to the finite range of the P+ particle prior to annihilation and to deviations from the 180' angle of emission of the two 511 keV annihilation photons. (iv) Non-linear distortion: due to the use of non-linear components in the imaging system. For example, a scanner detector or other component with excessive dead-time results in a non-linear response. Similarly, film, as a recording medium, is non-linear. (v) Artifacts: structures due to characteristics of the imaging mode and device; e.g., non-uniformity of sensitivity, scan line structure, spot structure, scalloping. (vi) Interference: due to normal structures whose images may affect the detectability or perceptibility of abnormal structures of interest. In some cases, interference can be reduced by tomographic imaging, i.e., by reducing the depth of field and thus blurring the contribution from surrounding structures and by use of computer reconstruction algorithms (Chang et al., 1976). (vii) Attenuation distortion: due to the increase of y-ray absorption with depth and especially prominent with low energy photons. The use of coincidence imaging with P+ emitters permits correction for this phenomenon. Other methods have been developed for single photon emitters (Budinger et nl., 1977). The first and least demanding task for an observer using an imaging system is lesion detection. The more complex task, recognition of the object as belonging to a specific class, is more demanding. In brain imaging, for example, the ability to differentiate between tumors and cerebral vascular accidents involves recognition of characteristic differences in the normal and abnormal structures in the images. Further information is required for classification as to the type of the lesion; for example, meningioma vs. low grade glioma, hemorrhagic vs. ischemic infarct, or vessels involved. As the detection systems used in nuclear medicine have improved, the ability to specify lesion characteristics has also increased, and extensions of the models to include these additional observer tasks is needed. At present, it seems reasonable to utilize models for threshold detection of simple objects (Tsui et al., 1977) and for recognition of different simple shapes (Tsui et al., 1978).

5.2 ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

/

85

Threshold detection models can also be applied to dynamic imaging studies, such as myocardial infarct detection. Such analyses could be useful in assessing the added benefit derived from image gating. The same concepts are applicable to wall motion studies to determine the minimum displacement of the wall that could be assessed with a given combination of nuclides and detectors. When physiological parameters are extracted from dynamic studies that characterize the metabolic or physical properties of the system, classical statistical tests can be employed. These have the advantage of being less dependent on observer subjectivity, training, and experience than imaging studies, and the derived parameters can be utilized explicitly in diagnostic and therapeutic decision models.

5.2.2

Evaluation of Non-Imaging Procedures

For uptake and whole body counting studies, the comparison of the relative merits of different agents can be based on the number of detected photons per unit absorbed dose to the critical organ (or whole body, whichever is greater). For example, when one compares iodine131 (T, = 8 d ) with iodine-123 (T, = 13h) for thyroid uptake measurements, an increased photon yield of 120 to l per rad absorbed dose is obtained by using '=I rather than 13'I. Ten microcuries of iodine-123 will give the thyroid an absorbed radiation dose of 75 mrad while ten microcuries of iodine-131 will give a thyroid dose of about 15,000 mrad. However, some of the '=I dose advantage is lost when, in practice, a 100 pCi dose of '=I is administered. 5.2.3

Evaluation of Therapy Procedures

Different considerations are employed when radionuclides are used as therapeutic agents. Here, the most important variables are: the uptake in the target tissues relative to other tissues;"he distribution of radioactivity within the normal tissue relative to the tissue that is to be irradiated; the dose delivered to radiosensitive organs and tissues from the high concentration of radioactivity in the target organ under treatment. The ideal radiotherapeutic drug product would accumulate in high activity in all target cells to be irradiated; for cancers, its " T h e activities to be achieved depend in great measure on the nature of the radiobiologic effect sought and the degree of control expected (see Section 4.2); it is important to note that much higher lesion-to-background ratios are required for therapy than for diagnostic localization studies.

86

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

particulate radiation would have a mean path length equal to a tumor cell diameter. This desideratum has not yet been achieved by any known radiotherapeutic drug product, but is a standard against which new radiotherapeutic drug products can be compared. 5.2.4

A Posteriori Measures

Although considerable emphasis has been placed on prospective evaluation techniques, it is important to recognize that simple criteria such as the Figure of Merit discussed above cannot necessarily predict whether the implied advantages of a given procedure will be translated into increased diagnostic accuracy over one that it has supplanted. Such analyses can determine whether there is an inherent advantage or disadvantage over prior procedures (or none at all) but not whether this advantage will result in increased diagnostic efficiency as opposed to other gains such as reduction in absorbed radiation dose or time for the examination. Thus, it is important to use clinical experience to determine the practical consequences of a technical change in instrumentation or radiopharmaceutical drug products. It is certainly essential to identify an increase or decrease in diagnostic accuracy and its magnitude. In general, image interpretation can be divided into visual detection and recognition. Visual detection is concerned with whether an abnormality is present or absent; recognition refers to the test's ability to provide the observer with sufficient information to permit characterization and identification. For example, visual detection in the case of liver scanning may permit one to conclude that the liver is normal or abnormal; characterization sorts the abnormalities as focal or diffuse. The identification of focal lesions would categorize them as tumor, abscess, cyst, etc. Because the results of many nuclear medical tests can be expressed in binary terms: normal vs. abnormal, cancer vs. not cancer, one method of sorting the results is in terms of a decision matrix (McNeil et al., 1975b). The decision matrix relates results of a diagnostic test with a binary outcome (normal, abnormal) to clinical or pathologic findings, also with a binary outcome (disease, no disease). The following ratios can be derived from this approach: (1) The true positive (TP) ratio is the proportion of positive tests in all patients with disease and is called the sensitivity of the test. (2) The false positive (FP) ratio is the proportion of positive tests in all patients without disease. (3) The true negative (TN) ratio is the proportion of negative tests in all patients without disease and is called the specificity of the test.

/

5.2 ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

87

(4) The false negative (FN) ratio is the proportion of negative tests in all patients with disease. (5) The ratio of correct outcomes to all outcomes is often called the accuracy of the test. Table 12 shows the decision matrix for hepatic scintigraphy with technetium sulfur colloid and an Anger scintillation camera in 344 patients whose livers were examined by biopsy and autopsy. The T P ratio or sensitivity of the test is 0.90 while its TN ratio or specificity is 231 + 54 = 0.83. The probabilities of the four 0.63. The accuracy is 344 outcomes are not independent and in fact TP+FN=landTN+FP=l Thus, the results of the matrix can be expressed in terms of two entities only, e.g., T P and T N or FP and FN; alternatively, T P and FP or T N and FN. TABLE12-Decision matrix for hepatic scintigraphy Histologic Findin~s Disease Disease Present Absent lD+) fD-)

Abnormal (T+)

231

32

Normal (T-) Total

27 258

54 86

Scintigraphic results

231 True positive (TP) = - = 0.90 258 27 False negative (FN) = -= 0.10 258 32 False positive (FP) = - = 0.37 86 54 True negative (TN) = - = 0.63 86

Since practically all tests have a continuum of values, any one of which can be selected as the boundary between normal and abnormal, the true and false positive ratios vary with the value selected as the cutoff point. Similarly, in visual detection, such as scintigraphic interpretation in which the observer is required to make his decision a t varying thresholds, i.e., strict or lax, the true and false positive ratios will vary with the threshold selected. The continuum of values for normal and abnormal populations with a certain degree of overlap is shown in Figure 11. The TN, TP, FN, and FP components are labeled

88

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

NORMAL POPU1,A'I'l ON

CKI'I'ERION A X : S

Fig. 11. Frequency distribution of test results in two populations - one normal and the other diseased. The areas of overlap represent false negative (a)and false positive (/3) results; the relative proportion of each is determined by the value of X.

in the figure. These curves may be interpreted as two hypothetical distribution functions that result from a diagnostic test. For gaussian distributions, the difference in mean values between the two populations is represented by d'. An improved test increases the value of d', which can be expressed as the number of standard deviations separating the mean values. (For non-gaussian distributions, the interpretation of d' is not simple) (Goodenough et al., 1973). The cutoff point, X,, along the criterion axis determines the relative proportion between the false negative and false positive results; the farther X, is to the left, the smaller the proportion of FN and the greater the FP. As X, moves to the right, FN increases and FP decreases. The complementary relationship between FN and FP can be portrayed graphically by plotting T P = 1- FN vs. FP (Figure 12). In this figure, Curve A is the expected observer performance when the normal and abnormal distribution are identical. In this case, observer performance is based purely on chance. Curve B represents the expected observer performance for the distributions shown in Figure 11. Curve C represents the expected observer performance when the normal and abnormal distributions are more completely separated because of

5.2 ROLE OF NEW NUCLEAR MEDICAL PROCEDURES

/

89

Fig. 12. Receiver operating characteristic curves.

greater separation of mean values or smaller standard deviation. Curves B and C could be thought of as representing two tests, where the procedure generating Curve C is superior to the one generating Curve B. By using terminology current in signal detection theory, such curves are called receiver operating characteristic (ROC) curves (Swets et al., 1979). Alternatively, ROC Curves C and B might depict the performance of a skilled and unskilled observer, respectively, interpreting the same evidence. For any value of TP, the corresponding value of FP is larger for Curve B than for Curve C. In the case of hepatic scintigraphy, for example, all combinations of instruments and radiopharmaceutical drug products have a false positive rate of about 35 percent when the true positive rate (sensitivity) is 90-95 percent (Drum and Christacopoulos, 1972). The high false positive rate is only reduced at the expense of the true positive rate. Thus, the improvements in liver scanning that have taken place over the past decade and that are reflected in the Figures of Merit (see Section 5.2.1) have not been realized as increased diagnostic accuracy with the possible exception of metastatic colon cancer (Drum and Beard, 1976), but rather in lower radiation dose, shorter examination times, and perhaps a better classification of disease.

90

/

5.3

5. EVALUATION OF RADIONUCLIDE PROCEDURES

Measuring t h e Clinical Efficacy of Nuclear Medicine Procedures

In the case of patients who are to receive radionuclides for diagnostic or therapeutic purposes, it is particularly difficult to measure the benefits from individual clinical procedures. Medical practitioners have a large number of complex new diagnostic and therapeutic techniques available to them. The constellation of procedures that may be utilized in an average hospitalization makes it difficult to isolate the precise value of individual tests (Patton, 1978).Nonetheless, in this section we shall try to provide some guidelines for determining these values. Questions about the efficacy of a diagnostic test are generally asked at two levels: (1) Does it lead to new information about the patient and his condition so as to reduce the uncertainty with which a physician can state that he has or does not have a certain disease or extent of disease; and (2) Does use of the test ultimately save lives, restore health, and/or alleviate suffering? In general, the first question is more quickly and easily answered than is the second, but if answers to the second can be obtained, then a more definitive statement about the utility of a test can be made. In the following paragraphs, some examples will be given of both types.

5.3.1 A Nuclear Medicine Test Provides New Information About A Patient by Changing the Probability That He Is Diagnosed As Having or Not Having A Disease By using the decision matrix for hepatic scintigraphy given in Section 5.2.3, we can ask to what extent does a positive or negative liver scan change the probability that a patient is diagnosed as having or not having liver disease? To answer that question, we need to know the a prwri probability of liver disease in a given population and how the probability for the patient changes as a result of testing. The 344 patients included in the decision matrix given as Table 12 came from a larger population of 650 referred to a nuclear medicine clinic whose outcomes were determined by short- and long-term follow-up (Drum and Christacopoulos, 1972). The prevalence of liver disease in this group of patients was 66 percent and thus the prior probability of having disease, P ( D +), was 0.66;of not having disease, P(D-1, it was 0.34. From these prior probabilities plus the true positive, false positive, true negative, and false negative ratios derived from the decision matrix, the probability of having liver disease after a positive or negative scan can be calculated by using Bayes' theorem: a positive

5.3 CLINICAL EFFICACY OF NUCLEAR MEDICINE

/

91

scan increases the probability that such a patient has liver disease from 0.66 to 0.83, while a negative scan decreases it from 0.66 to 0.24' (McNeil and Adelstein, 1976). In this instance, and because the prevalence of liver disease is so high, the diagnostic test is particularly informative when it is negative and greatly reduces the uncertainty as to whether the patient has liver disease. 5.3.2

Introduction of A Test Improves Diagnostic Accuracy: Sensitivity And/or Specificity

Approximately 25 percent of patients under 40 who complain of acute pleuritic chest pain severe enough to seek medical attention have pulmonary embolism (McNeil et al., 1976). It can be shown by using an ROC analysis of clinical manifestations and laboratory tests that the lung scan can be very helpful in identifying those patients. For example, if the clinical and radiological criteria for diagnosis are fairly lax, 95 percent of patients with pulmonary embolism can be identified (i.e., TP = 0.95) but the false positive rate is 40 percent. If the lung scan is employed in this group of patients, the false positive rate drops to 5 percent (increase in specificity). If the lung scan is used in all patients with pleuritic chest pain, the TP rate increases to nearly 100 percent (increase in sensitivity); in this case, the false positive rate is 15 percent (see Figure 13). 5.3.3

The Introduction ofA Test Leads to A Reduction in Morbidity

At the time when the radioassay for digoxin was being developed, the incidence of digitalis toxicity was compared in two Boston hospitals in one of which the assay was available daily. In the hospital with the 'To calculate the posterior probabilities that, given a positive or negative test (T+ or T-),the patient has disease (D+), we use the following formulae:

92

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES 1.0

X-Ray-Effusion

L Y

.6

L Hx1-Postop Y

3

L C

.4

A

No Scan Scan

* Scan all

patients

FALSE POSITIVE RATIO

Fig. 13. Effect of lung scan on diagnostic performance; While sensitivity is increased, the major effect is increased specificity (McNeil et al., 1976).

assay, the incidence of digoxin toxicity was 4 percent of 291 patients; in the hospital without the assay, it was 10 percent of 272 patients (Duhme et al., 1974). 5.3.4

Survival Is Not Affected By the Introduction of A Nuclear Medicine Test

The outcomes in patients with primary and secondary brain tumors were studied over the decade 1962-1972, which saw the introduction and increased use of brain scanning (George and Wagner, 1975). In this same interval, there was a reduction in the duration of time between the onset of symptoms and the time of brain surgery from four years to one year. In spite of this, the percentage of patients surviving 50 months after surgery was relatively constant during this study. This is not to say that the brain scan did not provide new information during the diagnostic study; indeed, the shortened time

5.4 FINANCIAL COSTS AND COST EFFECTIVENESS

/

93

interval between the onset of symptoms and surgical operation was probably directly attributable to brain scanning and other neuroradiological procedures. However, this information was not translatable into increased survival. Indeed, the shortened interval between .onset of symptoms and surgery, coupled with a constant post-surgical survival time, actually decreased overall survival time. Improvements in therapy in this area will be required before advances in diagnosis can be used to advantage. On the other hand, the negative brain scan serves a prognostic purpose that can be of comfort to the patient and his physician. It strikingly reduces the probability that a patient with neurological symptoms has a brain tumor and thus increases the certainty that he has non-malignant disease. In the first two examples, questions about the information content of new tests were discussed. In the second two, questions about their utility were discussed. In the last example, the test provided new information that unfortunately could not be translated into increased survival. It should not be concluded from this shortcoming that a better test or even a perfect test (TP = 1, FP = 0) would improve the outcome. In many instances, the shortcoming is in the natural history of disease or of its therapy rather than in its diagnostic aspects. Sometimes it is informative to determine, in advance, what the impact of diagnostic improvement will be on the clinical outcome. For example, the detection of distant metastatic disease would be useful in sparing patients with inoperable lung cancer the morbidity and prolonged hospitalization associated with thoracic surgery, but a considerable improvement in the accuracy of current procedures will be required to attain this objective (McNeil et al., 1977). 5.4

Financial Costs and Cost Effectiveness

When two procedures of essentially the same sensitivity and specificity exist, the choice between them often rests on economic considerations. In addition, when diagnostic procedures are used as screening tests in large populations, their cost effectiveness in terms of the funds available must be taken into consideration. In considering the monetary aspects of the diagnostic process, the financial value of a test lies in its ability, if truly negative, to eliminate costs associated with unnecessary additional diagnostic procedures and therapeutic regimens and, if truly positive, to eliminate financial costs caused by the progression of untreated disease. These benefits are difficult to measure directly. Therefore, three other financial measures are frequently used in evaluating diagnostic tests: (1) the

94

/

5. EVALUATION OF RADIONUCLIDE PROCEDURES

average cost of achieving a given outcome (e.g., case finding, life saving); (2) the total cost of diagnosis and therapy once the test is introduced; and (3) the marginal cost of obtaining one additional unit of health by one procedure over another. For example, in the screening of hypertensives for renovascular disease, the cost of finding a patient with renovascular hypertension is about $2000 (McNeil et al., 1975a). The cost per cure is about $20,000 for a case finding rate of 80 to 90 percent. Increasing the case finding rate to nearly 100 percent raises the cost per cure to $50,000. Moreover, the total cost of screening and surgically treating the entire hypertensive American population (about 25 million persons) could be 10 billion dollars or 10 percent of the monies allocated to health care in the United States each year. Thus, society will need to decide how much it is willing and able to pay for health care and how much will be allocated to the different health care areas. Methods for measuring the efficacy, utility, cost/benefit ratios, and cost/effectiveness of nuclear medicine procedures are in an early state of development. Such analyses need to take into account the relative advantages, limitations, and costs of alternative procedures, patients' appreciation of the value and quality of life, and other factors for which there are no simple measures. As more sophisticated methods become available, it is important that those concerned with health care delivery, including the administration of radionuclides, be aware of them.

5.5

Summary

In this section some approaches to the evaluation of procedures employing radionuclides have been presented. For prospective analysis, some critical factors have been identified that are useful in determining whether a new procedure is likely to improve on an already existing one. These factors are particularly well defined for radiopharmaceutical drug products and instruments employed in organ imaging. In addition, one approach is presented for determining the diagnostic efficacy and clinical utility of radionuclide imaging procedures. In this instance, two questions are addressed Fiist, does the test provide new clinical infonnation; and second, does the new information help the physician in caring for his patient? Several examples are given to demonstrate how these questions may be answered in practical circumstances. I t is expected that, as other analytic techniques are developed, more precise methods will be available to answer these questions.

6. Guidelines for Performing

Nuclear Medicine Procedures The decision to administer radionuclides for diagnostic or therapeutic purposes is made by the physician and is based on the patient's condition and the expected benefits and risks of this action weighed against available alternatives. Once this decision is made, the next question is how to conduct the procedures so as to maximize patient benefits while concurrently minimizing patient risks. The relevant factors influencing this decision are presented below and the recommendations for the use of radiopharmaceutical drug products in man are summarized.

6.1

Basic Principles

The amount of radioactivity used for therapy should be adjusted so that the desired effect is achieved while assuring an acceptably low incidence of the side effects that necessarily accompany successful radiotherapy. The amount of radiation used in diagnosis should be the minimum consistent with obtaining information adequate for the diagnosis or investigation planned. Factors that influence the information content and radiation dose have been discussed above. These include the radionuclide (amount administered, half-life, and decay scheme), biological distribution and metabolism of the radiopharmaceutical drug product, and the instrument used for its measurement. The optimal combination should be sought among the available options, given the particular patient circumstances and the other diagnostic tests available.

6.2 Categories of Subjects When radioactive materials are employed in a medical installation, four categories of individuals may be exposed to ionizing radiation: patients receiving radionuclides for diagnostic or therapeutic purposes 95

96

/

6. GUIDELINES FOR NUCLEAR MEDICINE PROCEDURES

(NCRP, 1970); volunteer subjects receiving radionuclides for investigational purposes (NCRP, 1971); hospital personnel working with radioactive materials (NCRP, 1976);and persons exposed to radiation by being close to patients containing radionuclides (NCRP, 1970; ICRP, 1971). Recommendations for handling of the two last categories are contained in NCRP Report No. 39, paragraphs 267 and 268, and are paraphrased here. In all groups but the first, there are no necessary health benefits associated with their radiation exposure. Although it is difficult at present to assign quantitative values to costs and benefits, it is useful to identify them for each particular category. In the case of hospital personnel working with radioactive materials, the benefits are the intangible ones that accrue by contributing to the public's health and the pursuit of their occupations. The limits to their exposure are prescribed in NCRP Reports Nos. 39 and 48 (NCRP, 1971, 1976). Volunteers who accept radiation exposure for investigational purposes generally do so for the satisfaction associatedwith other altruistic acts, such as joining the Peace Corps, in spite of associated hazards. In this light, it is essential that volunteers should understand the nature of the study and the best estimates of the risks involved. I t is implicit that there be no coercion to their participation and that it be in accord with the institutional and federal regulations concerning human investigation and informed consent (CFR, 1981a). See 6.2.2. For further discussion of this subject, see paragraphs 270-273 of Report No. 39 (NCRP, 1971) and ICRP Publication 17 (ICRP, 1971).New regulations, pertaining to informed consent, became effective 27 July 1981 and are promulgated in 46 FR 8942 (Federal Register, 1981). 6.2.1

Patients Receiving Radwnuclides for Diagnostic Purposes

(a.) Adult Patients. Experience has shown that most diagnostic tests can be carried out successfully with amounts of radioactivity that give rise in adult patients to organ doses of about 1 rad, and usually not greater than 5 rads, per investigation. However, the value of the test to the patient's well-being and/or the seriousness of the disease being investigated may often outweigh possible long-term radiological hazards. In the latter cases, a higher administered activity may be acceptable (NCRP, 1971). (b.) Pregnant Women. Investigations carried out on pregnant women often involve radiation doses to both the mother and the fetus. Con-

6.2 CATEGORIES OF SUBJECTS

/

97

sideration must be given to the amount of radiation as well as the quantity of radioactivity transmitted across the placenta and to the resulting exposure to the fetus. In view of the findings summarized in NCRP Reports Nos. 39 and 55 (NCRP, 1971,1977)relating to radiation protection of the fetus and the fact that radiation doses of the order of a few rads may be associated with an increased incidence of leukemia and childhood malignancies, it is important to keep the fetal doses below these levels and to carry out only investigations that are imperative during pregnancy. (c.) Child Patients. The activities to be administered may be calculated approximately by adjusting the activity given to adults on a weight or body surface area basis so that the normalized activity administered is comparable. In general, the doses to the organs should be of the same order as or if possible less than those received by adults during the same procedure to hold to a minimum the hazard of somatic effects of ionizing radiation. Particular care is required to ensure that the radiation doses received by the gonads are as low as possible in view of the possibility of damaging the genetic material in the germinal epithelium of children. More specific guidance will be presented in a forthcoming NCRP report on pediatric nuclear medicine. 6.2.2

Volunteer Subjects Receiving Radionuclides for Investigative Purposes

The evaluation and testing of new radiopharmaceutical drug products and procedures necessarily initially involve basic studies that establish the feasibility and safety of a procedure. The next step is to conduct studies in a few patients with the pathologic condition(s) that the test is designed to evaluate, together with subjects without that condition. These preliminary investigations should be carried out under the supervision of a Radioactive Drug Research Committee at major medical centers. Subjects who participate in these studies must be volunteers from whom suitable informed consent has been obtained. The purposes, exact nature, and possible hazards of the investigation must be explained to these volunteers and the investigations should be carried out with the minimum radiation exposure consistent with obtaining the required information. Regulations concerning the use of human subjects in federally-sponsored research, together with the institutional responsibility regarding informed consent and surveillance of human research, are described in the Code of Federal Regulations, Title 21, Part 361 (CFR, 1981a). Appropriate local review of

98

/

6. GUIDELINES FOR NUCLEAR MEDICINE PROCEDURES

proposed studies must be relied upon for judgment and approval, as is the case for all investigational procedures in all patient categories. New regulations effective 27. July, 1981 are promulgated in 46 FR 8942 (Federal Register 1981). A further requirement for the interpretation of all clinical investigations designed to detect abnormality is that measurements be obtained in subject. who are known to be normal in the relevant respect. This procedure establishes the normal ranges for test results. This requirement is equally true for investigations involving radionuclides; and hence, there is a need for investigations involving matched control individuals who may not themselves benefit from the investigation. For investigations where the range of values within the normals is small, these volunteer groups can ordinarily be limited in number. The source of such control groups may be individuals seeking medical attention for other purposes, but if so, care must be taken that they are normal in regard to the particular procedure that is under investigation and that they are not pregnant. Control subjects may be relatives of the patient or members of the general public. There should be reluctance to use members of the staff or related groups such as medical students, since they may feel under some obligation to volunteer and also because they are likely to be used in this capacity by other investigators without regard to the total radiation dose received. (a) Adult Normal Volunteers. The same guidelines apply as for adult patients studied with well established agents and new procedures. There are limits placed on radiation dose applied to individuals receiving drugs for research purposes. They are, as stated in Part 361 of Title 21 (CFR, 1981a),for exposure to the whole body, active blood-forming organs, lens of the eye, and gonads-3 rems per year for a single dose and 5 rems per year for an annual and total dose commitment; and for other organs, 5 rems and 15 rems respectively for single dose and annual and total dose commitment. For research subjects under 18 years of age, the radiation dose shall not exceed 10 percent of these limits. (b) Child Normal Volunteers. Children are presumed to be intermediate in radiosensitivity between the fetus and the adult. Thus, guidelines for acceptable dose must take this into account. An additional problem is encountered with children regarding informed consent. ICRP Publication 17 (1971) states that "studies of children or persons regarded as incapable of giving their true consent should only be

6.4

RADIATION PROTECTION GUIDES

/

99

undertaken if the expected radiation dose is low (e.g., of the order of magnitude of one year's exposure from natural radiation, i.e., approximately 100 mrad) and if valid approval has been given by those legally responsible for such persons."

6.3 6.3.1

Methods of Patient Dose Reduction

Routine Practices

The radioactive compound with optimal radiological and biological properties should be used for each study, the radioactive half-life of the tracer should approximately equal the time interval between injection and completion of the study, and the measurement instrument should have the sensitivity and resolution appropriate to the diagnostic problem. The time used for the study represents a compromise between the time available, based largely on patient condition, and unusual factors relating to the amount of tracer that can be administered. Excretion of the tracer should be promoted when the study is completed or when retention, such as in the urinary bladder, is not a desired part of the study. The preceding sections of this report provide information designed to help the physician make these decisions.

6.3.2 Misadministrations (See Section 2.9)

6.4 Radiation Protection Guides NCRP recommendations concerning the use of diagnostic and therapeutic radiations in medicine are directed mainly toward the reduction of nonproductive exposures. As stated in NCRP Report No. 39 (paragraph 34),the amount of ionizing radiation given to a patient as a portion of a medical procedure is pertinent to the individual but is not limitable in the sense that occupational exposures are limited. Medical exposures depend on the needs of the individual's health problem. Various NCRP recommendations, however, are issued in an attempt to reduce that part of the exposure that does not contribute to the efficiency of treatment or diagnosis. "In the judgment of the NCRP, there can be no rational means to regulate uniformly or to

100

/

6.

GUIDELINES FOR NUCLEAR MEDICINE PROCEDURES

limit radiation exposure prescribed for patients for necessary and proper diagnostic or therapeutic purposes. On the other hand, steps can be taken to minimize unnecessary or medically unproductive radiation exposure." A number of NCRP Committees have been established, composed of experts in various disciplines related to nuclear medicine. The following recent publications from these committees provide information of importance to nuclear medicine practitioners and related personnel. Report No.

Title Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Basic Radiation Protection Criteria (1971) Review of the Current State of Radiation Protection Philosophy (1975) Radiation Protection for Medical and Allied Health Personnel (1976) Review of NCRP Radiation Dose Limit for Embryo and Fetus in Occupationally Exposed Women (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977) Protection of the Thyroid Gland in the Event of Releases of Radioiodine (1977) Instrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook of Radioactivity Measurements Procedures (1978) Tritium and Other Radionuclide Labeled Organic Compounds Incorporated in Genetic Material (1979) Influence of Dose and Its Distribution in Time on DoseEffect Relationships for Low-LET Radiations (1979) Management of Persons Accidentally Contaminated with Radionuclides (1980) Mammography (1980) Radiation Protection in Pediatric Radiology

In addition, other committees are preparing reports on topics of central importance to nuclear medicine practitioners. These commit-

6.5 COUNCIL RECOMMENDATIONS

/

101

tees include the following: Comm. No.

Title

44

Radiation Associated with Medical Examinations Radiation Protection in Pediatric Nuclear Medicine Priorities for Dose Reduction Efforts Quality Assurance and Accuracy in Radiation Protection Measurements Efficacy Studies Quality Assurance and Measurement in Diagnostic Radiology

51 62 65 69 70

6.5

Recommendations

Nuclear Medicine is a medical specialty in which new procedures, instruments, and radiopharmaceutical drug products are being introduced at a rapid pace. Guidelines are intended to present principles that may be utilized over a long period of time, whereas recommendations need to be updated more frequently. Based on current knowledge (1980), the following recommendations are offered: 6.5.1

General Recommendation

The main principle guiding diagnosis and treatment of patients is that the amount of radioactivity administered should be the minimum consistent with adequate information for the diagnosis or procedure being performed. This consideration will ensure that the minimum radiation dose is delivered to the patient (ICRP, 1971). 6.5.2

Thyroid Uptake of Iodine in Children

For a number of reasons, including the proportionately higher radiation dose to the child's thyroid than to the adult thyroid for the same amount of radioactivity administered, and a possible greater sensitivity of the child's thyroid to the induction of malignancy, I3'I should not be used for routine thyroid function testing, especially in children. In subjects for whom '?I therapy is planned, diagnostic uptake studies with I3'I are useful. Similarly, in children suspected of enzymatic defects in iodine metabolism, or in whom estimates of regional thyroid function are needed, studies of uptake and turnover of radioiodine may be indicated. In such circumstances, the radionuclide of iodine or

102

/

6. GUIDELINES FOR NUCLEAR MEDICINE PROCEDURES

analogs used should give the minimal radiation exposure while providing the needed information. 6.5.3

Radionuclides in Women in Reproductive Years

(a) Diagnostic Studies. Elective procedures, especially those involving radiation doses in excess of 0.5 rad (whole body dose) or with agents having a propensity for localization in the conceptus, e.g., radioiron incorporated in erythropoietic cells of the fetus and colloids that concentrate in reticuloendothelial cells of the placenta, should be avoided whenever possible during pregnancy. See Report No. 39 (paragraphs 265,266) and Report No. 55 (NCRP, 1971, 1977). (b) Therapeutic Procedures. Therapeutic procedures with radiopharmaceutical drug products should be avoided during pregnancy unless abortion of the pregnancy is planned. Based on radiobiological data on genetic effects in mice (Russell, 1965), in order to minimize the possibility of genetic hazards after radiation therapy of non-pregnant females in the child-bearing years, it is prudent that the patient should be advised to postpone possible pregnancies for at least several months to permit repair to such genetic damage as may have occurred. 6.5.4

Use of New Agents

Physicians are encouraged to utilize new radionuclides when they become available which provide improved image quality and result in lower radiation doses or decreased examination time. Old agents that result in higher radiation doses than newer tracers should be replaced by the newer agents as soon as their effectiveness is demonstrated and problems in instrumentation and availability dxe solved. When new tests providing equivalent or superior diagnostic information and lower radiation exposures become available, they should be adopted and the older tests discontinued.

APPENDIX A

GUIDELINES FOR THE CLINICAL EVALUATION OF RADIOPHARMACEUTICAL DRUGS (Prepared by a Subcommittee of the FDA Radiopharmaceutical Drugs Advisory CommitteeLarson, S. M., Siegel, B. A., and Robinson, R. G.) (DHEW, 1977)

I. Introduction "General Considerations for the Clinical Evaluation of Drugs" should be reviewed before reading this guideline. It contains suggestions that are applicable to investigational drug studies for most classes of drugs and helps to eliminate repetitious material in each of the specific guidelines. Investigational studies of radiopharmaceutical drug products (RDPs) should be carefully designed to provide the scientific evidence that will substantiate their safety and efficacy for proposed diagnostic or therapeutic indications. These investigations should be conducted so that safety and efficacy are demonstrated with minimum exposure of patients to unnecessary radiation. Much of the information in these guidelines is applicable to the clinical investigation of both diagnostic and therapeutic RDPs. However, the major emphasis in Sections 1-111is on the requirements for diagnostic RDPs, whereas the information in Section IV considers the special requirements for therapeutic RDPs. The evaluation of diagnostic RDPs will differ from that of most therapeutic drugs in several ways because of certain special-characteristics: 1. Since diagnostic RDPs do not usually elicit a pharmacologic response, evaluation of safety often requires less detailed study of pharmacologic toxicity and is primarily related to adequate estimation of radiation absorbed dose. 2. A diagnostic RDP is considered to be effective if its use results in information leading to a decision concerning the presence or absence of disease or abnormality. It is recognized that with some diagnostic agents it may not be possible to specify the nature of the disease or abnormality. 3. The diagnostic value of a radiopharmaceutical is a function of its 103

biodistribution and the character of the radiations emitted. The degree to which the biodistribution is altered by disease or abnormalities is of particular importance. Thus, the investigation should demonstrate the normal biodistribution, the pathologically altered distribution, and how the altered distribution is determined in patients-e.g., through imaging studies, in vivo uptake studies, or by in vitro tests.

11. Preclinical Studies Sufficient preclinical animal data, manufacturing information, and quality control information to establish reasonable safety must be available before the administration of a RDP to human subjects. Characterization and quantification of the radiochemical and radionuclidic purity of the radiopharmaceutical are important preliminaries to the evaluation of radiation dosimetry in order to determine any trace radiocontarninants (including daughter products) and altered chemical forms that might significantly influence biodistribution and radiation absorbed dose. Preclinical studies will generally include both biodistribution studies and animal toxicity studies. These data may be obtained from experiments performed by the investigator, the published literature, or other valid sources, provided that the sponsor can demonstrate that the data are applicable to the substance under consideration (i.e., dosage form, route of administration, etc.)

A. Radiation Dosimetry

Preclinical (animal) studies are required to determine the biologic distribution, translocation, and the route and extent of excretion of the RDP. This information is essential for meaningful dosimetry calculations. Dosimetry calculations on these animal data should be determined before initiating human studies. In general, it is desirable to assay for the concentration of the RDP a t selected time intervals in all major organs and tissues so that the organs (tissues) receiving the highest radiation absorbed doses can be identified. With a diagnostic RDP used for imaging purposes, the organ (tissue) receiving the highest radiation absorbed dose is often, but not always, the same as the organ (tissue) of primary interest that is to be imaged. For example, in liver imaging with radiocolloids, the liver is generally both the organ

A. GUIDELINES FOR RDP EVALUATION

/

105

receiving the highest radiation absorbed dose and the organ of primary interest, whereas in bone imaging with Tc-99m-labeled phosphate compounds the skeleton is the organ of primary interest, while the bladder is usually the organ receiving the highest absorbed dose.

B. Animal Toxicity Studies I t is recognized that only trace chemical quantities of radionuclides are used in most radiopharmaceutical procedures and that for diagnostic RDPs the absolute amount of the radioactive element generally is well below those levels expected to produce pharmacologic and/or toxic effects. Thus, the chemical toxicity of the other components of the RDP may be of greater importance than the toxicity of the radionuclide itself-e.g., in the case of In- 111-tagged bleomycin, the toxicity of the bleomycin may be more significant than that of the indium. In special circumstances, no animal toxicity studies will be required when the radiopharmaceutical is a tracer quantity of a normal body constituent (e.g., radiosodium). Under these circumstance, it is the responsibility of the sponsor to provide data showing that toxicity studies are not required for the specific formulation to be used clinically. Part of the toxicology testing may be performed using the nonradioactive form of the drug substance if the radiation dose to the test animals interferes with the test results or if such tests create an unnecessary radiation hazard. 1. Acute toxicity testing will generally require studies in a t least two animal species: a. To determine the acute LD5,,of the stable form of the RDP; or b. To demonstrate that no acute toxicity would be expected from doses of the clinical dosage form of the RDP that are several orders of magnitude higher on a dose-per-kilogram basis than those proposed for human use, using the intended clinical route of administration. 2. Subacute toxicity testing (2-3 wk) usually should be performed in two animal species, a rodent and a nonrodent, at several dose levels providing adequate margins of safety relative to the equivalent maximum clinical dose. Where feasible, dosages should be selected so that the highest level can be expected to produce some toxicity and the lowest level can be expected to produce minimal or no toxicity. The clinical dosage form of the radiopharmaceutical should be adminis-

106

/

APPENDIX A

tered daily for 2-3 wk by the route to be employed clinically. Hematologic and biochemical evaluations and gross pathologic and histologic examinations of the organs of primary interest and of the organs receiving the highest radiation absorbed doses should be performed. Some portions of this evaluation may be omitted if factual evidence can be provided to substantiate that it is unnecessary. 3. Chronic toxicity studies are usually not required, since RDPs (especially diagnostic products) are administered only once or infrequently to most patients. 4. Evaluation of carcinogenic potential of the chemical substance is generally not necessary; however, it may be necessary if the parent compound is structurally related to a known carcinogen. 5. Evaluation of ophthalmologic toxicity is generally not required. However, it should be noted that there is increasing concern for possible ophthalmologic toxicity of all drugs. Therefore, during biodistribution studies of a radiopharmaceutical, evaluation of the distribution to the eye may provide useful information concerning potential ophthalmologic toxicity and may serve as a guideline to the necessity for performing additional preclinical and clinical ophthalrnologic toxicity studies. 6. Reproduction-teratology studies are generally not necessary but may be required in some specific instances.

111. Clinical Studies

A. Investigators for studies involving patients should be physicians or clinical pharmacologists qualified by training and experience in the e~~aluation of new RDPs. B. W ~ ~informed X I consent is obtained, a statement that the patient will receive radiation exposure as a part of the study must be included as part of the consent form. C. Phase I Studies* Initial studies in man (Phase I) should demonstrate normal biodistribution, the organs receiving the maximum concentration of the RDP, the clearance halftime, the routes of excretion, and optimum imaging or sampling times. 1. Population. A small number of normal or diseased subjects is usually sufficient; they may be either hospitalized patients or outpatients who can be adequately monitored. The extent of the use of Section 111. D, 2 contains guidelines for Phase I1 and Phase 111 protocols; much of the material therein will apply also to Phase I studies.

A. GUIDELINES FOR RDP EVALUATION

/

107

normal subjects generally should be limited to that number necessary to obtain normal biodistribution and metabolic data. The criteria for determining normality or the presence of a given disease should be established prospectively. Children and pregnant or lactating females are excluded from Phase I. In some cases, patients with selected diseases may be the only appropriate subjects for study in Phase I trials. Diseased patients may also be appropriately studied to evaluate distribution and excretion in those cases in which these parameters are significantly altered by the disease process. (Absorbed radiation may be increased or decreased by changes in distribution and excretion.) 2. Dose. Determination of the optimal dose range for a diagnostic RDP may include the following considerations: a. The radiation absorbed dose should be kept as low as practicable b. An adequate number of usable particles or photons should be available to ensure statistically meaningful images or counting results with the instrumentation likely to be employed clinically. c. Imaging time per view (or sample counting time) must be kept within reasonable limits - e.g., to prevent image degradation due to patient motion. 3. Clinical Laboratory Tests. To permit an initial evaluation of the safety of the radiopharmaceutical, appropriate laboratory tests are needed. Suggested laboratory tests to help define medically significant abnormalities are: hematologic profile (including platelet estimate), BUN (or creatinine), fasting blood sugar (or 2-hr postprandial blood sugar), liver enzymes, bilirubin, and urinalysis. EKG and other tests should be done if appropriate. Such tests should be done both before and after the use of the RDP. 4. Drug Distribution. Data are required on blood clearance, urinary (and, if appropriate, fecal) excretion, and in some cases, the results of dynamic quantitative external organ imaging, to provide a more accurate basis of dosimetry calculations. With radionuclides having a long physical half-life, serial wholebody counting data may be valuable.

D. Phase I1 and Phase I11 Studies 1. General Considerations. Phase 11 studies should be designed to extend the evaluation of the RDP in a limited number of patients to provide further evidence of safety and the initial evidence of diagnostic or therapeutic efficacy.

108

/

APPENDIX A

Phase I11 studies involve the study of sufficient numbers of patients by two or more investigators to establish safety and efficacy and directions for use for the particular dosage form of the RDP for each proposed indication. Phase I11 studies will ordinarily require less extensive laboratory testing than is required in Phase 11. In those cases where crossover studies initially were deemed appropriate, they may be discontinued when the RDP under investigation is shown to be equivalent or superior to established diagnostic procedures. It is important that both the objectives and the study population be carefully defined in advance so that adequately controlled studies are performed. 2. Protocols. All of the following points should be determined and included in the protocol before the study is initiated in order to minimize bias and to promote the acquisition of reliable data which can then be analyzed satisfactorily: a. The objectives should be clearly stated. Example: To demonstrate the safety and efficacy of gallium-67 as an aid in the diagnosis of lymphoma, Hodgkin's disease, and bronchogenic carcinoma. b. Rationale for the study. Example: Gallium-67 has been observed to selectively concentrate in these neoplasms, and thus may offer a suitable noninvasive diagnostic technique. c. The criteria by which efficacy will be evaluated. Example: Comparison with radiographic findings, with other RDPs, etc. d. A clear statement should be made regarding the hypotheses to be tested, the Type I** and Type II** statistical error and the incidence of false-positive and false-negative decisions that will be tolerated. e. Experimental design. 1. Patient population. The criteria for admitting patients to the study must be specified to ensure that the patients in the study will provide an appropriate sample of the population for whom the RDP is intended. If it is anticipated that the RDP will have an important use in children, they should be included in Phase 111 studies. Example: Source from which the patients are drawn; number (sample size); age, sex, height, weight, medical history, physical findings, laboratory findings, initial diagnostic impression, etc. * * Type I and Type I1 errors are terms used in the statistical theory of hypothesis testing. A Type I error is defined as the probability of rejecting the null hj.pothesis when it is true. A Type 11error is the probability of accepting the null hypothesis when it is false. A statistician may be consulted for a more detailed explanation and for assistance in planning of study sample sizes.

A. GUIDELINES FOR RDP EVALUATION

/

109

The criteria for excluding subjects must be specified. Examples: Concurrent diseases that may interfere; concomitant medications that may interfere. 2. Type of experimental controls a. Description of and the rationale for the particular study design selected-e.g., cross-over, parallel, historical reference, singleblind, double-blind, etc. It should be noted that historical controls and single-blind studies are the least desirable of experimental controls. If either of these methods are chosen, adequate evidence must be presented to support the necessity or validity of such a choice. b. Relevant categorization of patients included in the study. c. If patients are to be subdivided or stratified into groups for comparative purposes, the groups should be comparable to each other regarding age, sex, severity of condition, concomitant therapy, etc. d. Description of types of instrumentation and techniques usede.g., instrument make, model, interval between dose injection and imaging, use of image enhancement, etc. e. If data from multiple investigators are to be combined for statistical analysis, special attention should be directed toward assuring compatibility of protocols, instrumentation, population characteristics, etc., between the several studies. Such pooling of data from a multiclinic study will not be allowed unless evidence of close clinical monitoring by the sponsor is presented. 3. Dosage Regimen. Specify for each patient the lot number, dose (in millicuries, etc.), the volume of RDP administered, and the route of administration. a. Specify the duration of the study as a whole. b. Specify the interval between administration of the RDP and imaging or study in each patient. In the case of a diagnostic procedure a single dose is commonly used; however, if any of the subjects will receive more than one dose the number of doses and the interval between studies should be specified. 4. Efficacy Considerations. The criteria by which efficacy is to be evaluated should be stated in the protocol prospectively-e.g., correlations of imaging findings with other specific diagnostic modalities. 5. Radiation Dosimetry. Projected human radiation dosimetry calculations should be shown for the primary organ(s) of concern, the organ receiving the highest absorbed radiation dose, the critical organs (whole body, active bloodforming organs, lens of the eye, gonads), and any other organs with significant radiation exposure from the RDP (e.g., bladder).

110

/

APPENDIX A

These calculations should include equations based on the highest dose of the radionuclide to be administered. The actual equation(s) used for the dosimetry calculations should be given in full. The system set forth by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine or the system set forth by the International Commission on Radiological Protection for the calculation of radiation absorbed dose are the recommended methods of calculation. All underlying assumptions concerning distribution and effective half-lives should be documented. In general, biologic distribution studies for the radiopharmaceutical should be sufficiently complete to account for as much of the administered dose as possible. 6. Case Report Forms. A well-designed case report form will facilitate tabulation and evaluation of results. A proper case report form for each patient would include: a. Identification of the study, preferably by sequential numerical code and investigator's name; designation of Phase I, 11, or 111; the date(s) on which the RDP was administered, observations made, scans performed, lab tests obtained, etc. b. Subject information: age, sex, height, weight, medical findings, diagnostic impression. c. Reason(s) for doing the study--e.g., to obtain initial diagnosis, to obtain additional diagnostic data, to evaluate therapy, etc. d. Dose, volume administered, route of administration, time interval over which the RDP will be administered. e. Technical information: drug manufacturer or source. Name of radionuclide-e.g., 131-I-19-iodocholesterol. Tc-99m sulfur colloid drug; lot number; dose-to-imaging time interval; instrument (s) used; types of view obtained; information density irnageenhancement, etc. f. For diagnostic imaging procedures a description of all normal and abnormal image findings, including an evaluation of image quality (with reasons, if unacceptable), and interpreter's conclusions. g. Correlation of image findings with other diagnostic modalitiese.g., radiographs, blood chemistries, biopsies, clinical course, autopsy findings, other nuclear medicine procedures, etc. h. Overall evaluation of utility in each patient--e.g., "diagnostic," "confirmatory of prior data," "resulted in alteration of therapeutic plan," "resulted in misdiagnosis due to false-positive (or falsenegative) result," etc. i. Adverse reactions-subjective and -objective. Include any

A. GUIDELINES FOR RDP EVALUATION

/

111

changes in physical findings, laboratory data, etc. Also, information regarding product defects should be noted, such as size of aggregates, drug deposits in wrong organ (tissue), etc. E. Considerations in Evaluation, Summarization, and Presentation of Completed Studies. 1. Plan for evaluation of the data. In evaluating and comparing diagnostic products the statistical methods for assessing the accuracy and reliability of the diagnostic RDP should be presented in detail. In most cases the objectives of the studies will include the assessment of the sensitivity, specificity, and misclassification rates of RDPs. From a statistical viewpoint these terms are defined as: Sensitivity-the ability of a test to give a positive finding when the subject tested truly has the disease under study. Specificity-the ability of a test to give a negative finding when the person tested is free of the disease under study. Misclassification rates-the frequency of false-negatives and falsepositives, which is a function of sensitivity and specificity. Suitable statistical methods should be employed that may assist in the study design-e.g., whether reliability, accuracy, or false-positives/negatives are a function of investigator technique, differences in instrumentation, dosage, etc. In particular, the plan for evaluation should include the allowable statistical risks (Type I and Type I1 errors) and the precision with which the false-positive, false-negative, and misclassification rates will be estimated. 2. Plan for summarization and presentation of data and findings. In keeping with the study objectives, the summary findings should be presented in sufficient detail to allow judgments to be made concerning whether findings are consistent across relevant subgroups, and the extent to which safety and efficacy of the RDP under study are demonstrated. Such presentation should at least contain: a. For each study, a separate tabulation of the data and laboratory findings so that it may be analyzed independently of the other studies. b. If applicable, a rationale and justification for combining findings from more than one investigator. c. Displays of findings by relevant subgroups (i.e., sex, severity of condition, dose, imaging equipment, time of test) and by those factors that the protocol designated as being controlled. d. Displays of all clinical and laboratory findings obtained before and after the RDP is administered and a n appropriate statistical evaluation of the changes of the pre- and postadministration findings.

112

/

APPENDIX A

e. A detailed explanation and documentation of the methods of statistical analysis used in the study, along with the appropriate conclusions derived from the analysis. f. A well-organized presentation of dl the pertinent data upon which the statistical analyses and summaries were based. IV. Special Considerations for Therapeutic Radiopharmaceutic Drug Products Much of the information in Sections I, I1 and I11 is applicable to the clinical investigation of therapeutic RDP's. The following points represent modifications in the plan of investigation which may be required for the proper evaluation of therapeutic RDP's. For the purpose of this guideline a therapeutic RDP is defined as a radiopharmaceutical drug product which is administered to patients a t a dosage level which is intended to produce a therapeutic effect (response). This therapeutic response will, in general, be the result of the deposition of energy from ionizing radiations in a specific organ(s) or tissue(s) of primary interest. For the purposes of this discussion it is important to distinguish between administrations of a therapeutic RDP in tracer doses and therapeutic doses. Tracer doses will be administered, in general, for initial biodistribution studies. The tracer dose and its resulting radiation absorbed dose will not be expected to elicit significant radiation effects.

A. Preclinical Studies 1. Radiation Dosimetry Biodistribution studies in animals wiU be

the basis for initial calculation of the radiation dosimetry for the therapeutic RDPI. Since the biodistribution of a tracer dose and a therapeutic dose of the same radiopharmaceutical may differ, biodistribution studies in animals a t several dosage levela (i.e., different masses of the labeled compound) should be performed. 2. Animal Toxicity Studies. Because the therapeutic dose may contain a larger mass of material than the tracer dose, more extensive animal toxicity testing may be required in the evaluation of therapeutic RDP's. In some cases, chronic toxicity testing may be required. 3. Radiobiologic Toxicity Studies: Evaluation of radiation toxicity should include the study of two animal species over a sufficient dosage range of the therapeutic RDP to allow determination of radiation effects. In the case of therapeutic RDP's, long-term folIow-up study may be necessary to properly evaluate radiation effects.

A. GUIDELINES FOR RDP EVALUATION

/

113

4. Pre-clinical Evaluation in Animal Model: If an appropriate animal model is available, evidence of potential therapeutic efficacy should be demonstrated in that model prior to the initiation of human studies employing therapeutic dosage levels of the RDP.

B. Clinical Studies 1. Investigators for studies involving patients should be physicians or clinical pharmacologists qualified by training and experience in the evaluation of therapeutic RDP's; the active participation of other specialists (oncologist, therapeutic radiologist, etc.) may be appropriate.

2. Phase I Studies Initial Phase I studies will be primarily designed to obtain biodistribution data in man utilizing tracer quantities of the proposed therapeutic RDP. Such studies should initially be performed in normal adult volunteers and then in patients with the disease in which use of the therapeutic RDP is intended (and in whom the biodistribution may be substantially different). The purpose of these studies is to permit projection of absorbed radiation dose to the intended target organ(s) or tissue(s) and to critical organ(s) or tissue(s) at therapeutic doses. Such studies .should include blood clearance data, excretion data, organ distribution data (from external imaging and quantitation or from limited biopsy sampling). Evaluation of bone marrow distribution may be particularly important since the radiation dose to the marrow may be the limiting toxicity. After performance of the tracer biodistribution studies and calculation of projected therapeutic radiation doses, studies to determine the proper therapeutic dose should be undertaken (assuming that the therapeutic index is not unacceptably low). A reasonable starting dose might be at the lower limit of the calculated dose range expected to produce a therapeutic response. The drug dosage may be reasonably increased thereafter until a dose (or dose range) is found which produces the desired therapeutic effect without inducing disabling toxicity. If the RDP is used to treat a neoplastic disease, the therapeutic schedules should include maximally tolerated doses for a period of time sufficient to allow recognizable neoplastic regression

114

/

APPENDIX A

(i.e., as compared with the natural progression of the neoplasm which would be expected in the absence of effective therapy). 3. Phase I1 and I11 Studies As with all RDP's, careful attention must be given to adequately

specifying: a. Study objectives Example: To demonstrate the effect of Sodium 32P polyphosphate on bone metastases from carcinoma of the prostate.

b. Rationale for study Example: Prostatic metastases are frequently osteoblastic, and high concentrations of a bone-seeking RDP are likely to be achieved near the tumor. c. The criteria by which efficacy will be evaluated Example: The magnitude of regression of bony lesions will be determined by X-ray, bone scan and effect on the patient morbidity and mortality. Clinical studies involving therapeutic RDP's should have a clearly defined objective end-point by which therapeutic effect can be evaluated. Examples: a. If the RDP is used as an anti-tumor (solid) agent, objective response would consist of a 25% or greater reduction in the sum, or a !jO% or greater reduction in the product, of the two largest right angle diameters of a measurable lesion. (This reduction must be maintained for a t least 30 days without evidence of progressive disease elsewhere.) b. Sustained reduction in red cell mass in patients with polycythermia Vera. If the RDP is used for treatment of an endocrine disorder involving hyperfunction, sustained decrease in hormonal secretion by the target organ should be documented. Subjective evidence of improvement, such as an improved sense of well-being, diminution of pain, increased performance status are acceptable as corroborative but not primary evidence of drug effect. As in Phase I, compilation of data relating to the safety of the RDP should continue in Phases I1 and 111, with particular reference to the organ(s) of primary interest, target organ(@, and critical organs, including bone marrow and gonads. As the study progresses into Phase 111, fewer laboratory studies m a y be necessary. If other therapeutic modalities are used concomitantly in a Phase I1

A. GUIDELINES FOR RDP EVALUATION

/

115

study, these may be discontinued in Phase I11 if the RDP under investigation appears to be effective In the evaluation of therapeutic drug products, long-term follow-up may be required to evaluate properly the incidence of late adverse effects as well as therapeutic efficacy.

APPENDIX B

Radiation Absorbed Dose Estimates The estimation of radiation absorbed dose to humans from radionuclides administered in the course of diagnostic medical procedures involves a number of uncertainties. In Section 4.1 of this document, a summary of the mechanics of carrying out a radiation dose calculation was presented with commentary on the assumptions that went into such calculations. Here, estimates are provided of the radiation absorbed doses resulting from the use of various radionuclides in patients. The International Commission on Radiological Protection (ICRP) and the International Commission on Radiation Units and Measurements (ICRU) have undertaken a thorough treatment of the principles and methodology involved in the experimental and calculational aspects of internal radiation dosimetry. It is recommended that anyone seriously undertaking dose calculations should refer to ICRP Publication No. 30 (ICRP, 1979), ICRU Report 32, (ICRU, 1979) and the MIRD publications (MIRD, 1972; 1973; 1975a, b, c, d, e; 1976). The clinician who uses this table as a guideline must be alert to the fact that the physical factors used in the calculations are based upon a mathematical model of a "reference man" and not the individual patient being considered by him (ICRP, 1975). An even more important caution to the user of these tables is to remember that the specific biological data used as a basis for the radiation dose calculations and particularly the biological uptake and distribution data for the different radionuclide agents were obtained from the published literature as referenced. Published biological data for humans are sparse and are usually obtained by external measurements of patients undergoing studies and rarely over long periods of time. Seldom are sufficient tissue samples obtained to determine fully the radioactive uptake and retention. In some cases, only animal data are available and the extrapolation to humans introduces a further uncertainty in the final dose values. Thus, the biological data used to generate the radiation dose may not 116

APPENDIX B

/

117

represent the situation for each clinical case. The biokinetic parameters established for one member of a class of compounds, for example human serum albumin (HSA) labelled with I3'I were assumed to apply for all other radiolabelled HSA compounds. For those radionuclides that are less tightly bound, revised dose estimates, which take account of differences in the biological behavior of the particular RDP employed, will need to be computed by the user. It should be noted that the radiation dose to the gonads includes dose from photons emitted anywhere in the body and includes the dose from electrons in the gonads. The calculation is based on a uniform distribution of the activity present in the source called Restof-Body. The radiation dose estimates were made by the Health Physics Division, Oak Ridge National Laboratory (ORNL) for most of the entries in Table A-1. The ORNL calculations were based on nuclear decay and biokinetic data as known through 1976. Data presented in MIRD publications were not recalculated for these tables since ORNL programs had been used for the original calculations. The dose values for intrathecally administered radionuclides were not recalculated since the standard man phantom does not include the CSF space in its anatomical catalogue. The ORNL computer code uses the reference man model and physical parameters for radionuclide data (Dillman and Von der Lage, 1975) to calculate absorbed dose per unit cumulated activity for selected radionuclides and organs-"S" tables (Snyder et al., 1975). The biological data presented in the dose table are used to calculate the cumulative activity, A, for the source organs. The computer code calculates the total radiation dose to the selected target organ from the radioactivity in the different source organs. Roedler, Kaul, and Hine (1978) have also attempted to provide the clinician with a guide book of radiation dose values tabulated according to medical subspecialties. Their dose values are based upon much the same literature as is used in this document. Since the biological factors used in their calculations cannot clearly be identified, one cannot readily determine the cause in those cases where there is a difference between their dose values and the values in this report. In general, there is agreement within a factor of 2 between their dose values and those presented in this report.

Note: The footnotes which describe the assumptiom employed in the particular computations in Table A-1 are shorn below.

ah

1. Bladder contents calculated on basis of 0.44 exmetad in urine in 4 hours el oL. 1973) and an exponential loan from rest of body. 2. Bladder amtents calculated on baeie of 0.40 from rest of body appears in urine in 3 hours. 0.30 appears in 1 hour. 3. Does was computed on the baeis of a constant rate of entry of urine into the bladder of 1.4 liters/day and k u m i n g 7 voids per day of 200 ml. of urine per void. The surface dose fol beta radiation was added to the average doee from photons to give the total (Snyder and Ford, 1976). 4. Radiation absorbed dose values indude activity of injected "Fe plus the ingrowth of daughter products "'Mn and =Mn. The metabolic model for iron was assumed for the daughte~ products. Cumulated activity values are for G'qe.

5. A~sumethyroid blocked. 6. The ~ b i d i u mmetabolic model was aasumed for ""Kr (TI,l = 13 set). Only *'Rb is assumed to enter the body, but the dose estimates include the contribution from the ingrowth of ""Kr which is assumed to decay where produced. 7. 20 second bresth holding followed by expiration with 28 second outflow half-time. 8. Assumes exponential loss to bladder. 9. 0.75 of the radioiodine in the gallbladder was assumed to pass into the small intestine 3 hours after administration and the remaining 0.25 nine hours after administration. 10. h e s instantaneous equilibrium and a 5-minute rebreathing period followed by a lung activity washout with 0.35 minute half-time and rest of body biological half-time of 5

minutes. 11. Administered blocking dose of 39 mg mercury. 12. Biologicel data assumed 50& in total body. 50% in kidneys.

-

Note: Footnotes used in Table are given on Page 118. Some nuclides listed are contaminants rather than the desired agent.

TABLE A-I-Radiation

A b s o r b e d D o s e fmrad/uCil f r o m S ~ e c i f i cR a d i o a c t i v e Arrents C o m m o n l v Used in Patients Biological Assumptions

Radioactive Agent Tritium Water (HTO)

Fluorine-I8 ion

Mode of Administration oral/l.V.

I.V.

Physical HalfLife 12.3 y

1.8 h

Fraction Administered Activity Total body

1.

bCi-h)

12 d

414

0.53

1.4 0.51 0.44

Tissue

mrad/pCi

Red marrow

0.072

Ovaries Testes Total bodv

0.072 0 072 0.072

Total bone Bladder wall Red marrow Ovaries Testes Total body

0.16 0.96 0.13 0.043 0.035 0.040

Ref. ICRP, 1960

Kaul et af,1973 (page 372)

0.47

1h

49 d 49 d 49 d 49 d

7.668 7.668 241.5 126.5

Liver Spleen Total bone Testes Ovaries Red marrow Total bodv

6.3 63 56 3 3 67 8.1

Kaul el al, 1973 (page 240)

247 50 0.32

Total bone Red marrow Bladder wall Liver Ovaries Spleen Testes Total bodv

57 57 2.3 1.1 1.1 1.1 1.1 6.3

Kaul el al,1973 (aasumed to be same as for - T c polyphosphate) (page 550)

14.3 d

Liver Spleen Skeleton Rest of body

0.02 0.02 0.63 0.33

Phosphorua-32 polyphosphate

I.V.

14.3 d

Skeletal Rest of body Bladder"

0.5 0.1 0.4

0.5 h

Total body (except skeleton)

1.

58 d

12.4 h

Radiation Absorbed Dose

Bone Bladder contents' Rest of body

I.V.

I.V.

A

Biological Half-Time

Phosphorous-32 Phosphate

Potassium-42

Activity

Source Organ

18

Liver Lungs Muscle Spleen Red marrow Ovaries Testes Total body

0.96 0.95 0.96 0.96 0.04 1 0.98 0.96 0.96

ICRP, 1960

Biological Assumptions Radioactive Agent

Mode of Administration

Physical HalfLife

Source Organ Fraction Administered Activity

Potassium-43

I.V.

22.4 h

Total body (except skeleton)

1.

Chromium-51 DTPA or EDTA

I.V.

27.7 d

Kidney Rest of body

OM 0.10

Biological Half-Time 58 d

5.95 h. 5.95 h.

A

@Ci-h)

32

7.66 0.852

Bladder contents' Chromium-51 red blood cells (heat-treated)

1.V.

Chromium-51 red blood cells

I.V.

27.7 d

Blood Spleen

Chromium41 human serum albumin

LV.

27.7 d

Total body

Ferric-52 chloride'

I.V.

27.7 d

Spleen Rest of body

0.90 0.10

11.25 d

250

m

96

450 150

0.95 0.05

14.7 d 28 h.

319.2

Kidney Liver

0.0293 0.2227

800 d 800d

Tissue

0.35 2.7

mrad/pCi

Ref.

Liver Lungs Muscle Spleen Red marrow Ovaries Testes Total body

0.79 0.72 0.70 0.80 0.31 0.75 0.79 0.74

ICRP, 1960

Bladder wall Kidneys Ovaries Testes Red marrow Total body

0.14 0.4 0.0065 0.0031 0.0065 0.0058

Kaul et al, 1973 (page 388)

Ovaries Red marrow Spleen Testes Total bodv

0.1 0.14 23. 0.052 0.19

Kaul et al,1973 (page 366)

Blood Ovaries Red marrow Spleen Testes Total body

0.31 0.29 0.31 14. 023 0.31

Cloutier and Watson, 1970

Kaul et al,1973 (page 361)

Ovaries Testes Total bodv

0.27 0.19 0.190 0.16 0.17

Kidneys Liver

5.7 8

Kaul et al 1973 (page 370)

Bladder wall

Red marrow

Bladder contents' 8.2 b

Radiation Absorbed Dose

Activity

Ferric-55 chloride

Fenic-59 chloride

I.V.

I.V.

2.7 y

45d

Lungs Spleen Testes

0.0206 0.0369 0.0094

800 d 800 d 800d

0.25 0.44 0.11

Rest of body

0.6811

800d

8.2

Kidney Liver Lungs Spleen Testes Rest of body Kidney Liver Luw Spleen Testes Rest of body

Cobalt-57 Vitamin B12

Oral

270 d

Liver Stomach Spleen Kidney Ovaries Bone Testes Rest of body

Gallium-67 citrate

I.V.

78.0 hr

Spleen Kidneys Adrenals Marrow Liver Bone

Lungs Ovaries Red marrow Spleen Testes Total body Kidneys Liver Lungs Spleen Ovaries Testes Red marrow Total body Kidneys Liver Lungs Spleen Ovaries

0.0293 0.2227 0.020206 0.0369 0.0094 0.6811

0.0072 0.0076 0.0006 0.054 0.050 0.18

Testes Red marrow Total body Liver Stomach wall Spleen Kidneys Total bone Ovaries Testes Red marrow Total bodv 30h 17% 17% 17% 17% 17% 17%

613h 8% 83% 83% 83% 83% 83%

0.633 0.669 0.053 4.75 4.40 15.8

1.7 1.2 1.2 11 12 1.3' 19 24 5.8

Kaul et al, 1973 (page 370) ICRP, 1960

40

2 51 2 2.8 84

120 34 150

Kaul et al,1973 (page 370) ICRP. 1960

20

150 21 23 110 17 10 25 3.5 5.7 61 4.5 5.8

GI Tract Stomach S. 1. U.L.I. L.L.I. Ovaries

ICRP, 1960

Kaul e l al, 1973 (page 466)

MIRD, 1973 0.22 0.36 0.56 0.90 0.28

TABLE A-l-Continued Radioactive Agent

Mode of Administration

Physical HalfLife

Source Organ

Rest of body

Biological Assumptions Fraction Adminiskred Activity 0.70

BiBii=;

A

@Ci-h) 1%

83%

Radiation Absorbed Doee

Activity

61.6

Tkue Testes

Kidneys Liver Marrow Skeleton Spleen Total body Gallium-68 Albumin MacroAggregates

I.V.

68.3 min

Gallium-68 Colloid

1.V.

68.3 min

Gallium-68 DTPA or EDTA

I.V.

68.3min

Liver Lung Rest of body

0.015 0.045 0.090 0.80 0.05

250 h 9h 0.5 h 7s h .a

1.15 0.082

Bladder content2 Liver Spleen Red marrow

0.90 0.W 0.07

m m m

Kidney Rest of body

0.90 0.10

5.95 h 5.95 h

LV.

120 d

Blood Fat Kidneys Liver Lungs Musde

Ref.

0.24 0.41 0.46 0.58 0.44 0.53 0.26

Bladder wall Liver Lung Ovaries Testes Red marrow Total body

0.014 0.011 0.016 0.048

1.5 0.05 0.12

Liver Spleen Ovaries Testes Red rn-

1.6 0.49 0.0055 0.0016 0.10

MIRD. 1975b

1.24 0.138

Bladder wall Kidneys Ovaries Testes Red marrow Total bodv

2.5 6.9 0.024 0.014 0.028 0.050

Kaul et al. 1973 (page 388)

0.135

Bladder contents3 Selenium-75L-Selenomethionine

mrad/pCi

190 81 35 190 41 660

Blood Kidney Liver Ovaries Pancreas Spleen

3.1 0.16

Kaul el al, 1973 (page 364)

1.9

9 23 25 5 12 16

MIRD. 1972

Biological Assumptions Radioactive Agent Strontium45 Nitrate

Strontiumd7m Nitrate

Krypton-8lm

Krypton-Blm

Krypion-85

Mode of Administration

I.V.

I.V.

Inhalation & Rebreathingl"

1.V. or single breath

I.V.or single breath

Physical Half. Life 65.2 d

2.8 h

138

138

10.7 y

Source Organ

Fraction Administered Activity

Biolo 'cal ~alf-#me

Bonecancellous cortical Rest of body

0.255 0.255 0.49

93 d 93 d 3.2 d

Bone cancellous cortical Rest of body

0.255 0.255 0.49

93 d 93 d 3.2 d

Lung Rest of body

.95 .05

0.35 m 5m

Lung

Lung

Cumulative Activity

Radiation Absorbed Dane

Ref.

Tiue 676

52

2.1 1.9

Bone Red marrow Ovaries Testes Total body Bone Red marrow Ovaries Testes Total body

13 10 3.1 1.9 4.3 0.07 0.062 0.017 0.015 0.021

Liver Lungs Red Marrow Ovaries Spleen Testes Total bodv

0.012 ,0002 .00013 1.8 x lo-'

Liver Lung Red marrow Ovaries Spleen Testes Total bodv

2.2 x 10-"aul 0.0014 1.4 X lo-" 1.1 x 2.0 x 10" 1.1 x lo-' 3.1 x

Liver Lung Red marrow Ovaries Spleen Testa Total bodv

6.4 x lo-' 0.ooSS 3.4 X lo-' 4 2 X lo4 5.7 x lo-' 6.7 x lo-' 1.3 x lo4

Kaul et al, 1973 (page 524)

Kaul et dl, 1973 (page 524)

MIRD, 1980

.00019

5.9 x lo-$

.00029 et a1, 1973

(page 302)

Kaul et a1. 1973 (page 302)

-

Molybdenum-99

+

I.V.

66.7 h

Liver Rest of body

0.75 0.25

20 h 20 h

LV.

6.03 h

Kidney Rest of body

0.90 0.10

5.95 h 5.95 h

0.05

12 h 12 h 12 h

-

Kidneys Liver Lung Red manow Spleen Ovaries Testes Total bodv

0.22 8.9 0.17 0.14 0.12 0.1 1 0.092 0.35

Kaul et al, 1973 (page 480)

3.89 0.432

Bladder wall Kidneys Ovaries Testes Red marrow Total body

0.28 0.74 0.013 0.0057 0.018 0.011

Kaul el al, 1973 (page 388)

0.290 4.92 0.578

Bladder wall Liver Lungs Ovaries Testes Fled marrow Total body

0.18 0.026 0.26 0.0067 0.0040 0.013 0.013

Kaul at d 1973 (page 390)

8.5

Bladder wall Red marrow Ovaries Testes Total body Bladder wall Liver Lungs ovaries Testes Red marrow Total body

0.032 0.025 0.021 0.014 0.017

Kaul et al, 1973 (page 364)

0.29 0.030 0.21 0.0085 0.0052 0.011 0.012

Kaul el al, 1973 (page 364)

16.7 5.56

99ms

Technetium-% DTPA or EDTA

Bladder contents' Technetium-99m Fe OH colloid

I.V.

6.03 h

Liver Lung Rest of body

0.85 0.10

Bladder contents' Technetium-% human serum albumin

I.V.

Technetium-% albumin macro-aggre-

I.V.

gam

6.03 h

Total bod9

0.95 0.05

14.7 d

0.015 0.045 0.090 0.80 0.05

%Oh

28 h

Bladder contents3 6.03 h

Liver L

U

~

Rest of

MY

Bladder contents'

9h 0.5 h 7.8 h .

w

0.42

3.94 0.43

TABLE A-I-Continued Biological Assumptions Radioactive Agent Technetium-99mmicraspheres (15 to 22 pm)

Technetium-9% Polyphosphate

Mode of Administration I.V.

I.V.

Physical HalfLife 6.03 h

6.03 h

Source Organ

Fraction Administered Activity

LungS Rest of body Bladder Contents"

Radiation Absorbed Dose

Activity

-

Biolo 'cal ~alf-#me

0.57 0.37 0.06

A

(pCi-h)

Tissue

45 h 4h

5.7

Bladder wall Ovaries

rn

0.52

Testm Red marrow Lung Total bodv

Bladder contents2 Bone Rest of body

0.5 0.1 0.4

m

4.35

0.5 h'

1.14

0.28 m

Technetium-% Red blood cells

I.V.

6.03 h

Total body

1

m

8.7

Technetium-% Red blood cells (heat treated)

I.V.

6.03 h

Spleen Rest of

0.90 0.10

m

7.8 8.7

Technetium-99m Sodium Pertechnetate

I.V.

MY

mrad/pCi

Ref.

0.17 0.0060 0.0036 0.013 0.26 0.014

Kaul et a!, 1973 (page 548)

Bladder wall Total bone Red marrow Ovaries Testes Total body Liver Red marrow Spleen Ovaries Testes Total body

0.051 0.051 0.033 0.0080 0.0061 0.012

Kaul ef al, 1973 (page 550)

0.019 0.025 0.019 0.021 0.014 0.017

Kaul et al, 1973 (page 364)

Liver Red marrow Spleen ovaries Testes Total body

0.0096 0.016 2.6 0.0052 0.0018 0.019

Kaul et al, 1973 (page 366)

Bladder wall Stomach (wall) Upper large int. (wall) Lower large int. (wall) Ovaries Red marrow Testes Thyroid Total bodv

0.053 0.25 0.068

6.03 h

a Extravaseular Large inteatine Plasma Red blood cells Salivary glands Stomach Thyroid

a-resting population b-non-resting population

b 0.085 MIRD, 1976 0.051 0.12

TABLE A-1-Continued Biological Assumptions Mode of Admin- Physical Halfistration Life

Radioactive Agent Indium-113111 Microsp' .es (15to7

I.V.

99.4 rnin

)

.-... i

I V.

I

32 h

Organ Fraction Administered Activity ~ u n g Rest of body Bladder contents" Total body (except skeleton)

Biological Half-Time

0.57 0.37 0.06

OD

1

58d

45 h

Radiation Absorbed Dose

Activity

A @Ci-h)

1.94

4h 0.143

46

TiPPue Bladder wall Ovaries Testes Red marrow Lungs Total body Liver Lungs Muscle Spleen Fkdmarrow

-

.

. --. -- .

Cesiwn. !:I i

I.\!.

9.7 d

Total body (except aheleton)

1

58 d

288

Cesium-132

I.V.

6.5 d

Total body (except skeleton)

1

58 d

202

0.4 1 0.004 1

Testes Total body Liver Lungs Muscle Spleen Red marrow Ovaries Testes Total hodv

0.0029 0.0065 0.64 0.016 0.30 0.27 0.25 0.31 0.22 0.30 0.27 0.27 0.27 0.27 0.23 0.27 0.22 0.27 0.22 0.26

Liver Lungs Muscle Spleen Red marrow Ovaries Testes Total body

2.2 1.9 1.8 2.2 1.6 1.9 2.3 2.0

Ovaries . . . ..-

nuad/pCi

Ref. Kaul el al, 1973 (page 548)

ICRP, 1960

ICRP, 1960

ICRP, 1960

d

B V)**V)t?38S

N - O N

I 0 -

2 4-

;5 3 5 2 5 ggg&:

0

2

P-

N O O O O O

I-

9 o

.5 .c . E E 2r.Zrc

9 w NOONW-V! - 0 - 4 l .

b c

X

5

8

2

I-

PB

2-

2

2 n

CI

8 6

d

.B

G

Y qqg; 0000 4

.s .5

8 0

C

=

d

C

%

0

.c

C-

B

2!

a

2

-

s O O O O O P - 0

$ri

-2 ?j ,PC,

8 r

5s

c~s

e,g. e-.-

$Ec d

:3

$3 H

&

9 3 ~ ~ -

gi$$

B .e

3" 4 8

i] 8

3

s 6 6 6 6 6 z9 6

2

5 5 &

.P

m 4

m

4

.c

B # O Z ,

B .P

5 S

2

"s

,,

93

d

AY&Z

3? -g; * t-

X V)

9

El

2 3

3

-.4 2"'

Radioactive Agent

Mode of Administration

lodine- 125 Iodide

Oral

Iodine-125 orthoioriohippuri.: acid

I.V.

Physical HalfLife 60.2 d

602 d

Biological Assumptions

Source Organ

Fraction Administered Activity Intestine Liver Stomach Thyroid

Biological Half-Time

A (pCi-h)

See reference

0.34 0.10 0.05 0.01 0.4025 0.085 0.0125

Total body

Tissue Liver Ovaries Red marmw Stomach wall Testes Thyroid Total body

(MIRD, 1975~)for maximum thyroid uptake of 15%

Kidneys

Radiation Absorbed Dose

Activity

2 min 10 min 50 min 12 h 18 min Ih 7.5 h

0.271

0.432

mrad/pCi 0.22 0.033 0.077 0.26 0.018 450. 0.29

Ref. MIRD, 1975c

Kaul et al, 1973 (page 193)

Total body

1.9 0.069 0.008 0.0047 0.0026 0.0058

Bladder wall Red marrow Ovaries Testes Total bodv

1.2 1.0 0.69 0.56 0.67

Kaul et al, 1973 (page 364)

Liver Ov~es Red marrow Stomach wall Testes Thyroid Total bodv

0.35 0.14 0.20 1.6 0.085 800. 0.47

Bladder wall Kidneys Ovaries

Testes Red marrow

Bladder contents.' Iodiie- 125 human serum albumin

I.V.

60.2 d

Total bod9 Bladder contents'

Iodine-131 Iodide

Oral

8.06 d

Intestine Liver Stomach Thyroid

0.95 0.05

See

reference (MIRD, 1975~) for maximum thyroid uptake of 15%

14.7 d 28 h

391.2

MIRD, 1975c

Iodine-131 humari serum albumin

LV.

Iodine-131 orthoidohippuric acid

LV.

8.06 d

Total body

14.7 d 28 h

0.0125 0.085 0.4025 0.01 0.05 0.10 0.34

7.5 h 1h 0.3 h 12 h 50 min 10 min 2 min

173

Bladder contents' 8.06 d

Total body Kidney

Iodine-131 Microspheres (15 to 20 pm)

0.95 0.05

I.V.

8.06 d

~ung'' Rest of

i 5h

0.4272 Bladder wall Kidneys Ovaries Testea 0.264 Red marrow Total body

32

4h

MY

OD

17

Bladder contenti' Iodine- 131 albumin macroaggregab

I.V.

8.06 d

Liver Lung" Rest of

0.015 0.045 0.09 0.8 0.05

250 h

w

MY

Bladder cnntenta" Iodine-131 sodium rose bend

I.V.

8.06 d

Liver and biiiary tract Contents of gall bladder Small intestine and contents Contents of upper large intestine Contents of lower large intestine

2.6

9h

0.5 h 7.8 h

1.5 h

2.77 h 9.0 h 16.6 h

Bladder wall Ovaries Testes Red marrow Total body

8.4 14.3

Bladder wall Ovaries Testes Red marrow Lung Total body Bladder wax Liver Lungs Ovaries Testes Red marrow Total body Gall bladder wall GI tract small intestine Upper large int. (wall) Lower large int. (wall) Liver

3.4 1.9 1.8 1.9 1.7

Kaul et al, 1973 ( p g e 438)

13. 0.41 0.073 0.053 0.021 0.028

Kaul el al,1973 (page 193)

3.7

Kaul el aI, 1973 5 4 8 ) (page m

0.23 0.2 0.31 14.5 0.49 4.5 0.99

Kaul et al. 1973 (page 364)

4.

0.2 0.17 0.2 0.26 1.1 3.5 14. 35. 0.80

MIRD,1975e

Ytterbium-169 DTPA

Gold-198 sulfur wlloid

Intrathecal

I.V.

I.V.

32 d

2.7 d

65 h

Blood CSF Spinal segment C1-C7 03-T6 T7-L1 L2-Ca.1 Nerve roots Nerve roots Brain

1005 2922 2630 3151 5376 6160 4688

0.10 13-49 31 26-66 46 70

Morin and Brookernan, 197. Johnston and Staab, 1975

Liver Ovaries Red marmw Spleen Testes

39.

MIRD, 1975b

54.880

Liver Spleen Red marrow

Blood Liver Ovaries Renal Cortex Renal Medulla Skeletal muscle Skeleton Testes

Blood Spinal wrd mean value Nerve roots mean value Brain

0.90 0.03 0.07

reference (MIRD, 1975d) for details of biological data

See

Bladder wall Kidneys-Cortex Kidneys-Medulla Liver

0.14 2.7 12. 0.035 MIRD, 1975d

Testes

1.1 12. 1.4 1.5 0.040 0.11 0.028

Bladder wall Kidneys-Cortex Kidneys-Medulla Liver Ovaries Fied marrow Testes

1.2 9.5 1.2 0.66 0.046 0.082 0.K37

MIRD, 1975d

Ovaries

Red marrow

- -- ---, Mercury-197 Chlormerodrin (blocked)"

I.V.

65 h

Blood Liver Ovaries Ftenal Cortex Renal Medulla Skeleton muscle

Skeleton Testes Total body

See reference (MIRD, 1975d) for details of biological data

Radioactive Agent

Mode of Administration

Physical HalfLife 73.1 hr

Source Organ

Biological Assumptions Fraction Administered Activity

Stomach S. I. IJ.L.1. L.L.I. Heart Kidneys Liver Ovaries Testes Thyroid Rest of Body

Thallium-201 chloride

I.V.

Mercury-203 Chlormerodrin

I.V.

46.5 d

Blood Liver Ovaries Renal Cortex Renal Medulla Skeletal muscle Skeleton Testes Totrl balv

Mercury-203 Chlormerodrin (blocked) "

I.V.

46.5 d

Blood Liver Ovaries Renal Cortex Renal Medulla Skeletal muscle Skeleton Testes Total body

Biological Half-Time 240 hr 240 hr 240 hr 240 hr 27.8 hr 240 hr 240 hr

Cumulative Activity

Radiation Absorbed Dose Tiue

mrad/pCi

Ref.

GI Tract Stomach Wall S.I. U.L.I. Wall L.L.I. Wall Heart Wall Kidneys Liver Ovories Testes Thyroid Total Bodv

0.40 0.38 0.25 0.21 0.50 1.2 0.57 0.47 0.52 0.64 0.21

See reference (MIRD. l975d) for details of biological data

Bladder wall Kidneys-Cortex Kidneys-Medulla Liver Ovaries Red marrow Testes

2.1 100. 20. 19. 0.77 1.6 0.52

MIRD. 1975d

See reference (MIRD, 1975d) for details of biological data

Bladder wall Kidneys-Cortex Kidneys-Medulla Liver Ovaries Red marrow Testes

2.1

MIRD, 1975d

55.

15. 7.1 0.61 0.98 0.46

Atkins et al, 1977 Samson et al, 1976

References ADAMS,R. AND ZIMMERMAN, D. (1973). "Methods for calculating the deadtime of Anger camera systems," J. Nucl. Med. 14, 496. ADAMS,R., HINE,G. J. AND ZIMMERMAN, C. D. (1978) "Deadtime measurements in scintillation cameras under scatter conditions simulating quantitative nuclear cardiography" J. Nucl. Med., 19, 538. ALLEMAND, R.,GRESSET,C. AND VACHER,J. (1980). "Potential advantages of a cesium fluoride scintillator for a time-of-flight positron camera" J. Nucl. Med. 21, 153. ANGER,H.0. (1958). "Scintillation camera," Rev. Sci. Instrum. 29, No. 1,27. ANGER,H. 0. (1967). "Radioisotope cameras," page 486 in Instrumentation in Nuclear Medicine. Vot. 1, Hine, G . J., Ed. (Academic Press, New York). ANGER,H. 0. (1969). "Multiplane tomographic gamma-ray scanner," page 203 in Medical Radioisotope Scintigraphy, Vol. I , IAEA Publication No. STI/ PUB/193 (International Atomic Energy Agency, Vienna). ARCHER,V. E., WAGONER, J. K., AND LUNDIN, F. E. (1973). "Uranium mining and cigarette smoking effects in man," J. Occ. Med. 15, 204. ATKINS,H. L., BUDINCER, T. F., LEBOWITZ, E. et al. (1977). "Thallium-201 for medical use. Part 3: Human distribution and physical imaging properties," J. NucL Med. 18, 133. BARBE,D. F. (1975). "Imaging devices using the charge-coupled concept," Proc. IEEE 63, 38. BARBIZET,J., DUIZABO, PH., THOMAS,J., GALLE,P.,MORETTI, J. L., AND PITTON,R. (1972). "La Cisternographic e t la Ventriculographic Isotopiques," page 2899 in La Nouvelle Presse Medicale, 1, 43. BECK,R. N. (1961). "A theoretical evaluation of brain scanning systems," J. Nucl. Med. 2,314. BECK,R. N. (1964). "A theory of radioisotope scanning systems," page 35 in Medical Radioisotope Scanning. Vol. I , IAEA Publication No. STI/PUB/ 82 (International Atomic Energy Agency, Vienna). BECK,R. N. (1972). "Nomenclature for Fourier transforms of spread functions of imaging systems used in nuclear medicine," J. Nucl. Med. 13,704. BECK,R. N., SCHUH,M. W., COHEN,T. D., LEMBARES,N. (1969). "Effects of scattered radiation on scintillation detector response," page 595 in Medical Radioisotope Scintigraphy, Vol. I , IAEA Publication No. STI/PUB.193 (International Atomic Energy Agency, Vienna). BECK, R. N., ZIMMER,L. T., CHARLESTON, D. B., SHIPLEY,W. W., AND BRUNSDEN, B. S. (1973a). "A theory of optimum utilization of all detected radiation," page 87 in Proceedings of the University o f California Sympo-

136

/

REFERENCES

sium on Semiconductor Detectors in Medicine, U.S. Atomic Energy Commission Publication No. CONF. 730321 (National Technical Information Service, Springfield, Virginia). BECK,R. N., ZIMMER, L. T., CHARLESTON, D. B., HARPER,P. V., A N D HOFFER, P. B. (1973b). "Advances in fundamental aspects of imaging systems and techniques," page 3 in Medical Radioisotopes Scintigraphy, Vol. I, IAEA Publication No. STI/PUB/315 (International Atomic Energy Agency, Vienna). W. M., DOBYNS, B. M. et al. (1971). "The results BECKER,D. V., MCCONAHEY, of radioiodine treatment of hyperthyroidism," page 603 in Further Advances in Thyroid Research (Vienna Academy of Medicine, Vienna, Austria). BENDER,M. A. (1964). "The digital autofluoroscope," page 391 in Medical Radioisotope Scanning, Vol. I, IAEA Publication No. STI/PUB/82 (International Atomic Energy Agency, Vienna). BEN-PORATH, M., FEICE,Y., LUBIN,E., AND LEVITUS,S. (1970). "Microdosimetry of 125-1 in the thyroid follicle," J. Nucl. Med. 11,300. BIRKS, J. B. (1964). The Theory a n d Practice of Scintillation Counting (Macmillan Company, New York). BLOCH,P., GARAVAGUA, G.,MITCHELL,G., AND SHAPIRO,I. M. (1977). "Measurement of lead content of children's teeth in situ by x-ray fluorescence," Phys. Med. Biol. 22, 56. W. D. AND ADELSTEIN,S. J. (1982). "The mammalian radiation BLOOMER, survival curve," J. Nucl. Med. 23, 259. BLUMCART, H. L. AND WEISS,S. (1927). "Studies on the velocity of blood flow. 11. The velocity of blood flow in normal resting individuals, and a critique of the method used," J. Clin. Investigation 4, 15. BORKOWSKI, C. J. AND KOPP, M. K. (1972). "Proportional counter photon camera," IEEE Trans. Nucl. Sci. NS-19,No. 3. BOYD,E., FERGUSON-SMITH, M. A., MCDOUGALL, I. R., AND GRIEG,W. R. (1974). "Chromosome breakage in human peripheral lymphocytes after radioactive iodine ('*I) treatment," Radiat. Res. 57, 482. BROSER,I. AND KALLMAN, H. (1947). "The elementary process of light stimulation in luminous substances by a-particles, fast electrons, and y-quanta, 11," Naturforsch, 2a, 642. BROWNELL, G. L. (1964). "Theory of radioisotope scanning," page 3 in Medical Radioisotope Scanning, Vol. I, IAEA Publication No. STI/PUB/82 (International Atomic Energy Agency, Vienna). BROWNELL, G. L. (1968) Fundamental Problems in Scanning. Gottschalk, A. and Beck, R. N. Eds., (Charles C Thomas, Springfield, 111.) C . A. (1974). "Recent developments in BROWNELL, G. L. A N D BURNHAM, positron scintigraphy," page 135 in Instrumentation in Nuclear Medicine Vol. 2, Hine, G. J. and Sorenson, J. A., Eds. (Academic Press,New York). BROWNELL, G. L., ELLET,W. H., AND REDDY,A. R. (1968).Absorbed Fractions for Photon Dosimehy, MIRD Pamph. 3, Suppl. 1, J. Nucl. Med. BROWNELL, G. L., BURNHAM, C. A., WILENSKY, S., ARONOW, S., KAZEMI,H., AND STRIEDER, D. (1969). "New developments in positron scintigraphy and the application of cyclotron-produced positron emitten," page 163 in Medical Radioisotope Scintigraphy, Vol. I, IAEA Publication No. STI/Pub/l93

REFERENCES

/

137

(International Atomic Energy Agency, Vienna). BUDINCER, T. F. (1974). "Quantitative nuclear medicine imaging; Application of computers to the gamma camera and whole body scanner." page 41 in Progress in Atomic Medicine, Vol. 4. Recent Advances in Nuclear Medicine Lawrence, J. H., Ed. (Academic Press, New York). BUDINGER, T. F., DERENZO, S. E., GULLBERG, G. T. et al. (1977). "Emission computer assisted tomography with single-photon and positron annihilation photon emitters," J. Comput. Assist. Tomogr. 1, 131. CANTOLINO, S. J., SCHMICKEL, R. D., BALL,M., AND CISAR,C. F. (1966). "Persistent chromosomal aberrations following radioiodine therapy for thyrotoxicosis," N. Engl. J. Med. 276, 739. CASSEN,B., CURTIS,L., REED,C., AND LIBBY,R. (1951). "Instrumentation for 113' use in medical studies," Nucleonics 9, No. 2, 46. CASTRONOVO, F. P., JR., WEBSTER,E. W., STRAUSS,H. W., BREEN,C. P., HOLLEY,M. J., I n , AND FOLDING, F. J. (1982).A Health Physics Guide for Patient Care Units: The Radiation Precautions Associated with Patients Undergoing Diagnostic Radwpharmaceutical Procedures. (Massachusetts General Hospital Isotope Committee, Boston). CFR (1981a). Code of Federal Regulations. Title 21. Food a n d Drugs. Parts 50, 201, 210, 310, 312, 314, 361 (U.S. Government Printing Office, Washington). CFR (1981b). Code of Federal Regulations. Title 10. Energy. Parts 19,20,30, 31, 35 (U.S. Govenunent Printing Office, Washington). B., PEREZ-MENDEZ, V. (1976)."Axial tomography CHANG, L. T., MACDONALD, and three dimensional image reconstruction," IEEE Trans. Nucl. Sci. NS23, 1, 568. CHAPMAN, E. M. AND MALOOF, F. (1955). "The use of radioactive iodine in the diagnosis and treatment of hyperthyroidism: Ten years' experience," Medicine 34,261. CHARPAK, G. (1977). "Applications of proportional chambers and drift chambers in high-energy physics and other fields," Nature 270, 479. CLOUTIER, R. J. AND WATSON, E. E. (1970)."Radiation dose from radioisotopes in the blood," page 325 in Medical Radwnuclides: Radiation Dose a n d Effects, Cloutier, R. J., Edwards, C. E., and Snyder, W. S., Eds. Report No. CONF 691212 (National Technical Information Service, Springfield, Virginia). COHEN,B. L. (1982). "Failures and critique of the BEIR 111lung cancer risk estimates," Health Phys. 42,267. R. A. et al. (1967). ~ e d i c aSurvey l of the People of Rongelap a n d CONARD, Uterik Islands Eleven and Twelve Years after Exposure to Fallout Radiatwn (March 1965and March 1966)BNL 50029 (T-446)Brookhaven National Laboratory, Upton, New York (National Technical Information Service, Springfield, Virginia). CONARD, R. A., DOBYNS, B. M., A N D SUTOW, W. W. (1970)."Thyroid neoplasia as a late effect of acute exposure to radioactive iodines in fallout," J. Am. Med. Assoc. 214, 316. CONARD, R. A. et al. (1975). A Twenty-Year Review of Medical Findings in a Marshallese Population Accidentally Exposed to Radioactive Fallout,

138

/

REFERENCES

BNL 50424 (National Technical Information Service, Springfield, Virginia). CONARD, R. A. et a1 (1980). Review of Medical Finding in a Marshulk,se Population Twenty-six Years After Accidental Exposure to Radiouctive Fallout, BNL 5126 (National Technical Information Service, Springfield, Va. H. N. JR. (1971). "Automated DE BLANC,H. J., DELAND,F. H. AND WAGNER, radiometric detection of bacteria in 2,967 blood cultures," Appl. Microbiol. 22,846. DEWEY,W. C. A N D SINCLAIR, W. K. (1961)."Criteria for evaluating collimators used in in vivo distribution studies with radioisotopes," Int. J. Appl. Radiat. Isot. 10, No. 1, 1. DHEW (1968). Department of Health, Education and Welfare. Survey of the Use of Radionuclides in Medicine: Preliminary Report, MORP 68-10 by Williams, K. D. and Sutton, J. D. (U.S. Department of Health, Education and Welfare, Rockville, Md.). DHEW (1970). Department of Health, Education and Welfare, Public Health Service, Food and Drug Administration, Bureau of Radiological Health. Survey of the Uses of Radwnuclides in Medicine, BRH/DMRE 70-1 (US. Department of Health, Education and Welfare, RockviUe, Md.). DHEW ( 1976a).Department of Health, Education and Welfare, Public Health Service, Food and Drug Administration, Bureau of Radiological Health. Quality Control for Scintillation Cameras, HEW Publication No. (FDA) 76-8046 (US. Department of Health, Education and Welfare, Rockville, Md.). DHEW (1976b).Department of Health, Education and Welfare, Public Health Service, Food and Drug Administration, Bureau of Radiological Health. Workshop Manual for Quality Control of Scintillation Cameras in Nuclear Medicine, HEW Publication No. (FDA) 76-8039 (U.S. Department of Health, Education and Welfare, Rockville, Md.). DHEW (1976~). Department of Health, Education and Welfare, Public Health Service, Food and Drug Administration, Bureau of Radiological Health. Applications of Iodine-123 in Nuclear Medicine, HEW Publication No. (FDA) 76-8022 (U.S. Department of Health, Education and Welfare, Rockville, Md.). DHEW (1977). Department of Health, Education and Welfare, Public Health Service, Food and Drug Administration. Guidelines for the Clinical Evaluation o f Radiophannaceutical Drugs. HEW Publication (FDA) 77-3044 (Government Printing Office, Washington). DILLMAN, L. T. (1969). Radwnuclide Decay Schemes and Nuclear Parameters for Use in Radiation Dose Estimation, MIRD Pamph. 4, Suppl. 2, J. Nucl. Med. DILLMAN, L. T. (1970). Radionuclide Decay Schemes and Nuclear Parameters for Use in Radiation Dose Estimation, Part 2, MIRD Pamph. 6, Suppl. 4, J. Nucl. Med. DILLMAN,L. T . AND VON DER LACE, F. C. (1975). Radwnuclide Decay Schemes and Nuclear Parameters for Use in Radiation Dose Estimation, MIRD Pamph. 10 (MIRD Committee, Maryville, Tennessee). J. S. (1972). "Hepatic scintigraphy in DRUM,D. E. AND CHRISTACOPOULOS,

REFERENCES

/

139

clinical decision making," J. Nucl. Med. 13, 908. DRUM,D. E. AND BEARD,J. M. (1976). "Scintigraphic criteria for hepatic metastases from cancer of the colon and breast," J . Nucl. Med. 17,677. DUHME,D. W., GREENBLATT, D. J., A N D KOCH-WESER, J . (1974). "Reduction of digoxin toxicity associated with measurement of serum levels," AM. Int. Med. 80, 516. ECKELMAN, W. C. AND LEVENSON, S. M. (1978). "Radiopharmaceutical chemistry of Technetium and Iodine," page 197 in Textbook of Nuclear Medicine: Basic Science, Rocha, A.F.G. and Harbert, J.C., Eds. (Lea and Febiger, Philadelphia). ECKELMAN, W. C., REBA,R. C., GIBSON,R. E., RZESZOTARSKI, W. J., VIERAS, F., MAZAITIS, J. K., AND FRANCIS, B. (1979). "Receptor-binding radiotracers: A class of potential radiopharmaceuticals," J. Nucl. Med. 20, 350. ELLETT,W. H. A N D HUMES,R. M. (1971). Absorbed Fractions for Small Volumes Containing Photon-Emitting Radioactivity, MIRD Pamph. 8, Suppl. 5, J . Nucl. Med. EVANS,R. D. (1955). The Atomic Nucleus (McGraw-Hill, New York). EVANS,R. D. (1981). "Inception of standards for internal emitters, Radon and Radium," Health Phys. 41,437. EVANS,R. D., KEANE,A. T., KOLENKOW, R. J., NEAL,W. R., AND SHANAHAN, M. M. (1969). "Radiogenic tumors in the radium and mesothorium cases studied at M.I.T.," page 157 in Delayed Effects of Bone-Seeking Radionuclides, Mays, C. W., W. S. S., Lloyd, R. D., Stover, B. J., Dougherty, J. H., Taylor, G. N., Eds. (University of Utah Press, Salt Lake City, Utah). FEDERALREGISTER(1981). Vol. 46, No. 17, 8942 dated 27 January 1981, "Protection of Human Subjects," Title 21, Part 50, and "Radioactive Drugs for certain research uses," Title 21, Part 361.1. FENYVES, E. AND HAIMAN, 0. (1969). The Physical Principles of Nuclear Radiation Measurements (Academic Press, New York). FINKEL,A. J., MILLER,C. E., AND HASTERLIK, R. J. (1969). "Radium-induced malignant tumors in man," page 195 in Delayed Effects of Bone-Seeking Radionuclides, Mays, C. W., Jee, W. S. S., Lloyd, R. D., Stover, B. J., Dougherty, J . H., and Taylor, G. N., Eds. (University of Utah Press, Salt Lake City, Utah). FORD,L., SHROFF,A., BENSON,W., ATKINS,H., A N D RHODES,B. A. (1978). "SNM drug problem reporting system," J. Nucl. Med. 19, 116. FORD,M. R., SNYDER, W. S., A N D WARNER,G. G. (1975). Variation of the Absorbed Fraction with Shape and Size of Thyroid, ORNL Report 5046, Oak Ridge National Laboratory, Oak Ridge, Tennessee (National Technical Information Service, Springfield, Virginia). FRY,R. J. M., GRAHN,D., GRIEM,M., AND RUST,J . H. (1970). Late Effects of Radiation, Proceedings of a Colloquium, University of Chicago, May 1969 (Van Nostrand Reinhold Company, New York). GEORGE,R. A. A N D WAGNER, H. N., JR. (1975). "Ten years of brain tumor scanning a t Johns Hopkins: 1962-1972," page 3 in Noninuasiue Brain Imaging, De Blanc, H. J. and Sorenson, J. A., Eds. (Society of Nuclear Medicine, New York). GERBER,M. S., MILLER,D. W., SCHLOSSER, P. A., STEIDLEY,J. W., AND

140

/

REFERENCES

DEUTCHMAN, A. H. (1977). "Position sensitive gamma-ray detectors using resistive charge division readout," IEEE Trans. Nucl. Sci. NS-24, No. 1,182. GILLESPIE,F. C., ORR, J. S., AND GREIG,W. R. (1970). ''Microscopic dose distribution for ''=I in the toxic thyroid gland and its relation to therapy," Br. J. Radiol. 43,40. GOODENOUGH, D. J., METZ,C. E.,AND LUSTED,L. B. (1973). "Caveat on use of the parameter d' for evaluation of observer performance," Radiology 106, 565. GOTTSCHALK, A. AND BECK,R. N. (1968).Fundamental Problems in Scanning (Charles C. Thomas, Springfield, Illinois). HALPERIN, J. A,, STRINGER, F. A., AND EASTEP,R. E. (1979). "Regulation of radiopharmaceuticals an analysis of radiopharmaceuticals approved for marketing in the United States: 1950-1978" page xxi in Proceedings of the Second International Symposium on Radiophurmaceuticals, CONF-790321 (National Technical Information Service, Springfield, Virginia). HART,R. W. AND FARRELL, R. A. (1968)."Imaging distribution of radioactivity within the human body. I. Theoretical considerations in optiumum data processing," Invest. Radiol. 3, 199. HAYES,R. L. (1978). "The medical use of gallium radionuclides: a brief history with some comments." Sem. Nuc. Med. 8, 183. HEATH,R. L. (1964). Scintillation Spectrometry Gamma-Ray Spectrum Catalogue, 2nd Edition, U.S. Atomic Energy Commission, Idaho Operations Office Report IDO-16880-1 (National Technical Information Service, Springfield, Virginia). HETZEL,K.R. AND ICE, R. D. (1975). "Pitfalls in radiometric sterility assay." J. Nucl. Med. 16, 798. HINE, G. J. (1967). Instrumentation in Nuclear Medicine, Vol. I (Academic Press, New York). HHS. (1980). Department of Health and Human Services. Page 23 and page 55 in Research Into the Biological Effects of Ionizing Radiation in The Bureau of Radiological Health. H.H.S. Publication (FDA) 80-8125. (Bureau of Radiological Health, Rockville, Maryland). HHS. (1982). Department of Health and Human Services, Public Health Service, Food and Drug Administration, Bureau of Radiological Health. Radiation Safety in Nuclear Medicine: a Practical Guide. H.H.S. Publication (FDA) 82-8180. (Government Printing Office, Washington). HOFFER,P. B., JONES,W. B., CRAWFORD, R. B., BECK,R. N., AND GOTTSCHALK,A. (1968). "Fluorescent thyroid scanning: A new method of imaging the thyroid," Radiology 90, 2, 342. K ,(1971). Role of SemiconHOFFER,P. B., BECK,R. N. AND G O ~ C H A LA. ductor Detectors in the Future of Nuclear Medicine (Society of Nuclear Medicine, Inc., New York). G. A N D WALINDER, G. (1980) "Incidence of malignant HOLM,L. E., LUNDELL, thyroid tumors in humans after exposure to diagnostic doses of 1-131. 1. Retrospective cohort study" J. Nat. Cancer Inst. 64 No. 5, 1055 J. H. (1969). Photon Cross Sections, Attenuation Coefficients a n d HUBBELL, Energy Absorption Coefficients from 10 keV to 100 GeV. National Bureau of Standards, National Standard Reference Data Service Publication

REFERENCES

/

141

NSRDS-NBS-29 (Government Printing Office, Washington). IAEA (1973) International Atomic Energy Agency. Medical Radioisotope Scintigraphy Volumes I and 11, IAEA Publication No. STI/PUB/315 (International Atomic Energy Agency, Vienna). ICRP (1960). International Commission on Radiological Protection, Report of Committee II on Permissible Doses for Internal Radiation, ICRP Publication 2 (Pergamon Press, London). ICRP (1971).International Commission on Radiological Protection, Protection of the Patient in Radionuclide Investigations, ICRP Publication No. 17 (Pergamon Press, New York). ICRP (1975).International Commission on Radiological Protection. Reference Man: Anatomical, Physiological a n d Metabolic Characteristics, ICRP Publication No. 23 (Pergamon Press, New York). ICRP (1979). International Commission on Radiological Protection. Limits for Intakes of Radionuclides by Workers, ICRP Publication No. 30 (Pergamon F'ress, New York). ICRU (1979). International Commission on Radiation Units and Measurements. Methods of Assessment of Absorbed Dose in Clinical Use of Radionuclides, ICRU Report 32 (International Commission on Radiation Units and Measurements, Washington, D.C.). JEAVONS, A., SCHORR,B., KULL,K., TOWNSEND D., FREY,P. AND DONATH, A. (1981). "A large-area stationary positron camera using wire chambers," page 49 in Medical Radionuclide Imaging, 1980Vol. I. International Atomic Energy Agency Publication STI/Pub 564 (International Atomic Energy Agency, Vienna). JOHNSTON, R. E. A N D STAAB,E. V. (1975). "Radiation dose to the brain from I%-DTPA in cisternography," J. Nucl. Med. 16, 101. JOINTCOMMISSION ON ACCREDITATION OF HOSPITALS (1970). Hospital Accreditation Program, Accreditation Manual for Hospitals, Updated 1973 and 1976 (Joint Commission on Accreditation of Hospitals, 875 N. Michigan Ave., Chicago, Ill.). J. NUCL. MED. (1976) Journal of Nuclear Medicine, "American Board of Nuclear Medicine Information, Policies and Procedures, 1976," J. Nucl. Med. 17, 328. R. E. (1976). "Biology of Internal DosimeKAPLAN,W. D. A N D ZIMMERMAN, tly," in Radiopharmaceutical Dosimetry Symposium, HEW (FDA) 76-8044 (U.S. Government Printing Office, Washington, D.C.). KAUFMAN, L., PEREZ-MENDEZ, V., SHAMES,D., AND STOKER,G. (1972). "A multi-wire proportional chamber for nuclear medicine applications," IEEE Trans. Nucl. Sci. NS-19, No. 3, 169. KAUFMAN, L. HATTNER,R. PRICE,D., SWANN, S., AND HUBERTY,J. (1975). "Imaging with a small ultra pure germanium gamma-camera," IEEE Trans. Nucl. Sci. NS-22, 395. KAUL,A., OEFF, K., ROEDLER, H. D., AND VOCELSANC, T. (1973).Radiopharmaceuticals-Biokinetic Data a n d Results of Radiation Dose Calculations (Informationsdienst fiir Nuklearmedizin, Berlin). KUHL,D. E. (1964) "A clinical radioistope scanner for cylindrical and section scanning," page 273 in Medical Radioisotope Scanning, Vol. 1, IAEA

142

/

REFERENCES

Publication No. STI/PUB/82 (International Atomic Energy Agency, Vienna). LARSON,K. B. A N D COX,J. R., J R . (1974). Computer Processing of Dynamic Images from an Anger Scintillation Camera (The Society of Nuclear Medicine, Inc., New York). LARSON,S. M., RASEY,J. S., ALLEN,D. R. A N D NELSON,N. J. (1979) "A transfenin-mediated uptake of gallium-67 by EMT-6 sarcoma. 1. Studies in tissue culture." J. Nucl. Med 20,837. LATHROP,K. A., COHEN,T. D., BECK,R. N. A N D HARPER,P. V. (1970) "Comparison of '%a, *Tc and ""In used with the gamma camera and the 3-inch and 5-inch scanners for visualization of lesions in the brain, kidney, liver, and lung." P. 265 in Radioisotopes in Pharmakokinetik und Klinischer Biochemie, Keiderling, W., Hoffmann, G. and Ladnet, H. A. Eds. (F. K. Schattauer Verlag, New York). LEDERER,C. M., HOLLANDER, J. M., AND PERLMAN, I. (1968). Table of Isotopes 6th Ed. (John Wiley & Sons, Inc., New York). LEWITUS,Z., LUBIN,E., RECHNIC, J., BEN-PORATH, M. A N D FEIGE,Y. (1971). "The Treatment of thyrotoxicosis with Iz5I and '"I". Semin. Nucl. Med. 1, 411. LIN, M. S. A N D WINCHELL,H. S. (1970). "Kinetics of amino acid transport across bone marrow cell membranes," J. Clin. Invest. 49, 752. A., A N D WINCHELL, H. S. (1974a). "A -TC-chelate LIN, T. H., KHENTIGAN, substitute for organoradiomercurial renal agents," J . Nucl. Med. 15,34. LIN, T. H.,-KHENTIGAN, A., A N D WINCHELL, H. S. (19748). "A 99mTc-labeled replacement for I3'I-Rose Bengal in liver and biliary tract studies," J. Nucl. Med. 15,613. LINFOOT,E. H. (1964). Fourier Methods in Optical Image Evaluation (The Focal Press, New York). LOBERG, M. D., COOPER,M., HARVEY, E., COLLERY, P., A N D FAITH,W. (1976). "Development of new radiopharmaceuticals based on N-substitution of iminodiacetic acid," J. Nucl. Med. 17. 633. R A N D BERMAN,M. (1968). A Schema for Absorbed-Dose CalLOEVINGER, culations for Biologically-Distributed Radionuclides-MIRD Pamph. l , Suppl. 1, J. Nucl. Med. LOEVINGER, R. A N D BERMAN, M. (1976). A Revised Schema for Calculating the Absorbed Dose from Biologically Distributed Radionuclides, MIRD Pamph. 1, Revised (Society of Nuclear Medicine, New York). LOEWINGER, E., et al. (1975). "In uivo x-ray fluorescence measurements a s a diagnostic tool," Phys, Med. Biol. 20, 142. LOKEN,M. K. A N D KUSH,G. S. (1970). "Handling, uses, and radiation dosimetry of I3%e," page 253 in Medical Radionuclides: Radiation Dose and Effects, Cloutier, R. J., Edwards, C. L., and Snyder, W. S., Eds. Report No. CONF 691212 (National Technical Information Service, Springfield, Virginia). LUSTED,L. B. (1968). Introduction to Medical Decision Making (Charles C Thomas, Springfield, Illinois). LUSTED,L. B. (1971). "Decision-making studies in patient management," New Engl. J. Med. 284, 416.

REFERENCES

/

143

MACINTYRE, W. J., FEDORUK,S. O., HARRIS,C. C., KUHL, D. E., AND MALLARD, J. R. (1969)."Sensitivity and resolution in radioisotope scanning. A report to the International Commission on Radiation Units and Measurements," page 391 of Medical Radioisotope Scintigraphy, Vol. 1, IAEA Publication No. STI/PUB/193 (International Atomic Energy Agency, Vienna). MAXON,H. R., THOMAS,S. R., SAENGER, E. L., BUNCHES,C. R. AND KEREIAKES,J. G. (1977). "Ionizing radiation and the induction of clinically significant disease in the human thyroid gland." Amer. J . Med. 63, 967. MAYS,C. W. (1973). "Cancer induction in man from internal radioactivity." Health Phys. 25, 585. MAYS,C. W. A N D SPIESS,H. (1979) "Bone tumors in Thorotrast patients." Environ Res. 18,88. MAYS,C. W., SPIESS,H. A N D GERSPACH, A. (1978). "Skeletal effects following 224 Ra injections into humans," Health Phys. 35,83. MCCREADY, V. R., PARKER,R. P., GUNNERSEN, E. M., ELLIS,R., MOSS,E., GORE,W. G. A N D BELL,J. (1971). "Clinical tests with a prototype semiconductor gamma camera," page 157 in Role of Semiconductor Detectors in the Future of Nuclear Medicine, Hoffer, P. B., Beck, R. M. and Gottschalk, A. Eds. (Society of Nuclear Medicine, Inc., New York). MCNEIL, B. J. A N D ADELSTEIN,S. J. (1976). "Determining the value of diagnostic and screening tests," J. Nucl. Med. 17,439. B. A., A N D ADELSTEIN, S. J. (1975a) MCNEIL,B. J., VARADY, P. D., BURROWS, "Measures of clinical efficacy. Cost-effectivenesscalculations in the diagnosis and treatment of hypertensive renovascular disease," New Eng. J. Med. 293, 216. S. J . (1975b). "Primer on certain MCNEIL,B. J., KEELER,E., A N D ADELSTEIN, elements of medical decision making," N. Eng. J. Med. 293, 211. MCNEIL,B. J., HESSEL,S. J., BRANCH, W. T., BJORK,L., A N D ADELSTEIN, S. J . (1975~)."Use of signal detection theory in evaluating the efficacy and cost-effectiveness of lung scanning," in Proceedings of 22nd Annual Meeting, Society of Nuclear Medicine, Abstract in J. Nucl. Med. 16, 550. MCNEIL,B. J., HESSEL,S. J., BRANCH, W. T., BJORK,L., A N D ADELSTEIN, S. J. (1976). "Measures of clinical efficacy. I n . The value of the lung scan in the evaluation of young patients with pleuritic chest pain," J. Nucl. Med. 17, 163. MCNEIL,B. J., COLLINS,J. J., JR., A N D ADELSTEIN, S. J . (1977). "Rationale for seeking occult metastases in patients with bronchial carcinoma," Surg. Gynecol. Obstet. 144, 389. MEDIPHYSICS (1976). Product description. Package insert-biological dataIndium-111. (Medi Physics, Emeryville, California). METZ,C. E., AND BECK,R. N. (1974)."Quantitative effects of stationary h E a r image processing on noise and resolution of structures in radionuclide images," J. Nucl. Med. 15, 164. METZ,C. E., STARR,S. J., A N D LUSTED,L. B. (1977). "Quantitative evaluation of medical imaging," page 491 in Medical Radionuclide Imaging, Vol. 1, IAEA Publication No. STI/PUB/440 (International Atomic Energy Agency, Vienna).

144

/

REFERENCES

MIRD (1972). Medical Internal Radiation Dose Committee Supplement No. 6, Pamph. 9. "Radiation dose to humans from 76Se-Lselenomethionine," (Society of Nuclear Medicine, New York). MIRD (1973). Medical Internal Radiation Dose Committee Dose Estimate Report No. 2, "Summary of current radiation dose estimates to humans from =Ga-, 67Ga-,mGa-, and 72Ga-Citrate,"J. Nucl. Med. 14, 755. MIRD (1975a). Medical Internal Radiation Dose Committee Dose Estimate Report No. 3. "Summary of current radiation dose estimates to humans with various liver conditions from T c - s u l f u r colloid," J. Nucl. Med. 16,108A. MIRD (1975b). Medical Internal Radiation Dose Committee Dose Estimate Report No. 4, "Summary of current radiation dose estimates to humans with various liver conditions from 'geAu-coUoidalgold," J. Nucl. Med. 16, 173. MIRD (1975~).Medical Internal Radiation Dose Committee Dose Estimate Report No. 5, "Summary of current radiation dose estimates to humans from lZ3I,luI, '%I, '%I, '913' ,1, and 13'1 as sodium iodide," J. Nucl. Med. 16, 857. MIRD (1975d). Medical Internal Radiation Dose Committee Dose Estimate Report No. 6, "Summary of current radiation dose estimates to humans from Ig7Hg-and mHg-labeled chloromerodrin," J. Nucl. Med. 16,1095. MIRD (1975e). Medical Internal Radiation Dose Committee Dose Estimate Report No. 7, "Summary of current radiation dose estimates to humans from lZ3I,'%I, lZ6I,13'1, and 13'1 as sodium rose bengal," J. Nucl. Med. 16, 1214. MIRD (1976). Medical Internal Radiation Dose Committee Dose Estimate Report NO. 8, "Summary of current radiation dose estimates to normal humans from y c as sodium pertechnetate," J. Nucl. Med. 17,74. MIRD (1980). Medical Internal Radiation Dose Committee Estimate Report No. 9, "Estimate9 of radiation absorbed doses from radioxenons in lung imaging" J. Nucl. Med. 21.459. MODAN,B. AND LILIENFELD, A. M. (1965). "Polycythemia Vera and leukemia-the role of radiation treatment," Medicine 44,305. MOLE,R. H. (1978). "The radiobiological significance of the studies with aURa and Thorotrast," Health Phys. 35.167. MORIN,R. L. AND BROOKEMAN, V. A. (1974). ""Vb-DTPA distribution and dosimetry in cisternogaphy," J. Nucl. Med. 15, 786. MUEHLLEHNER, G., BUCHIN,M. P., AND DUDEK,J. H. (1976). "Performance parameters of a positron imaging camera," IEEE Trans, Nucl. Sci. NS-23, No. 1, 528. MULLANI, N. A., FICKE,D. C., HARTZ,R., MARKHAM J. AND WONG,G. (1981). "System design of fast PET scanners utilizing time-of-flight." IEEE Trans., Nucl. Sci. NS-28, No. 1, 104. MYERS,M. J., KEYES, W. I., AND MALLARD,J. R. (1973). "An analysis of tomographic scanning systems," page 331 in Medical Radioisotope Scintigraphy 1972, Vol. I , IAEA Publication No. STI/PUB/315 (International Atomic Energy Agency, Vienna). MYERS,W. G. (1966). "Radioisotopes of iodine," page 217 in Radioactive Pharmaceuticals, CONF-651111 (National Technical Information Service, Springfield, Virginia).

REFERENCES

/

145

NAS/NRC (1972).The Effects on Populations of Exposure to Low Levels of Ionizing Radiation. (National Academy o f Sciences, Washington). NAS/NRC (1980).Committee on Biological Effects of Ionizing Radiation of the National Academy o f Sciences/National Research Council. The Effects on Populations of Exposure to Low Levels ofzonizing Radiation. (National Academy o f Sciences, Washington). NCRP (1970).National Council on Radiation Protection and Measurements. Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides. NCRP Report No. 37, (National Council on Radiation Protection and Measurements, Washington). NCRP (1971). National Council on Radiation Protection and Measurements, Basic Radiation Protection Criteria, NCRP Report No. 39, (National Council on Radiation Protection and Measurements, Washington). NCRP (1975).National Council on Radiation Protection and Measurements. Review of the Current State of Radiation Protection Philosophy, NCRP Report No. 43, (National Council on Radiation Protection and Measurements, Washington). NCRP (1976).National Council on Radiation Protection and Measurements. Radiation Protection for Medical and Allied Health Personnel, NCRP Report No. 48, (National Council on Radiation Protection and Measurements, Washington). NCRP (1977).National Council on Radiation Protection and Measurements. Medical Radiation Elcposure of Pregnant and Potentially Pregnant Women, NCRP Report No. 54, (National Council on Radiation Protection and Measurements, Washington). NCRP (1978a).National Council on Radiation Protection and Measurements. Instrumentation and MonitoringMethods for Radiation Protection, NCRP Report No. 57, (National Council on Radiation Protection and Measurements, Washington). NCRP (1978b).National Council on Radiation Protection and Measurements. A Handbook of Radioactivity Measurements Procedures, NCRP Report No. 58, (National Council on Radiation Protection and Measurements, Washington). NCRP (1979).National Council on Radiation Protection and Measurements. Tritium and Other Radionuclide Labeled Organic Compounds Zncorporated in Genetic Material, NCRP Report No. 63, (National Council on Radiation Protection and Measurements, Washington). NCRP (1980a).National Council on Radiation Protection and Measurements. Influence of Dose and Its Distribution in Time on Dose-EffectRelationships for Low-LET Radiations, NCRP Report No. 64, (National Council on Radiation Protection and Measurements, Washington). NCRP (1980b).National Council on Radiation Protection and Measurements. Management of Persons Accidentally Contaminated with Radionuclides, NCRP Report No. 65, (National Council on Radiation Protection and Measurements, Washington). OLDENDORF, W . H. (1974)."Lipid solubility and drug penetration of the bloodbrain barrier." Proc. Soc. Exp. Biol. Med. 147,813. O'NEILL,E. L. (1963). Introduction to Statistical Optics. (Addison-Wesley

146

/

REFERENCES

Publishing Co., Inc., Reading, Mass.). OSGOOD,E. E. (1965). "The relative dosage required of total body x-ray vs. intravenous '"P for equal effectiveness against leukemic cells of the lyrnphocytic series or granulocytic series in chronic leukemia," J. Nucl. Med. 6,421. J. -4. (1978). Personal communication. Vanderbilt University. PATTON, PATTONJ. A. A N D BRILLA. B. (1978). "X-ray fluorescence techniques for thyroid imaging; methods and results", page 287 in Radioaktive Isotope in Klinik und Forschung Vol. 13, Hofer, R. and Bergmam, H. Eds. (Verlag H. Egermann, Vienna). PATTON,J. A., BRILL,A. B., AND JOHNSTON, R. E. (1971). "Potential use of fluorescent scanning for brain tumor identification," page 258 in Role of Semiconductor Detectors in the Future of Nuclear Medicine, Hoffer, P. B., Beck, R. N., and Gottschalk, A. Eds. (Society of Nuclear Medicine, Inc., New York). E. (1980)."Separation of PINKERTON, T. C. HEINEMAN, W. R., A N D DEUTSCH, technetium hydroxyethylidene diphosphonate complexes by anion exchange high performance liquid chromatography." Anal. Chem. 52, 1106. PIZER,S. M. (1981). "An automatic intensity mapping for the display of CT scans and other images," in Proceedings of the VIIth International Conference on Information Processing in Medical Imaging, Stanford University. (to be published). PIZER,S. M. A N D TODD-POKROPEK, A. E. (1976)."Noise character is processed scintigrams ," page 1 in Information Processing in Scintigraphy, Raymond, C. and Todd-Pokropek, A., Eds. CEA Publication No. DEA-CR-6 (Centre d' Etudes Nucleaires de Saclay 91, Gif-sur-Yvette, France). PIZER,S. M., JOHNSTON, R. E., ZIMMERMAN, J. B., A N D CHAN,F. H. (1982). "Contrast perception with video displays," in Picture Archiving and Communication Systems for Medical Applications, Proc. Soc. Photo-Opt. Instrum. Eng. 318, 222. E. F., CULLEN,D. E. AND HOWERTON, R. J. (1978). Tables a n d PLECHATY, Graphs of Photon-Interaction Cross Sections from 0.1 keV to 100 MeV derived from the LLL Evaluated-Nuclear-DataLibrary, Lawrence Livermore Laboratory Report No. UCRL-50400, Vol. 6, Rev. 2. (National Technical Information Service, Springfield, Va). POCHIN, E. E. (1969). "Long-term hazards of radioiodine treatment of thyroid carcinoma," page 293 in Thyroid Cancer, UICC Monograph Series Bal. 12, Hedinger, C. Ed. (Springer-Verlag, Berlin). POLEDNAK, A. P., STEHNEY, A. G., A N D ROWLAND, R. E. (1978). "Mortality among women f m t employed before 1930 in the U. S. radium dial-painting industry. A group ascertained from employment lists." Am. J. Epidemid. 107, 179. POSTON,J. W. (1976). "The effects of body and organ size on absorbed dose: There is no standard patient," Radiopharmaceutical Dosimetry Symposium, HEW (FDA) 76-8044 ( U S . Government Printing Office, Washington). QUINN,J . L., 111 (1975). The American College of Radiology Survey on Regionalization in Nuclear Medicine-A Report. (American College of Radiology, Chicago, Ill.). C. G., et al. (1957). "Radiation RALL,J. E., ALPERS,J . B., LEWALLEN,

REFERENCES

/

147

Pneumonitis and Fibrosis, a Complication of Radioiodine Treatment of Pulmonary Metastases from Cancer of the Thyroid," J. Clin. Endoc. 17, 1263. ROEDLER,H. D. (1980). "Radiation Dose to the Patient in Radionuclide Studies." Proceedings of the International Symposium on Medical Radionuclide Imaging. Heidelberg, Federal Republic of Germany, 1-5 September 1980. Sponsored by IAEA/WHO. ROEDLER, H. D., KAUL,A. A N D HINE,J. J. (1978). Internal Radiation Dose in Diagnostic Nuclear Medicine, (Verlag H. Hoffman, Berlin). ROWLAND, R. E. AND DURBIN,P. W. (1976). "Survival, causes of death and estimated tissue doses in a group of human beings injected with plutonium," Page 329 in Health Effects of Plutonium a n d Radium, Jee, W. S. S. Ed. (J. W. Press, University of Utah, Salt Lake City). R. E. A N D STEHNEY, A. F. (1978). "Radium-induced malignancies" ROWLAND, Page 259 in Argonne National Laboratory Report ANL 78-65, Part II (National Technical Information Service, Springfield, Virginia). RUSSELL,W. L. (1965) "Effect of interval between irradiation and conception on mutation frequency in female mice". Proc. Natl. Acad. Sci. 54, 1552. SAENGER, E. L., THOMA,G. E., AND TOMPKINS, E. A. (1968). "Incidence of leukemia following treatment of hyperthyroidism," J. Am. Med. Assn., 205, 855. SAMSON, G., WACKERS, F. J . TH., BECKER,A. E., et al. (1976). "Distribution of Thallium-201 in man," in Proceedings of the 14th Annual Meeting of the West German Society of Nuclear Medicine. SARKAR, S. D., BEIERWALTES, W. H., GILL,S. P., AND COWLEY, B. J . (1976). "Subsequent fertility and birth histories of children and adolescents treated with I:" I for thyroid cancer," J. Nucl. Med. 17, 460. SASAKI,Y., WAGNER,H. N., AND IIO, M. (1971). "Catheter semiconductor detector and its application to clinical and experimental medicine," Page 144 in Role of Semiconductor Detectors in the Future of Nuclear Medicine, Hoffer, P. B., Beck, R. N., and Gottschalk, A,, Eds. (Society of Nuclear Medicine, Inc., New York). L. C. (1971). "Simulation SCHULZ, A. G., KNOWLES, L. G., AND KOHLENSTEIN, studies of nuclear medicine instrumentation," Applied Physics Laboratory Technical Digest 10, 2. SCHULZ,A. G., KOHLENSTEIN, L. C., A N D KNOWLES, L. G. (1973). "Factors affecting recognition of scintigraphic abnormalities," J. Nucl. Med. 3,327. SEYDEL,H. G. (1973). "Thyroid neoplasms in therapeutically irradiated patients," Page 44 in Radionuclide Carcinogenesis, Sanders, C. L. Busch, R. H. Ballou, J . E., and Mahlum, D. D., Eds. AEC Symp. Series 29 (National Technical Information Service, Springfield, Virginia). SHELINE,G. E., LINDSAY, S., MCCORMACK, K. R., AND GALANTE, M. (1962). "Thyroid nodules occurring late after treatment of thyrotoxicosis with radioiodine," J . Clin. Endoc. 22.8. SNYDER, W. S. (1970)."Estimation of absorbed fraction of energy from photon sources in body organs," Page 33 in Medical Radionuclides: Radiation Dose a n d Effects, Cloutier, R. J., Edwards, C. L., and Snyder, W. S., Eds. AEC Symposium Series 20 CONF 691212 (National Technical Information

148

/

REFERENCES

Service, Springfield, Virginia). SNYDER, W. S. AND FORD,M. R. (1976). "Estimation of dose to the urinary bladder and to the gonads," in Radiopharmaceutical Dosimetry Symposium, ORNL Report No. CONF 760444 (National Technical Information Service, Springfield, Virginia). SNYDER, W. S., FORD,M. R., WARNER, G. G., A N D WATSON,S. B. (1974). A Tabulation o f Dose Equivalent per Microcurie-Day for Source and Target Organs of an Adult for Various Radwnuclides, ORNL Report 5000 (National Technical Information Service, Springfield, Virginia). SNYDER, W. S., FORD,M. R., WARNER, G. G., A N D WATSON,S. B. (1975). ''S" Absorbed Dose per Unit Cumulated Activity for Selected Radionuclides and Organs, MIRD Pamph. 11 (Society of Nuclear Medicine, MIRD Committee, Maryville, Tenn.). SNYDER, W. S., FORD,M. R., AND WARNER, G. G. (1978). Estimates of Specific Absorbed Fractions from Photon Sources Uniformly Distributed in Various Organs of a Heterogeneous Phantom, NM/MIRD Pamph. 5, Revised, (Society of Nuclear Medicine, New York). SORENSON, J. A. (1975). "Deadtime characteristics of Anger Cameras" J. Nucl. Med. 16,284. SORENSON, J. A. (1976). "Methods of correcting Anger camera deadtime losses" J. Nucl. Med., 17, 137. SPIESS,H. (1969). "P4Ra-induced tumors in children and adults," Page 227 in Delayed Effects of Bone-Seeking Radwnuclides, Mays, C. W . ,Jee, W. S. S., Lloyd, R. D., Stover, B. J., Dougherty, H. H., and Taylor, G. N., Eds. (University of Utah, Salt Lake City, Utah). SRIVASTAVA, S. C., BANDYOPADHYAY, D., MEINKEN,G., A N D RICHARDS, P. (1981)."Characterization of Tc-99m bone agents (MDP, EHDP) by reversephase and ion-exchange high performance liquid chromatography." J. Nucl. Med. 22 (6),P69. E. M. (1976). "Non-operative management STANBURY, J . B. AND CHAPMAN, of hyperthyroidism," in Controversy in Surgery, Varco, R. L. and Delaney, J. P., Eds. (W. B. Saunders Co., Philadelphia). I. (1978)."image artifacts a t high photon fluence STRAND, S. E., AND LARSSON, rates in single crystal NaI scintillation cameras," J. Nucl. Med. 19, 407. SWETS,J. A., PICKE'IT, R. M., WHITEHEAD, S. F., GE'ITY,D. J., SCHNUR, J. A., SWETS,J . B. AND FREEMAN, B. A. (1979). “Assessment of diagnostic technologies," Science 204, 753. TER-POCOSSIAN, M. M., PHELPS,M. E., BROWNELL, G. L., COX,J. R., JR., DAVIS,D. O., AND EVANS,R. G. (1977). Reconstruction Tomography in Diagnostic Radiology and Nuclear Medicine. (University Park Press, Baltimore). TER-POGOSSIAN, M. M., MULLANI, N. A., FICKE,D. C., MARKHAM, D. J., AND SNYDER,D. L. (1981). "Photon time-of-flight-assisted position emission tomography," J . Comput. Asst. Tomog. 5, 227. TONKIN,A. K. AND DE LAND,F. H. (1974). "Dihydro-thioctic acid: A new polygonal cell imaging agent," J. Nucl. Med. 15,539. K. A. (1973). "Experimental methods for TSIALAS,S. P. AND PSARRAKOS,

REFERENCES

/

149

determining the septum penetration of focused collimators," Page 47 in Medical Radioisotope Scintigraphy 1972 Vol. I , IAEA Publication No. STI/PUB/316 (International Atomic Energy Agency, Vienna). TSUI, B. M. W., METZ,C. E. AND BECK,R. N. (1977). "Optimum detector spatial resolution for tumor identification." Presented at the AAPM 19th Annual Meeting, 1977. Abstracted in Medical Physics 4, 340. Summarized in Medical Imaging 2, (4), 49. TSUI, B. M. W., METZ,C. E.. ATKINS,F. B., STARR,S. J. AND BECK,R. N. (1978). "A comparison of optimum collimator resolution based on a theory of detection and observer performance." Phys. Med. Biol. 23(4), 654. (Errata are noted in Phys. Med. Biol., 23(6), 1203. TUBIS, M. (1978). "Quality control of radiopharmaceuticals," page 234 in Textbook of Nuclear Medicine: Basic Science, Rocha A. F . G., and Harbert, J. C., Eds. (Lea and Febiger, Philadelphia). UNSCEAR (1966). United Nations Scientific Committee on the Effects of Atomic Radiation. Report of the United Nations Scientific Committee on the Effects of Atomic Radiation General Assembly: Twenty-First Session Supplement No. 14. (United Nations, New York.) UNSCEAR (1969). United Nations Scientific Committee on the Effects of Atomic Radiation. Report of the United Nations Scientific Committee on the Effects of Atomic Radiation General Assembly: Twenty-FourthSession Supplement No. 13. (United Nations, New York). UNSCEAR (1972). United Nations Scientific Committee on the Effects of Atomic Radiation. Ionizing Radiation: Levels and Effects.(United Nations. New York). UNSCEAR (1977). United Nations Scientific Committee on the Effects of Atomic Radiation. Ionizing Radiation Sources and Effects. (United Nations. New York). USP (1975). The United States Pharmacopoeia 19th Revision, (The U.S. Pharmacopeial Convention, Inc., Rockville, Maryland). USP (1980). The United States Pharmacopoeia 20th Revision, (The U.S. Pharmacopeial Convention, Inc., Rockville, Maryland). L. H., LAWRENCE, J. N. P., A N D MOSS, W. D. VOELZ,G. H., HEMPELMANN, (1979). "A 32 year medical follow-up of Manhattan Project plutonium workers," Health Phys. 37,445. D. L., Scorn, A., PELLER,J. A., VALE,J. M., EZRIN,C., VOLPE,R., SCHATZ, AND JOHNSTON, M. W. (1961). "Radioactive iodine in the treatment of hyperthyroidism (experience at the Toronto General Hospital, 1950-1958). Part 111. Possible biological hazards from radioactive iodine therapy," Can. Med. Assoc. J. 84: No. 2,84. WAGNER,H. N., JR., AND EMMONS, H. (1966). "Characteristics of a n ideal radiopharmaceutical," Page 1 in Radioactive Pharmaceuticals, CONF 651111 (National Technical Information Service, Springfield, Virginia). WAGNER, J., DUNN,W., RAMMAYA, A. V. AND BRILL,A. B. (1977). "Positron imaging using time of flight techniques," Proceedings of IVLhInt. Conf. on Medical Physics, Ottawa, Canada, July 25-30, 1976. (Abstract published in Phy. Med. Biol. 22, 110.

150

/

REFERENCES

WANG,S. C., TING, K. S., A N D WU, G. G. (1965). "Chelating therapy with NaDMS in occupational lead and mercury intoxication," Chinese Medical J. 84,437. WEINER,R. E., THAKUR, M. L. GOODMAN, M. M. et al. (1979). "Relative stability of In-111 and Ga-67 desferrioxamine and human transferrin complexes," Page 331 in Radiopharmaceuticals ZI: Proceeding 2nd International Symposium on Radiopharmaceuticals (Society of Nuclear Medicine, New York). WELLMAN, H. N., KEREIAKES, J. G., A N D BRANSON, B. M. (1970). "Total- and partial-body counting of children for radiopharmaceutical dosimetry data," Page 133 in Medical Radionuclides: Radiation Dose and Effects, Cloutier, R. L., Edwards, C. L., and Snyder, W. S., Eds. AEC Symposium Series 20 (National Technical Information Service, Springfield, Virginia). WINCHELL, H. S. (1970). "Dosimetry considerations for radioisotopically labeled organic compounds," Page 225 in Medical Radionuclides: Radiation Dose and Effects, Cloutier, R. L., Edwards, C. L., and Snyder, W. S., Eds. AEC Symposium Series 20 (National Technical Information Service, Springfield, Virginia). H. S., Pollycove, M., Kusubov, N. and Fawwaz, R. (1964). "Kinetics WINCHELL, of 13'1 albumin and I3'I transfemn in lymph," Page 273 in Proceedings of the International Symposium on the Preparation and Biomedical Application of Labeled Molecules, Sirchis, J . , Ed. EUR 2200.e (European Atomic Energy Community, Brussels, Belgium). A., LAMB,H. FLEISCHER,A., WINWINSTEAD.M., LIN, T. H., KHENTIGAN, CHELL. H.S., AND MYERS,W. (1973a). "Synthesis and evaluation of "Clabeled organic compounds for use in nuclear medicine," Page 451 in Radiopharmaceuticals and Labelled Compounds, Vol. 1, IAEA Publication No. STI/PUB/344 (International Atomic Energy Agency, Vienna). WINSTEAD, M. B., LAMB,J. F., AND WINCHELL,H. S. (1973b). "Relationship of chemical structure to in v i m scintigraphic distribution patterns of "C compounds: 1. "C-carboxylates," J. Nucl. Med. 14, 747. WHO (1976). World Health Organization. Nuclear Medicine. Report of a Joint ZAEA/ WHO Expert Committee on the Use of Ionizing Radiation and Radioisotopes for Medical Purposes (Nuclear Medicine). WHO Technical Report Series No. 591 (World Health Organization, Geneva).

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 information 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 the application of these concepts, and about radiation protection; 4. Cooperate with the International Commission on Radiological Protection, 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. The Council is made up of the members and the participants who serve on the seventy-four Scientific Committees of the Council. 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: Officers

President Vice President Secretary and Treasurer

WARRENK. SINCLAIR HYMERL. FRIEDELL W. ROGERNEY

152

/

T H E NCRP

Assistant Secretary Assistant Treasurer

Members SEYMOUR ABRAHAMBON S. JAMES ADELSTEIN ROYE. ALBERT EDWARD L. ALPEN JOHN A. AUXIER WILLIAMJ. BAIR JOHND. BOICE.JR. VICTORP. BOND ROBERTL. BRENT ANTONEBROOKS F. BROWN REYNOLD MELVIN W. CARTER GEORGEW. CASARETT RANDALL S. CASWELL ARTHURB. CHILTON GERALDDODD PATRICIAW. DURBIN MERRILEISENBUD MORTIMERM. ELKIND THOMAS S. ELY EDWARD R. EPP HYMERL. FRIEDELL R. J. MICHAELFRY ROBERTA. GOEPP BARRYB. COLDBERC ROBERT0. GOWN DOUGLAS GRAHN ARTHURW. GUY ERICJ. HALL JOHNH. HARLEY NAOMIHARLEY JOHNW. HEALY LOUISM. HEMPELMANN, JR. JOHNM. HESLEP GEORGEB. HUTCHISON JABLON SEYMOUR A. EVERETTEJAMES BERNDKAHN

JAMES C.'KERELAKES

CHARLESE. LAND EDWARDB. LEWIS THOMAS A. LINCOLN RAYD. LLOYD CHARLESW. MAYS ROGER0. MCCLELLAN JAMESMCLAUGHLIN CHARLESB. MEINHOLD MORTIMERM. M E N D E ~ H N WILLIAME. MILLS DADEW. MOELLER A. ALANMOOHISSI PAULE. MORROW ROBERTD. MOSELEY,JR. JAMES V. NEEL WESLEYNYBORC FRANKPARKER ANDREW K. POZNANSKI NORMAN C. RASMU8SEN WLLLIAMC. REINIC CHESTERR. RICHMOND HARALDH. Ross1 ROBERTE. ROWLAND EUGENEL. SAENGER LEONARD A. SAGAN WARRENK. SINCLAIR GLENNE. SHELINE JOHN B. STORER HERMAND. SUIT ROYC. THOMPSON JAMESE. TURNER ARTHURC. UPTON GEORGEL. VOELZ EDWARD W.WEBSTER GEORGEM. WILKENINC MCDONALD E. WRENN Honorary Members

LAURI~TON S . TAYLOR, Honorwy President ROBERTJ. NELBEN RICHARD F. FOSTER PAULC. HODGEE HERBERTM. PARKER GEORGEV. LEROY EDITHH. QUIMBY WILPRIDB. MANN WILLIAMG. RUSSELL KARLZ. MORGAN JOHNH. RUST J. NEWELLSTANNARD RUSSELLH. MORGAN HAROLD0. WYCKOFF

EDGARC. BARNES CARLB. BRAESTRUP AUSTINM. BRUES FREDERICX P. COWAN JAMESF. CROW ROBLEYD. EVANS

THE NCRP

/

153

Currently, the following subgroups are actively engaged in formulating recommendations: Basic Radiation Protection Criteria Medical X-Ray, Electron Beam and Gamma-Ray Protection for Energiea Up to 50 MeV (Equipment Performance and Use) X-Ray Protection in Dental Offices Standards and Measurements of Radioactivity for Radiological Use Radiation Protection in the Use of Small Neutron Generators Dose Calculations Maxirnum Permieaible Concentrations for Occupational and Non-Occupational Exposurea Waste Disposal Task Group on Krypton-& Task Group on Carbon-14 Task Group on Iodine-129 Task Group on Disposal of Accident Generated Wash Water Task Group on Disposal of Low-Level Waste Task Group on the Actinides Task Group on Xenon Biological Aspects of Radiation Protection Criteria Task Group on Atomic Bomb Survivor Dosimetry Subgroup on Biological Aspects of Dosimetry of Atomic Bomb Survivors Industrial Applications of X Rays and Sealed Sources Radiation Associated with Medical Examinations Radiation Received by Radiation Employees Operational Radiation Safety Instrumentation for the Determination of D m Equivalent Apportionment of Radiation Exposure Surface Contamination Radiation Protection in Nuclear Medicine Applied to Children Conceptual Basis of Calculations of Dose Distributions Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Radiation Bioassay for Aaseesment of Control of Intake of Radionuclides Experimental Verification of Internal Dosimetry Calculations Internal Emitter Standards . Task Group 2 on Respiratory Tract Model Task Group 3 on General Metabolic Models Task Group 4 on Radon and Daughters Task Group 6 on Bone Problem Task Group 7 on Thyroid Cancer Risk Task Group 8 on Leukemia Riek Task Group 9 on Lung Cancer Risk Task Group 10 on Liver Cancer Risk Task Group 12 on Strontium Human Radiation Exposure Experience Dosimetry of Neutrons from Medical Accelerators Radon Measurements Priorities for Dose Reduction Efforts Control of Exposure to Ionizing Radiation from Accident or Attack Radionuclidesin the Environment

154

/

THE NCRP

Task Group 2 on Identification and Evaluation of Environmental Models for Estimate of Dose from Discharge to Surface Waters Task Group 3 on Identification and Evaluation of Environmental Models for Estimate of Dose from Discharge to Atmosphere Task Croup 5 on Public Exposure to Nuclear Power Task Group 6 on Screening Models SC-65: Quality Assurance and Accuracy in Radiation Protection Measurements SC-66: Biological Effects and Expoeure Criteria for Ultrasound SC-67: Biological Effects of Magnetic Fields SC-68: Microprocessors in Dosimetry SC-69: Efficacy Studies SC-70: Quality Assurance and Measurement in Diagnostic hdiology SC-71: Radiation Exposure and Potentially Related Injury 32-72: Radiation Protection in Mammography SC-73: Population Exposure from Technologically Enhanced Sources SC-74: Radiation Received in the Decontamination of Nuclear Facilities Committee on Public Education Committee on Public Relations Ad Hoc Committee on Policy in Regard to the International System of Units Ad Hoc Committee on Comparison of Radiation Exposures Study Group on Acceptable Risk (Nuclear Waste) Study Group on Comparative Risk Task Group on Comparative Carcinogenicity of Pollutant Chemicals Task Force on Occupational Exposure Levels

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. The present Collaborating Organizations with which the NCRP maintains liaison are as follows:

American Academy of Dermatology American Association of Physicists in Medicine American College of Radiology American Dental Association American Industrial Hygiene Association American Institute of Ultrasound in Medicine American Insurance Association American Medical Association American Nuclear Society American Occupational Medical Association American Podiatry Association American Public Health Association

THE NCRP

/

155

American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists American Society of Therapeutic Radiologists Association of University Radiologists Atomic Industrial Forum College of American Pathologists Federal Emergency Management Agency Genetics Society of America Health Physics Society National Bureau of Standards National Electrical Manufacturers Association Radiation Research Society Radiological Society of North America Society of Nuclear Medicine United States Air Force United States Army United States Department of Energy United States Department of Labor United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission United States Public Health Service

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 an interest in radiation protection and measurements. This liaison relationship provides: (1) an 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 the 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 an opportunity to make suggestions on new studies and related matters. The following organizations participate in the special liaison program: Defense Nuclear Agency Federal Emergency Management Agency National Bureau of Standards Office of Science and Technology Policy OFfice of Technology Assessment United States Air Force United States Army United States Coast Guard United States Department of Energy

156 /

THE NCRP

United States Department of Health and Human Services United States Department of Labor United States Department of Transportation United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission

The NCRP values highly the participation of these organizatiom in the liaison program. 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: Alfred P. Sloan Foundation Alliance of American Insurers American Academy of Dental Radiology American Academy of Dermatology American Association of Physicists in Medicine American College of Radiology American College of Radiology Foundation American Dental Association American Industrial Hygiene Association Ammican Insurance Association American Medical Association American Nuclear Society American Occupational Medical kssociation American Osteopathic College of Radiology American Podiatry Association American Public Health Association American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists American Veterinary Medical kssociation American Veterinary Radiology Society Association of University Radiologists Atomic Industrial Forum Battelle Memorial Institute Bureau of Radiological Health College of American Pathologists Commonwealth of Pennsylvania Defense Nuclear Agency Edison Electric Institute Edward Mallinckrodt, Jr. Foundation Electric Power Research Institute Federal Emergency Management Agency Florida Institute of Phosphate Research Genetics Society of America Health Physics Society James Picker Foundation National Association of Photographic Manufacturers National Bureau of Standards

THE NCRP

157

National Cancer Institute National Electrical Manufacturers Association Radiation Research Society Radiological Society of North America Society of Nuclear Medicine United States Department of Energy United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission

To all these organizations the Council expresses its profound appreciation for their support. Initial funds for publication of NCRP reports were provided by a grant from the James Picker Foundation and for this the Council wishes to express its deep appreciation. The NCRP seeks to promulgate information and recommendations 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 NCRP publications are distributed by the NCRP Publications' office. Information on prices and how to order may be obtained by directing an inquiry to: NCRP Publications 7910 Woodmont Ave., Suite 800 Bethesda, Md 20814 The currently available publications are listed below.

Proceedings of the Annual Meeting No. 1

Title Perceptions ofRisk, Proceedings of the Fifteenth Annual Meeting, Held on March 14-15, 1979 (Including Taylor Lecture No. 3) (1980) Quantitative Risk in Standards Setting, Proceedings of the Sixteenth Annual Meeting, Held on April 2-3, 1980 (Including Taylor Lecture No. 4) (1981) Critical Issues in Setting Radiation Dose Limits, Proceedings of the Seventeenth Annual Meeting, Held on April 8-9, 1981 (Including Taylor Lecture No. 5) (1982) Radiation Protection and New Medical Diagnostic Procedures, 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) (1984) Some Issues Important in Developing Basic Radiation Protection Recommendations, Proceedings of the Twentieth Annual Meeting, Held on April 4-5, 1984 (Including Taylor Lecture No. 8) (1985) Radioactive Waste, Proceedings of the Twenty-first Annual Meeting, Held on April 3-4, 1985 (Including Taylor Lecture No. 9) (1986)

NCRP PUBLICATIONS

8

9

10 11

12

1

159

Nonionizing Electromagnetic Radiation 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 5-6, 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). Radiation Protection Today-The NCRP at Sixty Years, Proceedings of the Twenty-fifth Annual Meeting, Held on April 5-6, 1989 (Including Lecture No. 13) (1989). Health and Ecological Implications ofRadioactively Contaminated Environments, Proceedings of the TwentySixth Annual Meeting of the National Council on Radiation Protection and Measurements, Held on April 4-5, 1990 (Including Taylor Lecture No. 14) (1991). Symposium Proceedings

The Control of Exposure of the Public to Ionizing Radiation in the Event of Acczdent or Attack, Proceedings of a Symposium held April 27-29, 1981 (1982) Lauriston S. Taylor Lectures No. 1 2 3 4

5

Title and Author The Squares of the Natural Numbers in Radiation Protection by Herbert M. Parker (1977) Why be Quantitative About Radiation Risk Estimates? by Sir Edward Pochin (1978) Radiation Protection-Concepts and Trade O f f s by Hymer L. Friedell (1979) [Available also in Perceptions of Risk, see abovel From "Quantity of Radiation" and 'Dose" to "Exposure" and "Absorbed Dose9'-An Historical Review by Harold 0.Wyckoff (1980) [Available also in Quantitative Risks i n Standards Setting, see abovel How Well Can We Assess Genetic Risk? Not Very by James F. Crow (1981) [Available also in Critical Issues in Setting Radiation Dose Limits, see abovel

NCRP PUBLICATIONS

Ethics, Trade-offs and Medical Radiation by Eugene L. Saenger (1982) [Available also in Radiation Protection and New Medical Diagnostic Approaches, see abovel The Human Environment-Past, Present and Future by Merril Eisenbud (1983) [Available also in Environmental Radioactivity, see abovel Limitation and Assessment in Radiation Protection b y Harald H. Rossi (1984) [Available also in Some Issues Important in Developing Basic Radiation Protection Recommendations, see abovel Truth (and Beauty) in Radiation Measurement by John H . Harley (1985) [Available also in Radioactive Waste, see abovel Nonionizing Radiation Bioeffects: Cellular Properties and Interactions by Herman P. Schwan (1986) [Available also in Nonionizing E2ectromagnetic Radiations and Ultrasound, see above] How to be Quantitative about Radiation Risk Estimates by Seymour Jablon (1987) [Available also in New Dosimetry at Hiroshima and Nagasaki and its Zmplications for Risk Estimates, see abovel 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 above]. Radiation Protection and the Internal Emitter Saga by J. Newel1 Stannard (1990)

NCRP Commentaries No. 1 2

3 4

Title Krypton-85 in the Atmosphere-With Specific Reference to the Public Health Significance of the Proposed Controlled Release at Three Mile Island (1980) Preliminary Evaluation of Criteria for the Disposal of Transuranic Contaminated Warte (1982) Screening Techniques for Determining Compliance with Environmental Standards (19861, Rev. (1989) Guidelines for the Release of Waste Water from Nuclear Facilities with Special Reference to the Public Health SigniJicance of the Proposed Release of Treated Waste Waters at Three Mile Island (1987)

NCRP PUBLICATIONS

1

161

A Review of the Publication, Living Without Landfills ( 1989) Radon Exposure of the U.S. Population-Status of the Problem (1991) Misadministration of Radioactive By-Product Material in Medicine-Scientific Background (1991)

NCRP Reports No. 8

Title

Control and Removal of Radioactive Contamination in Laboratories (1951) Maximum Permissible Body Burdens and Maximum Permissible Concentrations of Radionuclzdes in Air and in Water for Occupational Exposure (1959:l [Includes Addendum 1 issued in August 19631 Measurement of Neutron F l u and Spectra for Physical and Biological Applications (1960) Measurement o f Absorbed Dose ofNeutmns and 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 in Veterinary Medicine (1970) Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Protection Against Neutron Radiation (1971) Protection Against Radiation from Brachytherapy Sources (1972) Specifications of Gamma-Ray Brachytherapy Sources (1974) Radiological Factors Affecting Decision-Making in a Nuclear Attack (1974) Krypton-85 in the Atmosphere-Accumulation, Biological Signijkance, 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 Measurement (1976)

NCRP PUBLICATIONS

Radiation Protection Design Guidelines for 0.1 -1 00 MeV Particle Accelerator Facilities (1977) Cesium-137 from the Environment to Man: Metabolism and Dose (1977) Review of NCRP Radiation Dose Limit for Embryo and Fetus in Occupationally Exposed Women (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977) Protection of the Thyroid Gland in the Event of Releases of Radioiodine (1977) Instrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook of Radioactivity Measurements Procedures, 2nd ed. (1985) Operational Radiation Safety Program (1978) Physical, Chemical, and Biological Properties ofRadwcerium Relevant to Radiation Protection Guidelines (1978) Radiation Safety Training Criteria for Industrial Radiography (1978) Tritium in the Enuironment (1979) Tritium and Other Radwnuclide Labeled Organic Cornpounds Incorporated i n Genetic Material (1979) Influence of Dose and Its Distribution in Time on DoseResponse Relationships for Low-LET Radiations (1980) Management of Persons Acczdentally Contaminated with Radionuclides (1980) Mammography (1980) Radiofreqency 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 i n 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)

NCRP PUBLICATIONS

1

163

Biological Effects of Ultrasound: Mechanisms and Clinical Implications (1983) Iodine-129: Evaluation of Releases from Nuclear Power Generation (1983) Radiological Assessment: Predicting the Transport Bioaccumulation, and Uptake by Man ofRadionuclldes Released to the Environment (1984) Exposures from the Uranium Series with Emphasis on Radon and its Daughters (1984) Evaluation of Occupational and Environmental Exposures to Radon and Radon Daughters in the United States (1984) Neutron Contamination from Medical Electron Accelerators (1984) Induction of Thyroid Cancer by Ionizing Radiation (1985) Carbon-14 in the Environment (1985) SI Units in Radiation Protection and Measurements (1985)

The Experimental Basis for Absorbed-Dose Calculations in Medical Uses of Radionuclides (1985) General Concepts for the Dosimetry of Internally Deposited Radionuclldes (1985) Mammography-A User's Guide (1986) Biological Effects and Exposure Criteria for Radiofreqwncy Electromagnetic Fields (1986) Use of Bioassay Procedures for Assessment of Internal Radionucllde Deposition (1987) Radiation Alarms and Access Control Systems (1987) Genetic Effects of Internally Deposited Radionuclides (1987)

Neptunium: Radiation Protection Guidelines (1987) Recommendations on Limits for Exposure to Ionizing Radiation (1987) Public Radiation Exposure from Nuclear Power Generation in the United States (1987) Ionizing Radiation Exposure o f the Population of the United States (1987) Exposure of the Population in 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)

164

/

NCRP PUBLICATIONS

Measurement of Radon and Radon Daughters in Air (1988)

Guidance on Radiation Received in Space Activities (1989)

Quality Assurance for Diagnostic Imaging (1988) Exposure of the U.S.Population from Diagnostic Medical Radiation (1989) Exposure of the U.S. Population From Occupational 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 in Houses (1989) The Relative Biological Effectiveness ofRadiations ofDifferent Quality (1990) Radiation Protection for Medical and Allied Health Personnel (1989) Limits of Exposure to "Hot Particles" on the Skin (1989) Implementation of the Principle of as Low as Reasonably Achievable (ALARA)for Medical and Dental Personnel (1990)

Conceptual Basis for Calculations ofAbsorbed-Dose Distributions (1991) Effects of Ionizing Radiation on Aquatic Organisms (1991)

Some Aspects of Strontium Radiobiology (1 991) Developing Radiation Emergency Plans for Academic, Medical or Industrial Facilities (1991) Calibration of Survey Instruments Used in Radiation Protection for the Assessment o f Ionizing Radiation Fields and Radioactive Surface Contamination (1991) Binders for NCRP Reports a r e available. Two sizes make it possible to collect into small binders the "old series" of reports (NCRP Reports Nos. 8-30) a n d into large binders the more recent publications (NCRP Reports Nos. 32-112). 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 of NCRP Reports a r e 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

NCRP PUBLICATIONS

1

165

Volume IV. NCRP Reports Nos. 38,40,41 Volume V. NCRP Reports Nos. 42,44,46 Volume VI. NCRP Reports Nos. 47, 49,50,51 Volume VII. NCRP Reports Nos. 52, 53, 54, 55, 57 Volume VIII. NCRP Reports 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 XII. 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 (Titles of the individual reports contained in each volume are given above). The following NCRP Reports are now superseded andlor out of print: No. 1 2

Title X-Ray Protection (1931). [Superseded by NCRP Report No. 31 Radium Protection (1934). [Superseded by NCRP Report No. 41 X-Ray Protection (1936). [Superseded by NCRP Report No. 61 Radium Protection (1938). [Superseded by NCRP Report No. 131 Safe Handling of Radioactive Luminous Compounds (1941). [Out of Print] MedicalX-Ray Protection U p to Two Million Volts (1949). [Superseded by NCRP Report No. 181 Safe Handling of Radioactive Isotopes (1949). [Superseded by NCRP Report No. 301 Recommendations for Waste Disposal of Phosphorus -32 and Iodine-131 for Medical Users (19511. [Out of Print] Radiological Monitoring Methods and Instruments (1952). [Superseded by NCRP Report No. 571

NCRP PUBLICATIONS

Maximum Permissible Amounts of Radioisotopes in the Human Body and Maximum Permissible Concentrations in Air and Water (1953). [Superseded by NCRP Report No. 221 Recommendations for the Disposal of Carbon-14 Wastes (1953). [Superseded by NCRP Report No. 811 Protection Against Radiations from Radium, Cobalt-60 and Cesium-237 (1954). [Superseded b y NCRP Report No. 241 Protection Against Betatron-Synchrotron Radiations Up to 100 Million Electron Volts (1954). [Superseded by NCRP Report No. 5:l.l Safe Handling of Cadavers Containing Radioactive Isotopes (1953). [Superseded by NCRP Report No. 211 Radioactive Waste Disposal in the Ocean (1954). [Out of Print]

Permissible Dose from External Sources oflonizing Radiation (1954)including Maximum PermissibleExposure to Man, Addendum to Natioml Bureau of Standards Handbook 59 (1958). [Superseded by NCRP Report No. 391 X-Ray Protection (1955). [Superseded by NCRP Report No. 261 Regulation of Radiation Exposure by Legislative Means (1955). [Out of Print] Protection Against Neutron Radiation U p to 30 Million Electron Volts (1957). [Superseded by NCRP Report No. 381 Safe Handling of Bodies Containing Radioactive Isotopes (1958). [Superseded by NCRP Report No. 371 Protection Against Radiations from Sealed Gamma Sources (1960). [Superseded by NCRP Report Nos. 33, 34, and 401 Medical X-Ray Protection Up to Three Million Volts (1961). [Superseded by NCRP Report Nos. 33, 34,35, and 361 A Manual of Radioactivity Procedures (1961). [Superseded by NCRP Report No. 581 Exposure to Radiation in an Emergency (1962). [Superseded by NCRP Report No. 421 Shielding for High Energy Electron Accelerator Installations (1964). [Superseded by NCRP Report No. 5:l.l Medical X-Ray and Gamma-Ray Protection for Energies up to 10 MeV-Equipment Design and Use (1968). [Superseded by NCRP Report No. 1021

NCRP PUBLICATIONS

34 39 43

45 48 56 58

1

167

Medical X-Ray and Gamma-Ray Protection for Energies Up to 10 MeV-Structural Shielding Design and E Valuation (1970). [Superseded by NCRP Report No. 491 Basic Radiation Protection Criteria (1971).[Superseded by NCRP Report No. 911 Review of the Current State of Radiation Protection Philosophy (1975). [Superseded by NCRP Report No. 911 Natural Background Radiation in the United States (1975). [Superseded by NCRP Report NO. 941 Radiation Protection for Medical and Allied Health Personnel. [Superseded by NCRP Report No. 1051 Radiation Exposure from Consumer Products and Miscellaneous Sources (1977). [Superseded by NCRP Report No. 951 A Handbook on Radioactivity Measurement Procedures. (1978). [Superseded by NCRP Report No. 58,2nd ed.1 Other Documents

The following documents of the NCRP were published outside of the NCRP Reports and Commentaries series: "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 of the Whole Body," Am. J. Roentgenol., Radium Ther. and Nucl. Med. 84, 152 (1960) and Radiology 75, 122 (1960) 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). X-Ray Protection Standards for Home Television Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (National Council on Radiation Protection and Measurements, Washington, 1968) Specification of Units of Natural Uranium and Natural Thorium (National Council on Radiation Protection and Measurements, Washington, 1973) NCRP Statement on Dose Limit for Neutrons (National Council on Radiation Protection and Measurements, Washington, 1980)

168

/

NCRPPUBLICATIONS

Control ofAirEmissions ofRadionucli&s (National Council on Radiation Protection and Measurements, Bethesda, Maryland, 1984) Copies of the statements published in journals may be consulted in libraries. A limited number of copies of the remaining documents listed above are available for distribution by NCRP Publications.

Index Absorbed radiation dose, 8, 9, 22, 50-65, 85,116-134 absorbed fractions, 51, 52, M anatomic model, 60 assumptions, 50, 51, 52, 62, 63 biological determinants, 50, 52, 62-63 calculations, 51, 58-65 charged particle radiations, 53, 56 children, 57 complicating factors, 50 conversion electron range, 59 critical organs, 22 critical tissues, 22 cumulated activities, 63 dose rate, 51, 60 energy deposited, 56 excretion, 51 gonad dose, 57 Graves disease, 59 iodine kinetics, 59 kidney, 60,61 liver, 64 mechanisms, 61 microdosimetry, 56, 59 Monte Carlo type calculations, 56,57 organ size,51,57 physical data, 53 radiocontaminant, 8,9, B radioiodines, nuclear data, 53 RUP,22 red bone marrow, 65 reference man, 51 reference organs. 51 residence time in kidney, 51 reticuloendothelial system, 62 spleen, 64 stomach walls and intestine, 50 sources of data, 56 S values, 53 technetium sulfur colloid, 62 testes, 65 thyroid, 53,55,58,59, 85 uncertainties, 57

Accelerators, 3, 5,6, 17, 18 BLIP, 5 cyclotrons. 17 LAMPF, 6 linear accelerators, 17 low-cost cyclotrons, 5 radionuclide manufacturers, 6 TRIUMF, 6 Van de Graaff, 17, 18 AEC, 3,4.23 accelerator produced products, 23 accelerators, 3 broad licenses, 23 medical applications. 3 nuclear reactors, 4 reactor by-product material, 23 routine medical use list, 23 Bromine, 7 Calcium, 12, 15 Carbon, 7. 18 Categories of subjects, 73, 95-98 adult patients, 96 child patients, 97 hospital personnel, 96 normal volunteers, 73,96,97,98 patients, 73, 95 persons exposed by proximity to patients, 96 pregnant patients, 96 Clinical evaluation-aposteriori tests, 8689 accuracy, 87 characterization, 86 decision matrix, 86 detection, 86 example, 87 false negative, 87, 88 false positive, 86, 88 identification, 86 receiver operating characteristic, (ROC), curves, 89

Clinical evaluation-Continued recognition, 86 sensitivity, 86 specificity. 86 true negative, 86,88 true positive, 86, 88 Cyclotron-hospital, 18 Dead time, 45,46 measurement, 46 non-paralyzable detectors, 45 paralyzable detectors, 45 Decision making, 1, 3, 26, 45 choice of RDP, 3 collimator, 45 efficacy, 26 informed consent, 1 instrumentation. 1 labeled compound, 1 new RDPs, 1 patient benefit, 26 patient risk, 26 practice of nuclear medicine, 1 procedure cost, 26 production delays, 26 radionuclide, 1 R D P cost, 26 spatial resolutions, 45 spatial sensitivity, 45 Decision matrix, 87, 88 Department of Transportation (DOT), 24 Diffusion, 14, 15 amino acids, 14, 15 extracellular fluid, 15 intracellolar protein, 15 Dose Calibrators, 32 amount of radioactivity, 32 energy discrimination, 32 ionization chambers, 32 principle of operation. 32 standard sources, 32 Efticacy, 26, 90-95 Bayes' theorem, 90 brain scanning, 92, 93 cost effectiveness, 93 decision matrix, 90 detection of distant metastases, 93 diagnostic accuracy. 91 digoxin radioassay. 91 examples, 90, 91 instrumentation. 26

measurement methods, 94 new information, 90 reduction in morbidity, 91 ROC analysis, 91, 92 screening, 94 summary, 95 Evaluation of new procedures, 73, 74 Excretion, 16

FDA, 24.25 efficacy, 24 GMP. 24 IND, 24 Figures of merit (FOM), 74-81.83-85 assumptions, 78 calculations, 78, 79 classification, 84 collimator. 77 comparisons. 80 contrast, 77 criteria, 75, 85 detection, 84 detector FOM, 77,81 effective detectability, 77 evaluation of therapy procedures, 85 examples, 77, 78, 79, 81 ideal rndiotherapeutic drug, 85 index of confidence, 76 information content, 75 instrument evaluation, 81 mathematical formulation, 75.76 model predictions, 83 modulation transfer function, (MTF), 77 normalized FOM, 77 radiopharmaceutical, favored, 81 radiopharmaceutical, ideal, 85 recognition, 84 resolution, 81 sensitivity, 77, 81 signal-to noise ratio, 75, 76 superficial vs deep lesions, 79 thyroid uptake, 85 visual response, 83 Fluorine, 6, 13, 15. 72 Gallium, 6, 17 Generator, 5, 7 !N'M~-WI~'T~, ""Os-lq'Ir, 7 *'Hb-'"Kr, 7 Gold, 81 Guidance, 1, 2, 26, 31,96,97

INDEX absorbed dose assessment. 2 choice of RDP for D, or R,, 26 dose guidelines, 97 equipment, 1 facility, 1, 2 factors in choice of instrument, 31 hospital personnel, 96 management of misadministration, 26 NCRP reports, 2.96 personnel, 1, 2 Radioactive Drug Research Committee, 97 space, 1 training, 1 Guidelines, 95-99, 103-1 15 adult normal volunteers, 98 adult patients, 96 amount used, 95 basic principles, 95 categories of subjects, 95 child normal volunteers, 98 child patients. 97 clinical evaluation, 103-115 diagnostic administration, 96 dose guidelines. 98 information content, 95 informed consent. 98 instrument, 95 optimal combination, 95 patient dose reduction, 99 pregnant women, 96 radiation dose, 95 radiation protection guides, 99 radionuclide, 95 KDP, 95 volunteer subjects, 97 History, 3, 4, 31 measurement systems, 31 radionuclide production, 4 KDPs in medicine, 3 Image quality, 83, 84 artifacts, 84 attenuation. 84 blur, 84 interference, 84 limiting factors, 83 noise, 83 non-linear distortion, &1 reduction of contrast, 83 Imaging systems. 34-37, 42

1

171

cesium fluoride scintillator, 36 computers, 36 drift chambers, 35 longitudinal tomography, 35 mosaic crystal cameras, 35 NaI(T1) scintillation detectors, 34, 42 positron emission tomography (PET), 36 positron imaging system, 35 properties, 37 resolution, 35 semiconductor detectors, 42 scintillation cameras, 34 transverse section tomography. 36 X-ray fluorescence, 36 Imaging system properties, 37,39-46 artifacts, 46 collimated detectors. 37,44, 45 Compton scattering, 39 dead time, 45 detector resolution. 37 detector sensitivity. 37 energy resolution, 37, 39-42 energy selection efficiency, 39 Fourier transform, 43 full width a t half maximum (FWHM), 39,42 geometrical efficiency, 37 ideal detector. 43 image contrast, 42 image quality, 46 inherent detector efficiency, 37 line source response function, 43 line spread function, 45 modulation transfer function. (MTF), 42. 43, 45 non-paralyzable detectors, 45,46 paralyzable detectors, 45, 46 plane source sensitivity, 37 point source sensitivity. 37 recording devices, 46 resolution, 37, 39,42, 45 resolving time, 45 scattered radiation, 39.40.43.44 sensitivity, 37.45 signal to noise ratio, 39 Indium, 6. 17.81 Instrumentation, 31-34,48,49 Anger camera, 31 blood flow studies, 48 choice, 31, 32 collimators, 31

172

1

INDEX

Instrumentation-Conlinued dead time, 49 dose calibrators, 32 dynamic studies, 49 factors affecting choice of systems, 48 figure of merit (FOM), 49 historical. 31 imaging, 31 image contrast, 49 nature of problem, 32 probe systems, 34 resolution, 49 sample counters, 33 sample measurement, 31 sample type, 32 scintillation cameras, 49 sensitivity, 32 signal-to noise ratio. 49 statistical fluctuation, 48 survey type, 32 temporal factors, 48 time available, 32 Investigational new drugs (INDs), 21, 25, Appendix A contaminants, 21 efficacy, 25 general safety tests, 21 guidelines. 25 kits, 21 phase I studies, 25 phase I1 studies, 25 phase 111studies, 25 safety, 25 Indium, 6 Iodine, 6, 17, 50, 53, 56, 58, 61, 67-69, 72, 85,99

Iridium. 7 Kidney dose, 60-62 assumptions, 62 chlormerodrin, 61 chlormerodrin retention data, 61 model, 60 non-functioning transplant, 62 normal kidney, 62 reaidence time. 61 uremia, 62

broad licenses, 23 experience and training, 23 facilities, 23 institutional review, 23 routine medical use l i t , 23 FDA, 24 Liver dose, 62,7741 technetium sulfur colloid, 62 Localization of labeled materials, 11-17, 20,21

Mercury, 61 Microdosimetry, 60 Misadministration, 26-28 administrative responsibilities, 27 adverse reaction, 28 defined, 27 diagnostic, 27 FDA, 28 approved therapeutic agents, 27 consequence, 27 guidance for responsible physician, 27 IND, 28 management, 27 NCRP guidance, 27 NDA, 28 NRC, 27 therapeutic, 27 therapeutic options, 27 Misadministration management, 28, 29 blocking agents, 29 cation exchange, 29 chelating agents, 29 dosimetric data. 28 fust aid, 28 free-radical scavengers, 29 medical care responsibilities. 28 oral, 28 Molybdenum, 17 New drug application (NDA), 25 Nitrogen, 7 NRC, 21,27 agreement state. 24 DOT, 24 regulatory function, 24 Nuclear reactor, 4, 17

Krypton, 7

Oxygen, 7 Licensing, 23, 24 authorizations, 23 authorizing physicians, 23

Phosphorus, 69, 72 Plutonium, 66,67

INDEX Potassium, 18 Probe systems, 34 Cd Te eemiconductors, 34 G-Mcounters, 34 HgI eemiconductors, 34 intracavitary probes, 34 intravascular probes, 34 NaI(TI), 34 Si(Li) semiconductors,34 surgical probes, 34 thyroid uptake, 34 Quality 899-IX. 18-22 absorbed radiation dose, 22 animal test system, 21 apyrogenicity, 22 bacterial endotoxin, 22 chemical toxicity, 20 chemical treatment, 22 "C-labeled sugars, 22 dose calibrators, 19 FDA regulations, 22 filtration, 22 Ge detectors, 19 general safety. 21 heat, 22 high intensity radiation, 22 high performance liquid chromatopaP ~ Y19 , in viuo distribution, 20,21 ionization chambers, 19 limulus arnebocyte lysate coagulation, 22 multichannel analyzers, 19 NaI detectors, 19 parenteral drugs,22 pyrogenic reactions, 22 radiochemical identity and purity, 18,19 radiochromatogaphy, 19 radionuclide identity, 18,19 radionuclide purity. 18,19 radionuclide quantity, 18 single channel analyzers, 19 solvent and eluting systems, 19 sterility, 22 testing recommendations, I9 validation, 21 Radiation detectors, 3, 4, 31-46 (See Instrumentation and Imaging system) Radiation dose (See Absorbed radiation dose)

/

173

Radiation effects, 65-72 accidental exposures, 65 alpha particle emitters, 65, 66,71 anemia, 66 Bikini, 67 cancer, 66,67,68, 71 chromosome abnormalities, 69 cytogenetic changes, 68 diagnostic studies, 70 fission products, 67 high-LET, 71 historical summary,70 hypothyroidism, 69 iodine isotopes, 67.68 late, 71 leukemia, 66,68,69 low-LET, 71 miners, 66 negative findings, 70 occupational exposures, 65 phosphorus therapy, 69 plutonium. 66 radium dial painters, 65 radium therapy, 65 selective localization, 71,72 sources of information, 65 Thorotrast, 66,67 thyroid nodules, 69 thyroid therapy, 68.69 transmutation, 72 tumors, 66 WBC count, 68 Radioactive Drug Research Committee, 25 authority, 25 Code of Federal Regulations, 25 human metabolic research, 25 number of patients, 25 radiation dose, 25 research studies, 25 Radiochromatography, 19 Radionuclides, 6 bromine. 7 calcium, 12.15 carbon, 7.18 diisopropyl fluorophosphate, 13 fluoride ion, 15 fluorine, 6,72 gallium, 6,17 gold, 81 indium, 6,17,81 iodine, 6,17,50,53,56,58,61,67,68,69,

174

/

INDEX

Radionuclides-Continued 72,85,99 iridium, 7 mercury, 61 molybdenum, 17 nitrogen, 7 oxygen, 7 phosphorus, 69,72 plutonium, 66,67 potassium, 18 radium, 65,66 ruthenium, 7 strontium, 15 technetium, 17,62-65,81 thallium, 72 thorium, 66 tin,7 uranium, 66 xenon, 7, 17 Radiopharmaceuticals-Desirable characteristics for diagnostic use, 7-10 Radiopharmaceuticals-desirable characteristics for therapeutic use. 11 Radiopharmaceutical drug products, 3,4, Appendix B ideal, 3 Radiopharmaceutical localization, 12-17, 20,21 absorption, 20 active transport, 14 albumin, 12, 14 amino acids, 13, 14 apetite crystal, 14 blood-brain barrier, 14 blood flow, 15. 16 blood perfusion, 13 bone, 16 capillary endothelium, 13 carbohydrates, 13 cell membranes, 14 cells, 21 colloidal material, 21 diffusion, 14, 15 distribution, 20 electrolytes, 13 endothelial pores, 13 excretion, 16,20 extracellular fluid, 14 fibrinogen, 14 high molecular weight molecules, 14 inert gases, 13 indium, 12

infarct, 16 inflammatory reactions, 14, 16, 17 intercapillary pores, 16 ion exchange, 15 labeled particles, 21 lipid insoluble, 14 low molecular weight molecules, 14 lymphatic blockage, 14 lymphatic drainage, 17 neoplasms, 14.16,17 neovascularization processes, 14 new vessel growth, 17 nuclide-dependent tracers, 21 pathophysiology. 20 permeability, 16 phagocytosis, 17 phosphates, 16 phosphonates, 16 plasma proteins, 16 polyphosphates, 16 proteins, 13,21 pyrophosphates, 16 receptor sites, 17 reticuloendothelial cells, 13, 15 reticulocudothelial system, 21 selectivity, 20 strontium, 12 transcapillary movement, 15 transferrin, 12, 14, 17 true tracer, 20 Radiopharmaceutical, mechanisms, 12 Hadiopharmaceutical, quality assurance, I8 (see quality assurance) Radium, 65,66 Reactors, 4, 17 Recommendations, 101,102 diagnostic studies, 102 discontinue replaced tests, 102 general, 101 new agents, 102 RDPs in women in reproductive years. 102 radioactive iodine in children, 101 therapeutic procedures, 102 Receiver operating characteristic (ROC), 89

Recording devices, 46-48 Regulations, 23,25 accelerator produced products, 23 AEC, 23 agreement states, 25 disposal, 23

INDEX distribution, 23 DOT, 25 human use, 23 medical practice. 25 NRC,25 production, 23 reactor by-product material, 23 shipping, 23 storage, 23 testing, 23 utilization, 23 Resolution, 39, 43,48,49 energy resolution, 39-41,49 factors affecting choice of systems, 48 full width a t half maximum (FWHM), 39,42 index of resolution, 42 modulation transfer function (MTF), 42 scattered radiations, 43 spatial resolution, 42, 49 temporal resolution, 45 Reticuloendothelial system, 63.64 absorbed dose, 64 assumptions, 63 dose calculation example, 64 radiocolloids, 63 technetium sulfur colloid, 63 Ruthenium, 7 Sample counters, 33 NaI(T1) crystal, 33 Si(Li) detectors, 33 Scintillation cameras, 34,35 Anger cameras, 34 dynamic studies, 34,35 high spatial resolution, 34 image intensifier, 35 mosaic crystal cameras, 35

semiconductor cameras, 35 sensitivity, 35 Short-lived radionuclides, 5, 6, 7 dose reduction, 5 fluorine-18, 6 generators, 5 indium-111, 6 iodine-124, 6 logistics, 5 w ~ o - " Y 5m ~ ~ , 'Y'Os-'"Ir, 7 production, 5 radiation detection. 5 "Rb-nlmKr,7 I I : I S ~1:lm - IIn, 5 Survey instruments, 32 Strontium, 15 Technetium, 17,62-65,81 Thallium, 72 Thorium, 66 Thyroid'dose, 53-55,58-60 absorbed fraction, 54 biological values for iodine, 53 dose calculations, 55, 58, 59 dose rate, 60 mean radiation dose. 55 microdosimetry, 59, 60 radioiodines, 58 Tin, 7 Transmutation, 51 Transportation, 24 Uranium. 66 Xenon, 7, 17 X-ray fluorescence imaging, 36

/

175