NCRP REPORT No 135 Liver Cancer Risk from Internally-Deposited Radionuclides Recommendations of the NATIONAL COUNCIL ON RADIATION PROTECTION AND MEASUREMENTS Issued March 9, 2001 National Council on Radiation Protection and Measurements 7910 Woodmont Avenue / Bethesda, Maryland 20814-3095 LEGAL NOTICE This Report was prepared by the National Council on Radiation Protection and Measurements (NCRP) The Council strives to provide accurate, complete and useful information in its documents However, neither the NCRP, the members of NCRP, other persons contributing to or assisting in the preparation of this Report, nor any person acting on the behalf of any of these parties: (a) makes any warranty or representation, express or implied, with respect to the accuracy, completeness or usefulness of the information contained in this Report, or that the use of any information, method or process disclosed in this Report may not infringe on privately owned rights; or (b) assumes any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this Report, under the Civil Rights Act of 1964, Section 701 et seq as amended 42 U.S.C Section 2000e et seq (Title VII) or any other statutory or common law theory governing liability Library of Congress Cataloging-in-Publication Data National Council on Radiation Protection and Measurements Liver cancer risk from internally-deposited radionuclides : recommendations of the National Council on Radiation Protection and Measurements p ; cm (NCRP report ; no 135) “Issued March 2001.” Includes bibliographical references and index ISBN 0-929600-68-1 (alk paper) Liver Cancer Contrast media Carcinogenicity Radiation carcinogenesis I Title II Series [DNLM: Liver Neoplasms etiology Radiation dosage Radioisotopes-adverse effects Risk Assessment WI 735 N277L 2000] RC280.L5 N37 2000 616.99’436071 dc21 00-053315 Copyright © National Council on Radiation Protection and Measurements 2001 All rights reserved This publication is protected by copyright No part of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyrightowner, except for brief quotation in critical articles or reviews For detailed information on the availability of NCRP publications see page 83 Preface This Report updates the liver cancer risk of Thorotrast® in humans Thorotrast®, a radiographic contrast medium containing naturally occurring radionuclides of thorium was widely used in the first half of the twentieth century An increased incidence of liver cancer in this population of patients has been known for some time Utilizing data on the liver cancer risk of Thorotrast® and of low-LET radiations in animals, the liver cancer risk of low-LET radiation in humans is also estimated This Report was prepared by Scientific Committee 57-10 on Liver Cancer Risk Serving on Scientific Committee 57-10 were: Co-Chairmen Antone L Brooks Washington State University-Tricities Richland, Washington Glenn N Taylor University of Utah Salt Lake City, Utah Members Steve Benjamin Colorado State University Fort Collins, Colorado Kurt Wegener Instituts des Klinikums Ludwigshafen Rhein, Germany G van Kaick Institut für Nuklearmedizin Deutsches Krebsforschungszentrum Heidelberg, Germany Horst Wesch Institut für Radiologie und Pathophysiologie Heidelberg, Germany iii iv / PREFACE NCRP Secretariat E Ivan White, Senior Staff Scientist (1979–1993) Thomas M Koval, Senior Staff Scientist (1993–1999) Lynne A Fairobent, Staff Scientist (1999–2000) Cindy L O’Brien, Managing Editor The Council wishes to express its appreciation to the Committee members for the time and effort devoted to the preparation of this Report Charles B Meinhold President Contents Preface iii Overview Affinity of Radionuclides for Liver Tissue 2.1 Characteristics of Liver Tissue 2.2 Affinity of Radionuclides in Ionic or Compound Forms in Various Tissues 2.3 Distribution of Radionuclides in Colloidal or Particulate Form 3 Effective Half-Life 10 Radiation Dose from Internally-Deposited Radionuclides 12 Radiosensitivity of Liver Tissue 5.1 Sensitivity to Morphological Changes 5.2 Sensitivity for Cell Killing 5.3 Influence of Latent Period on Cancer Risk 5.4 Sensitivity for Cancer Induction 14 14 15 15 16 Physical Variables that Alter Response 6.1 Cellular and Tissue Dose Distribution 6.1.1 Influence of Dose Distribution at the Cellular Level 6.1.2 Influence of Dose Distribution on Liver Cancer 6.2 Influence of “Particle Loading” on Cancer Induction 6.3 The Role of Injury on Cancer 6.4 The Role of Mechanistic Studies on Liver Cancer Risks 18 19 v 19 20 23 23 24 vi / CONTENTS Use of Experimental Animal Data 28 7.1 Relative Biological Effectiveness of the Radiation Emitted by Radionuclides 28 7.2 Liver Cancer Risk from Animal Data 28 Liver Risk Estimates in Humans 33 Uncertainty in Current Risk Estimates 9.1 Strengths of the Data 9.1.1 Identification of the Thorotrast® Population 9.1.2 Defined Dose and Response Relationships 9.1.3 Transfer of the Information to Other Populations 9.2 Weaknesses of the Data 9.2.1 Dose Range and Dose Used in Risk Estimates 9.2.2 Uncertainty Related to “Wasted Dose” Estimates 9.2.3 Uncertainty Associated with Dose Distribution 9.2.4 Uncertainty Associated with Extrapolations from Animal Data 9.2.5 Uncertainty Related to Environmental Insults 48 48 48 49 49 50 50 50 52 52 53 10 Summary 55 References 56 The NCRP 74 NCRP Publications 83 Index 93 Overview This Report provides an update of the cancer risk from radionuclides deposited in the liver The liver has been considered an organ with a low risk for cancer induction from ionizing radiation (ICRP, 1991; NCRP, 1993a) This may in part have been because of the long latency period required to detect increases in radiation-induced liver cancer Other estimates have increased the risk of liver cancer to a value of 300 cancers 10–4 Gy–1 (NAS/NRC, 1988; UNSCEAR, 1994) This Report provides a re-evaluation of the molecular, cellular, experimental animal and human liver cancer data, and an update of the risk of liver cancer from internally-deposited radionuclides To determine risk, it is first essential to calculate the radiation dose to the liver This is dependent on the affinity of the radionuclides for hepatic tissue, the radionuclide’s chemical form, the LET (linear energy transfer) of the emitted radiation, and the radionuclide’s physical and biological half-lives Risk assessment includes not only an understanding of dose to a tissue, but also an appreciation of biological factors that may impact cancer frequency, such as sensitivity to radiation-induced cell killing and the presence of liver disease such as necrosis, fibrosis and cirrhosis Other biological factors, such as sex, age at exposure, and exposure to other environmental insults, can also alter the sensitivity for radiation-induced liver cancer Obviously, variations in any of these relationships will have a significant influence on the risk of radiation-induced liver cancer and the uncertainty associated with such risk Each of these physical and biological variables are considered in this Report For many types of radiation exposures, e.g., chronic exposure to low-LET radiation, there are no statistically significant human data (UNSCEAR, 2000; Volume 2, Table 9) Therefore, animal and cellular data must be used for extrapolation of radiation risk to humans Liver cancer induced in experimental animals by internally-deposited radioactive materials can be used to estimate human cancer risks This is done by determining the relative biological effectiveness (RBE) for liver cancer in animals following / OVERVIEW exposure to both high- and low-LET radiation This information can be used to extrapolate to liver cancer risk in humans Of principle concern, in relation to the risk of liver cancer from internally-deposited radioactive material, are the radionuclides which concentrate in the liver and emit alpha particles The major source of information on such human liver cancer risk is from patients injected with a thorium-based contrast media, Thorotrast®.1 These human data are supplemented with animal and cellular data to solve problems associated with using Thorotrast® data as the basis for human liver cancer risk and for the extrapolation of these risks to other radionuclides Some of the problems that are addressed in this Report, using animal data, include nonuniform distribution, potential chemical toxicity, disease, and interaction of other biological factors in the cancer induction process Animal studies support the validity of using the human Thorotrast® cancer data as a model for cancer risk induced by other internally-deposited alpha-emitting radioactive materials (Brooks et al., 1983; Gilbert et al., 1998; Muggenburg et al., 1996; Taylor et al., 1993) This Report updates the risk estimates derived by the Committee on Biological Effects of Ionizing Radiation [BEIR (NAS/NRC, 1988)] and the United Nations Scientific Committee on the Effects of Atomic Radiation [UNSCEAR (1994)] The liver cancer risk for alpha emitters in this Report is calculated to be 560 ± 95 cases 10–4 Gy–1 Extrapolation from animal data makes it possible to estimate the risk for human liver cancer from protracted exposures to beta/gamma emitters as 15 to 40 liver cancers per 104 people per gray The uncertainty associated with these risk estimates is high because of the need to extrapolate between different types of radionuclides, different species and from very high to low levels of exposure In all these extrapolations, we have used a linear no-threshold model Even with these uncertainties, this Report concludes that the liver is not a radio-resistant organ Thorotrast® (van Heyden Company, Dresden-Radebeul, Germany) is a radiographic contrast medium comprised of a 25 percent colloidal solution of yellow dextrin and thorium dioxide It has a mean particle diameter of 9.3 ± 4.3 microns (Riedel et al., 1983) containing 228Th/232Th in a ratio of 0.4 in freshly obtained thorium preparations from natural thorium (van Kaick et al., 1984a) Thorium-228 and its daughter products are responsible for the majority of the radiation dose from Thorotrast® Affinity of Radionuclides for Liver Tissue 2.1 Characteristics of Liver Tissue The liver is an organ involved in many complex inter-relationships in the body It functions in a large number of endocrine, exocrine and regulatory capacities It is a major tissue in the mononuclear-macrophage system (Roser, 1979; Stuart, 1970) It is a site of many metabolic and detoxification functions and a depot for iron and a number of trace metals (Burch et al., 1978) In addition, it is the major production site for plasma proteins involved in the transport of numerous hormones (Madden and Zeldis, 1958), lipids, metals, etc (Boocock et al., 1970; Bruenger et al., 1971; Jacobs and Worwood, 1978; Stover et al., 1972) Transferrin, a protein of liver origin, is the primary iron transport protein and plays an important role in the hepatic localization of many actinide elements that are of special concern in this Report (Boocock et al., 1970; Bruenger et al., 1971; Jacobs and Worwood, 1978) 2.2 Affinity of Radionuclides in Ionic or Compound Forms in Various Tissues The deposition and retention of radioactive materials in the liver is dependent on both their physical and chemical form Based on metabolic studies in animals, a number of radionuclides (238/239Pu, 241Am, 252Cf, 144Ce, 210Po, 91Y, 90Y), including some of their decay products, are likely to have an affinity for human hepatic tissue (Brooks et al., 1982; Bruenger et al., 1972; 1976; Durbin, 1972; 1975; Durbin et al., 1985; Lloyd et al., 1972; 1984; Moskalev et al., 1980; Muggenburg et al., 1984; Stover et al., 1971; 1972; Taylor et al., 1993) Many studies have supported the affinity of the liver for many radionuclides Well established human data demonstrate that plutonium and americium, which move from the site of entry by way / AFFINITY OF RADIONUCLIDES FOR LIVER TISSUE of the vascular system, are retained in the liver in relatively high concentrations and for prolonged periods of time (Breitenstein et al., 1985; Foreman et al., 1959; Lagerquist et al., 1969; Magno et al., 1967; McInroy, 1976; McInroy et al., 1985; Palmer et al., 1985) For example, distribution data derived at the time of death for five workers who inhaled a mixture of 239Pu and 241Am provided the following data (McInroy et al., 1989) It was determined that for 239Pu the liver retained 35.4 ± 13 percent and the skeleton 53.7 ± 12 percent of the systemic body burden From these data, the investigators determined that the systemic distribution of the material was consistent with the 30:50 division between liver and skeleton proposed in International Commission on Radiological Protection (ICRP) Publication 30 (ICRP, 1979) and Publication 48 (ICRP, 1986) In three terminally ill patients given small amounts of plutonium intravenously, the average organ distribution to 15 months following injection was 31.2 percent in liver and 47.5 percent in skeleton The smaller mass of the liver relative to the skeleton results in a significantly higher concentration and dose to liver In occupationally exposed workers, McInroy (1976) observed that the distribution of plutonium between liver and skeleton was 30 ± 23 percent and 68 ± 24 percent, respectively To estimate dose in nonoccupationally exposed humans, he noted that the concentration in the liver (0.021 Bq kg–1) was higher than that detected in the vertebrae (0.0081 Bq kg–1) (McInroy, 1976) These data are consistent with that of Fisenne et al (1980) who found 0.013 Bq kg–1 in the liver and 0.0093 Bq kg–1 in the skeleton Two healthy humans were injected with tracer levels of 239Pu and the levels of activity in the liver and skeleton estimated (Talbot et al., 1993) From these studies it was determined that the liver retained about 55 to 68 percent of the injected activity This is higher than the 45 percent used in setting annual limits of intake for plutonium (ICRP, 1986) A person occupationally exposed to plutonium over a 12 y period, primarily by inhalation, had average concentrations of 165 Bq kg–1 (9.9 dis min–1 g–1) in liver and 23 Bq kg–1 (1.4 dis min–1 g–1) in skeleton (Foreman et al., 1959) Lagerquist et al (1969) observed a similar distribution with measured concentrations of 53 Bq kg–1 (0.32 dis min–1 g–1) in liver and 2.1 Bq kg–1 (0.13 dis min–1 g–1) in skeleton in a person who received two contaminated puncture wounds and several inhalation exposures during the y prior to death Magno et al (1967) found the vertebral concentration to be about 10 percent of that of the liver in nonoccupationally exposed persons whose plutonium was presumably received from fallout In German fallout studies, a ... Measurements Liver cancer risk from internally- deposited radionuclides : recommendations of the National Council on Radiation Protection and Measurements p ; cm (NCRP report ; no 135) “Issued... update of the cancer risk from radionuclides deposited in the liver The liver has been considered an organ with a low risk for cancer induction from ionizing radiation (ICRP, 1991; NCRP, 1993a)... human liver cancer data, and an update of the risk of liver cancer from internally- deposited radionuclides To determine risk, it is first essential to calculate the radiation dose to the liver